elastin and Cutis-Laxa

Elastic fibers provide recoil to tissues that undergo repeated deformation, such as blood vessels, lungs and skin. Composed of elastin and its accessory proteins, the fibers are produced within a restricted developmental window and are stable for decades. Their eventual breakdown is associated with a loss of tissue resiliency and aging. Rare alteration of the elastin (ELN) gene produces disease by impacting protein dosage (supravalvar aortic stenosis, Williams Beuren syndrome and Williams Beuren region duplication syndrome) and protein function (autosomal dominant cutis laxa). This review highlights aspects of the elastin molecule and its assembly process that contribute to human disease and also discusses potential therapies aimed at treating diseases of elastin insufficiency.

Topics: Aortic Stenosis, Supravalvular; Cutis Laxa; Elastin; Gene Dosage; Genetic Predisposition to Disease; Humans; Mutation; Williams Syndrome

Autosomal dominant cutis laxa (ADCL, OMIM #123700) is a rare connective tissue disorder characterized by loose, redundant skin folds that may be apparent form birth or appear later in life. Most severely affected areas are the neck, axillar regions, trunk, and groin. Typically, patients present with characteristic facial features including a premature aged appearance, long philtrum, a high forehead, large ears, and a beaked nose. Cardiovascular and pulmonary complications include bicuspid aortic valves, aortic root dilatation, and emphysema. Sporadically, these complications have been documented to cause premature death. Several rare findings including urogenital anomalies and gastroesophageal problems can be also occur. Most patients harbor a frameshift mutation in one of the five last exons of the ELN gene (ADCL1, OMIM #123700), whereas one patient was described to have a tandem duplication in the FBLN5 gene (ADCL2, OMIM #614434). Here, we present a female ADCL patient, from a consanguineous family, with a novel mutation in ELN and review 39 previously reported ADCL patients. All patients have various skin findings, whereas cardiovascular, pulmonary findings, and multiple hernia were present in 61, 28, and 38% of patients, respectively. Strabismus, urogenital anomalies, gastroesophageal problems, and scoliosis may rarely be present. A clear definition of the ADCL syndrome can enable more accurate genetic counseling.

Topics: Child, Preschool; Cutis Laxa; Elastin; Exons; Female; Frameshift Mutation; Humans; Pedigree

Cutis laxa is an extremely rare disorder characterized by marked skin laxity. Few cases of cutis laxa have been described worldwide. Clinical presentation and mode of inheritance show considerable heterogeneity; autosomal dominant, autosomal recessive, and X-linked recessive forms have been reported. Only 3 mutations in the elastin gene have been described as the genetic cause of the autosomal dominant form of cutis laxa.. A 45-year-old woman and her 19-year-old son presented with inelastic, loose-hanging, and wrinkled skin that appeared prematurely aged and were clinically diagnosed as having cutis laxa. Mutational analysis of the elastin gene evidenced a novel mutation (2292delC) that predicts a frameshift in the coding region and causes translation to proceed into the 3'-untranslated region. This would replace the C-terminal amino acid of the normal elastin protein with a novel sequence.. This article is the fourth report of autosomal dominant cutis laxa to appear in the literature in which a mutation in the elastin gene has been correlated with the disease.

Topics: Adult; Base Sequence; Cutis Laxa; Elastin; Female; Follow-Up Studies; Frameshift Mutation; Genes, Dominant; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Molecular Sequence Data; Reverse Transcriptase Polymerase Chain Reaction

Over the last decade, a considerable amount of new information has emerged describing the protein components of elastic fibers. It is now evident that elastic fibers are complex extracellular matrix polymers, composed of at least 19 different proteins that comprise both the microfibrillar and the amorphous components of elastic fibers. Mutations in three of the genes encoding the most abundant of these elastic fiber proteins result in a broad spectrum of elastic tissue phenotypes, ranging from skeletal and skin abnormalities to vascular and ocular defects. The following disorders will be discussed in this review: supravalvular aortic stenosis; Williams-Beuren syndrome; cutis laxa; Marfan syndrome; ectopia lentis; familial thoracic aortic aneurysms and dissections; MASS syndrome; isolated skeletal features of Marfan syndrome; Shprintzen-Goldberg syndrome; and congenital contractural arachnodactyly.

Topics: Aortic Stenosis, Supravalvular; Connective Tissue Diseases; Cutis Laxa; Elastic Tissue; Elastin; Extracellular Matrix Proteins; Fibrillins; Humans; Marfan Syndrome; Microfilament Proteins; Mutation; Phenotype

Three clinical conditions displaying phenotypic overlap have been linked to mutation or deletion of the elastin gene at 7q11.23. Supravalvar aortic stenosis, an autosomal dominant disorder characterized by elastin arteriopathy, is caused by mutation or intragenic deletions of ELN resulting in loss of function. Autosomal dominant cutis laxa, a primarily cutaneous condition, is the result of frameshift mutations at ELN that cause a dominant-negative effect on elastic fiber structure. Williams syndrome, a neurodevelopmental disorder is due to a 1.5 Mb deletion that includes ELN and at least 15 contiguous genes. The disorder is characterized by dysmorphic facies, mental retardation or learning difficulties, elastin arteriopathy, a unique cognitive profile of relative strength in auditory rote memory and language and extreme weakness in visuospatial constructive cognition, and a typical personality that includes overfriendliness, anxiety, and attention problems. The understanding of these disorders has progressed from phenotypic description to identification of causative mutations and insight into pathogenetic mechanisms for some aspects of the phenotype.

Topics: Aortic Stenosis, Supravalvular; Cognition Disorders; Cutis Laxa; Elastin; Humans; Language Development Disorders; Memory; Personality; Phenotype; Sequence Deletion; Williams Syndrome

Elastin, the protein responsible for the elastic properties of vertebrate tissues, has been thought to be solely restricted to that role. As a consequence, elastin was conventionally described as an amorphous polymer. Recent results in the biomedical, biochemical and biophysical fields have lead to the conclusion that the presence of elastin in the extracellular space has very complex implications involving many other molecules. The present review describes the current state of knowledge concerning elastin as an elastic macromolecule. First, the genetic, biological, biochemical and biophysical processes leading to a functional polymer are described. Second, the elastic function of elastin is discussed. The controversy on elastin structure and elasticity is discussed and a novel dynamic mechanism of elasticity proposed. Finally, pathologies where the elastin molecule is involved are considered. This updated description of functional elastin provides the required background for the understanding of its pathologies and defines clearly the properties a substance should possess to be qualified as a good elastic biomaterial.

Topics: Animals; Aortic Valve Stenosis; Cutis Laxa; Elastic Tissue; Elastin; Humans; Skin Diseases; Structure-Activity Relationship; Williams Syndrome

Cutis laxa acquisita is a rare disorder that affects collagen and elastin metabolism. The cause is unknown. Characteristic features include sagging and laxity of the skin, as well as involvement of the lungs, heart, gastrointestinal system, and urogenital tract. Three cases of cutis laxa acquisita have been reported in association with multiple myeloma. Due to the rarity of these disorders, a linkage has been postulated. The clinical and histologic data from the fourth case of cutis laxa acquisita associated with multiple myeloma were compared to the three other cases previously reported in the literature. The relationship between acquired cutis laxa and multiple myeloma is unclear, with only one case revealing possible immune-mediated elastin destruction via IgG immunoglobulin bound to dermal elastin fibers on immunofluoresence examination. No pattern in the clinical courses of the disorder can be seen on review of the four cases with coincident disease. We hypothesize that cutis laxa acquisita represents a paraneoplastic process of multiple myeloma, given the rarity of these diseases. Further investigation is necessary to determine the underlying linkage between these disorders. We suggest that serum and urine protein electrophoresis results be obtained in patients presenting with cutis laxa acquisita to screen for multiple myeloma given this association.

Topics: Antineoplastic Agents; Biomarkers; Cutis Laxa; Elastin; Humans; Male; Middle Aged; Multiple Myeloma

Elastin is rapidly deposited during late gestation in resilient tissues such as the arteries, lungs and skin owing to increased concentration of its mRNA. Pathological states can arise from congenital insufficiency or disorganization of elastin (cutis laxa). Other elastin deficiencies may be due to excess elastolysis or gene dosage effects. In the former, high turnover rates can be assessed by measurements of elastin degradation products in urine. Excess elastin accumulation by skin fibroblasts is characteristic of genetic diseases such as Buschke-Ollendorff syndrome, Hutchinson-Gilford progeria and keloid. Elastin expression is modulated by peptide growth factors, steroid hormones and phorbol esters, among which transforming growth factor beta (TGF-beta) is an especially potent up-regulator, acting largely through stabilization of mRNA. Recent evidence indicates cutis laxa fibroblasts that express little or no elastin have normal transcriptional activity but abnormal rates of elastin mRNA degradation. This defect is substantially reversed by TGF-beta through mRNA stabilization. Current studies explore the hypothesis that stability determinants lie within the 3' untranslated region of elastin mRNA. Post-transcriptional control of elastin expression appears to be a major regulatory mechanism.

Topics: Animals; Cutis Laxa; Elastin; Fibrosis; Humans; Keloid; Progeria

The recent progress made in understanding the normal biology and biochemistry of the extracellular matrix of human skin has allowed us to identify several different levels at which errors could be introduced into the structure and metabolism of collagen or elastin, the two major fibrillar components of the dermis. Currently, several heritable cutaneous diseases are known to display distinct collagen or elastin abnormalities. This article reviews some of the heritable cutaneous diseases and highlights those entities in which definite information on molecular alterations in collagen or elastin is available.

Topics: Adult; Collagen; Collagen Diseases; Cutis Laxa; Ehlers-Danlos Syndrome; Elastin; Fibroma; Humans; Male; Osteopoikilosis; Osteosclerosis; Pedigree; Skin Diseases; Skin Neoplasms

The elastic properties of many tissues such as the lung, dermis, and large blood vessels are due to the presence of elastic fibers in the extracellular space. These fibers have been shown by biochemical and ultrastructural analysis to be comprised of two distinct components, a more abundant amorphous component and the microfibrillar component. The microfibrillar component is found in 10- to 12-nm fibrils which are located primarily around the periphery of the amorphous component but, to some extent, interspersed within it. The protein, elastin, makes up the highly insoluble amorphous component and is responsible for the elastic properties. Elastin is found throughout the vertebrate kingdom except for very primitive fish and possesses an unusual chemical composition consonant with its characteristic physical properties. Elastin is composed largely of glycine, proline, and other hydrophobic residues and contains multiple lysine-derived cross-links, such as the desmosines, which link the individual polypeptide chains into a rubber-like network. The intervening, hydrophobic regions of the polypeptide chains between the cross-links are highly mobile, and the elastic properties of the fibers can be described in terms of the theory of rubber elasticity. Recent application of recombinant DNA techniques has led to further understanding of the structure of elastin. Analyses of the bovine and human elastin genes have demonstrated that the hydrophobic and cross-linking domains are encoded in separate exons. These exons tend to be small, varying from 27 to 114 base pairs, and are separated by large intervening sequences. Furthermore, DNA sequence analysis has demonstrated that the elastin molecule contains two cysteine residues which were not previously identified near the carboxy terminus and which may be important in the interaction of elastin with other extracellular matrix proteins. Further DNA sequencing should determine the complete amino acid sequence of elastin. Biosynthetic studies and in vitro translation of elastin mRNA have demonstrated that a 72,000-dalton polypeptide, designated tropoelastin, is the initial translation product. Analysis of several developing systems has demonstrated that elastin synthesis is controlled by the level of elastin mRNA. After packaging into membrane-bound vesicles in the Golgi apparatus, tropoelastin is secreted by exocytosis into the extracellular space where it is cross-linked by a copper-requiring extracellular enzyme, lys

Topics: Amino Acid Sequence; Amino Acids; Animals; Aorta; Base Sequence; Biological Evolution; Bone Diseases; Chemical Phenomena; Chemistry; Cutis Laxa; DNA; Elastin; Genes; Genetic Diseases, Inborn; Humans; Lung Diseases, Obstructive; Macromolecular Substances; Marfan Syndrome; Microscopy, Electron; Protein-Lysine 6-Oxidase; Pseudoxanthoma Elasticum; RNA, Messenger; Species Specificity; Syndrome; Tropoelastin; Vascular Diseases

Topics: Animals; Cells, Cultured; Ceruloplasmin; Collagen; Copper; Cutis Laxa; Ehlers-Danlos Syndrome; Elastin; Hepatolenticular Degeneration; Humans; Liver; Menkes Kinky Hair Syndrome; Mice; Protein-Lysine 6-Oxidase

Topics: Collagen; Connective Tissue Diseases; Cutis Laxa; Ehlers-Danlos Syndrome; Elastin; Fibronectins; Humans; Marfan Syndrome; Metabolism, Inborn Errors; Osteogenesis Imperfecta; Prenatal Diagnosis; Proteoglycans; Skin

The elastic fibers present in various connective tissues of the body are responsible for physiologic elasticity of the organs. These fibers consist of 2 distinct components, elastin and the elastic fiber microfibrils. Controlled synthesis and balanced interaction of these 2 components are essential for normal fibrillogenesis. The intracellular biosynthesis of elastin by connective tissue cells, such as smooth muscle cells, involves assembly of the polypeptide chains on the membrane-bound ribosomes, hydroxylation of some prolyl residues to hydroxyproline, and secretion of the polypeptides packaged in Golgi vacuoles. In the extracellular space the elastin molecules assemble into fiber structures which are stabilized by the synthesis of complex covalent cross-links, desmosines. Recently, aberrations in the structure or metabolism of elastin have been detected in a variety of heritable and acquired diseases affecting skin and other connective tissues. These conditions include pseudoxanthoma elasticum, cutis laxa, and elastosis perforans serpiginosa, as well as arteriosclerosis and other degenerative changes of the vascular connective tissues.

Topics: Amino Acids; Arteriosclerosis; Chemical Phenomena; Chemistry; Collagen Diseases; Connective Tissue; Contractile Proteins; Cutis Laxa; Desmosine; Ehlers-Danlos Syndrome; Elastic Tissue; Elastin; Female; Glycoproteins; Humans; Hydroxyproline; Marfan Syndrome; Menkes Kinky Hair Syndrome; Muscle Proteins; Pancreatic Elastase; Peptide Biosynthesis; Protein Precursors; Pseudoxanthoma Elasticum; X Chromosome

Topics: Biopsy; Collagen; Cutis Laxa; Elastin; Endoplasmic Reticulum; Female; Fibroblasts; Genes, Dominant; Genes, Recessive; Humans; Infant; Microscopy, Electron; Pancreatic Elastase; Pedigree; Rare Diseases; Skin; Vacuoles

Cutis laxa (CL) is a rare, inherited or acquired connective tissue disorder characterized by abnormal elastic fibers causing loose and redundant skin and a prematurely aged appearance. The syndrome has been associated with hypertension, but cases with early-onset ischemic heart disease have never been described. Here, we report a 21-year-old Danish female with activity-related shortness of breath and oedema of the lower extremities. The patient had a clinical diagnosis of autosomal dominant CL, but no genotyping had been performed prior to the index admission. The patient was diagnosed with ischemic heart disease, based on results of non-invasive cardiovascular imaging (including MRI and PET-CT) followed by invasive treatment of a critical left main coronary artery stenosis. Subsequent referral to genetic testing revealed a likely pathogenic intronic variant in ELN. This case report includes the clinical findings and relates these to known molecular mechanisms of CL.

Topics: Coronary Stenosis; Cutis Laxa; Elastin; Female; Humans; Introns; Mutation; Pedigree; Young Adult

Elastic fibers are extracellular macromolecules that provide resilience and elastic recoil to elastic tissues and organs in vertebrates. They are composed of an elastin core surrounded by a mantle of fibrillin-rich microfibrils and are essentially produced during a relatively short period around birth in mammals. Thus, elastic fibers have to resist many physical, chemical, and enzymatic constraints occurring throughout their lives, and their high stability can be attributed to the elastin protein. Various pathologies, called elastinopathies, are linked to an elastin deficiency, such as non-syndromic supravalvular aortic stenosis (SVAS), Williams-Beuren syndrome (WBS), and autosomal dominant cutis laxa (ADCL). To understand these diseases, as well as the aging process related to elastic fiber degradation, and to test potential therapeutic molecules in order to compensate for elastin impairments, different animal models have been proposed. Considering the many advantages of using zebrafish, we here characterize a zebrafish mutant for the

Topics: Animals; Aortic Stenosis, Supravalvular; Cutis Laxa; Elastin; Heart Valves; Williams Syndrome; Zebrafish

Cutis laxa (CL) comprises a heterogeneous group of entities mainly classified as X-linked, autosomal dominant and recessive forms, which differ in severity. We encountered a CL baby with no familial history. We performed targeted exome sequencing, and detected a de novo heterozygous frameshift mutation in the elastin gene of the baby.

Topics: Cutis Laxa; Elastin; Exome; Frameshift Mutation; Humans; Infant; Mutation

EMILIN1 (elastin-microfibril-interface-located-protein-1) is a structural component of the elastic fiber network and localizes to the interface between the fibrillin microfibril scaffold and the elastin core. How EMILIN1 contributes to connective tissue integrity is not fully understood. Here, we report bi-allelic EMILIN1 loss-of-function variants causative for an entity combining cutis laxa, arterial tortuosity, aneurysm formation, and bone fragility, resembling autosomal-recessive cutis laxa type 1B, due to EFEMP2 (FBLN4) deficiency. In both humans and mice, absence of EMILIN1 impairs EFEMP2 extracellular matrix deposition and LOX activity resulting in impaired elastogenesis, reduced collagen crosslinking, and aberrant growth factor signaling. Collagen fiber ultrastructure and histopathology in EMILIN1- or EFEMP2-deficient skin and aorta corroborate these findings and murine Emilin1

Topics: Animals; Bone Diseases, Metabolic; Collagen; Cutis Laxa; Elastin; Extracellular Matrix Proteins; Humans; Mice

To carry out genetic diagnosis for a pedigree affected with cutis laxa.. Genomic DNA was extracted from peripheral blood samples from members of the pedigree and 50 unrelated healthy controls. Potential mutation was screened by next-generation sequencing and verified by Sanger sequencing.. A heterozygous c.1985delG mutation was identified in the ELN gene among all patients from this pedigree. The same mutation was not found among unaffected family members and 50 healthy controls.. The genetic etiology for the pedigree has been elucidated, which has enabled genetic counseling and guidance for reproduction.

Topics: Cutis Laxa; Elastin; Heterozygote; High-Throughput Nucleotide Sequencing; Humans; Mutation; Pedigree

Cutis laxa (CL) is a rare connective tissue disorder characterized by loose, redundant, inelastic and wrinkled skin. Patients develop a prematurely aged appearance. Inheritance can be autosomal dominant or autosomal recessive. The X-linked form is now classified in the group of copper transport diseases. Autosomal dominant CL is characterized by wrinkled, redundant and sagging, inelastic skin and in some cases is associated with internal organ involvement.. We report a familial case of autosomal dominant CL, which includes a 33-year-old woman and her 11-year-old son with dry, thin and wrinkled skin that appeared prematurely aged. No serious involvement of internal organs was found. In both patients, we identified novel heterozygous mutation c.2323delG (p.Ala775fs) in exon 34 of elastin transcript NM_001278939.1. Similar frameshift mutations in the last exons of elastin gene were previously reported in patients with autosomal dominant CL.. Our results show a novel frameshift mutation that was found in patients with cutis laxa. Exome sequencing is effective and useful technology for properly diagnosis of diseases with similar phenotype to ensure proper treatment is provided.

Topics: Adult; Child; Cutis Laxa; DNA Mutational Analysis; Elastin; Exome Sequencing; Exons; Female; Frameshift Mutation; Heterozygote; Humans; Kazakhstan; Male

Topics: Animals; Cutis Laxa; Deer; Elastin; Histology; Male; Microscopy; Skin

Cutis laxa-like features were observed in a subset of patients with scleromyxedema. Given this observation, clinical and histopathologic features of scleromyxedema were reviewed in correlation with elastic tissue staining.. We retrospectively reviewed clinical records and histopathologic features from patients with scleromyxedema seen at our institution from 1992 through 2013. We also evaluated available skin biopsies with an elastin stain and assessed whether dermal elastin fibers were diminished in density or were fragmented (or both).. Nineteen patients with scleromyxedema and 34 skin biopsies were identified. Alcian blue (mucin) stain was used to grade mucin deposition as weakly positive (24%), positive (44%) and markedly positive (32%). Eight patients (42%) had clinical findings of cutis laxa, which were often observed in conjunction with areas of papular eruption or induration. Elastic tissue fibers were normal in 9 of 34 skin specimens (26%), 18 of 34 specimens (53%) had diminished elastic fiber density and 7 of 34 (21%) had markedly decreased density. The elastic tissue was fragmented in 25 specimens (74%).. A cutis laxa-like clinical presentation and decreased elastic tissue density on skin biopsy were consistent findings. Dermatologists and dermatopathologists should be aware of these previously unreported clinical and histopathologic findings.

Topics: Biopsy; Cutis Laxa; Dermis; Elastin; Female; Humans; Male; Middle Aged; Retrospective Studies; Scleromyxedema

Topics: Adolescent; Cutis Laxa; Elastin; Extracellular Matrix Proteins; Humans; Male

Recent studies have revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C), which is a severe disorder caused by defects of the elastic fiber network. Although the human gene involved in ARCL1C has been discovered based on similar elastic fiber abnormalities exhibited by mice lacking the short Ltbp-4 isoform (Ltbp4S(-/-)), the murine phenotype does not replicate ARCL1C. We therefore inactivated both Ltbp-4 isoforms in the mouse germline to model ARCL1C. Comparative analysis of Ltbp4S(-/-) and Ltbp4-null (Ltbp4(-/-)) mice identified Ltbp-4L as an important factor for elastogenesis and postnatal survival, and showed that it has distinct tissue expression patterns and specific molecular functions. We identified fibulin-4 as a previously unknown interaction partner of both Ltbp-4 isoforms and demonstrated that at least Ltbp-4L expression is essential for incorporation of fibulin-4 into the extracellular matrix (ECM). Overall, our results contribute to the current understanding of elastogenesis and provide an animal model of ARCL1C.

Topics: Animals; Animals, Newborn; Aorta; Cardiomegaly; Cutis Laxa; Elastic Tissue; Elastin; Extracellular Matrix; Extracellular Matrix Proteins; Female; Gene Silencing; Genes, Recessive; Glycosylation; Heart Ventricles; Humans; Latent TGF-beta Binding Proteins; Lung; Mice, Inbred C57BL; Models, Biological; Protein Binding; Protein Isoforms; Skin; Weight Loss

Topics: Child, Preschool; Cutis Laxa; DNA Mutational Analysis; Elastin; Genes, Dominant; Humans; Introns; Male

Topics: Adult; Area Under Curve; Biomechanical Phenomena; Case-Control Studies; Cohort Studies; Cutis Laxa; Elasticity; Elastin; Female; Humans; Latent TGF-beta Binding Proteins; Male; Mutation; Proton-Translocating ATPases; ROC Curve; Sensitivity and Specificity; Skin; Viscosity

Elastin gene mutations have been associated with a variety of phenotypes. Autosomal dominant cutis laxa (ADCL) is a rare disorder that presents with lax skin, typical facial characteristics, inguinal hernias, aortic root dilatation and pulmonary emphysema. In most patients, frameshift mutations are found in the 3' region of the elastin gene (exons 30-34) which result in a C-terminally extended protein, though exceptions have been reported.. We clinically and molecularly characterized the thus far largest cohort of ADCL patients, consisting of 19 patients from six families and one sporadic patient.. Molecular analysis showed C-terminal frameshift mutations in exon 30, 32, and 34 of the elastin gene and identified a mutational hotspot in exon 32 (c.2262delA). This cohort confirms the previously reported clinical constellation of skin laxity (100%), inguinal hernias (51%), aortic root dilatation (55%) and emphysema (37%).. ADCL is a clinically and molecularly homogeneous disorder, but intra- and interfamilial variability in the severity of organ involvement needs to be taken into account. Regular cardiovascular and pulmonary evaluations are imperative in the clinical follow-up of these patients.

Topics: Cutis Laxa; Elastin; Exons; Female; Frameshift Mutation; Genes, Dominant; Hernia, Inguinal; Humans; Male; Pulmonary Emphysema; Severity of Illness Index; Skin

Elastic fibres are critical connective tissue components providing elasticity and resilience to skin and other tissues. These fibres are composed of elastin and a number of elastin-associated microfibrillar proteins that assemble in a complex fibre network in a multi-step process. Multiple cellular processes, including mitochondrial function, specific molecules in the secretory pathways and temporally and spatially ordered production of elastic fibre components, are required for the biogenesis of functional elastic fibres. Abnormalities in these processes can lead to loss of functional elastic fibres manifesting phenotypically as a skin disease. The paradigm of elastic fibre diseases affecting the skin is cutis laxa, a clinically and genetically heterogeneous group of disorders characterized by loose and sagging skin, frequently associated with extracutaneous manifestations in the lungs and the arterial blood vessels. The complexity of cutis laxa is emphasized by the fact that as many as 10 distinct genes can harbour mutations in this and related disorders. Understanding of the pathomechanistic pathways involved in perturbed elastic fibre assembly in cutis laxa provides information potentially helpful for the development of molecular strategies towards treatment of these, currently intractable, diseases.

Topics: Arteries; Chromosomes, Human, X; Cutis Laxa; Elastic Tissue; Elastin; Genes, Recessive; Humans; Lung Diseases; Microfibrils; Mitochondria; Mutation; Phenotype; Skin

Topics: Abnormalities, Multiple; Beckwith-Wiedemann Syndrome; Child, Preschool; Chromosome Duplication; Chromosomes, Human, Pair 11; Cleft Lip; Cleft Palate; Costello Syndrome; Cutis Laxa; Elastin; Female; Humans; Hydrocephalus; Karyotype; Proto-Oncogene Proteins p21(ras)

Elastin is the extracellular matrix protein in vertebrates that provides elastic recoil to blood vessels, the lung, and skin. Because the elastin gene has undergone significant changes in the primate lineage, modeling elastin diseases in non-human animals can be problematic. To investigate the pathophysiology underlying a class of elastin gene mutations leading to autosomal dominant cutis laxa, we engineered a cutis laxa mutation (single base deletion) into the human elastin gene contained in a bacterial artificial chromosome. When expressed as a transgene in mice, mutant elastin was incorporated into elastic fibers in the skin and lung with adverse effects on tissue function. In contrast, only low levels of mutant protein incorporated into aortic elastin, which explains why the vasculature is relatively unaffected in this disease. RNA stability studies found that alternative exon splicing acts as a modifier of disease severity by influencing the spectrum of mutant transcripts that survive nonsense-mediated decay. Our results confirm the critical role of the C-terminal region of tropoelastin in elastic fiber assembly and suggest tissue-specific differences in the elastin assembly pathway.

Topics: Alternative Splicing; Animals; Aorta; Chromosomes, Artificial, Bacterial; Cross-Linking Reagents; Cutis Laxa; Elasticity; Elastin; Exons; Fibroblasts; Frameshift Mutation; Genes, Dominant; Humans; Mice; Mice, Transgenic; Mutation; Protein Structure, Tertiary; RNA; Transgenes

Topics: Adult; Biopsy; Chronic Disease; Cutis Laxa; Elastin; Extracellular Matrix Proteins; Humans; Male; Mutation; Skin; Urticaria; Young Adult

Autosomal dominant cutis laxa (ADCL) is characterized by a typical facial appearance and generalized loose skin folds, occasionally associated with aortic root dilatation and emphysema. We sequenced exons 28-34 of the ELN gene in five probands with ADCL features and found five de novo heterozygous mutations: c.2296_2299dupGCAG (CL-1), c.2333delC (CL-2), c.2137delG (CL-3), c.2262delA (monozygotic twin CL-4 and CL-5), and c.2124del25 (CL-6). Four probands (CL-1,-2,-3,-6) presented with progressive aortic root dilatation. CL-2 and CL-3 also had bicuspid aortic valves. CL-2 presented with severe emphysema. Electron microscopy revealed elastic fiber fragmentation and diminished dermal elastin deposition. RT-PCR studies showed stable mutant mRNA in all patients. Exon 32 skipping explains a milder phenotype in patients with exon 32 mutations. Mutant protein expression in fibroblast cultures impaired deposition of tropoelastin onto microfibril-containing fibers, and enhanced tropoelastin coacervation and globule formation leading to lower amounts of mature, insoluble elastin. Mutation-specific effects also included endoplasmic reticulum stress and increased apoptosis. Increased pSMAD2 staining in ADCL fibroblasts indicated enhanced transforming growth factor beta (TGF-β) signaling. We conclude that ADCL is a systemic disease with cardiovascular and pulmonary complications, associated with increased TGF-β signaling and mutation-specific differences in endoplasmic reticulum stress and apoptosis.

Topics: Adolescent; Child; Child, Preschool; Chromosome Disorders; Cutis Laxa; Elastic Tissue; Elastin; Female; Humans; Male; Mutation; Transforming Growth Factor beta; Tropoelastin

Heterozygous elastin gene mutations cause autosomal dominant cutis laxa associated with emphysema and aortic aneurysms. To investigate the molecular mechanisms leading to cutis laxa in vivo, we generated transgenic mice by pronuclear injection of minigenes encoding normal human tropoelastin (WT) or tropoelastin with a cutis laxa mutation (CL). Three independent founder lines of CL mice showed emphysematous pulmonary airspace enlargement. No consistent dermatological or cardiovascular pathologies were observed. One CL and one WT line were selected for detailed studies. Both mutant and control transgenic animals showed elastin deposition into pulmonary elastic fibers, indicated by increased desmosine levels in the lung and by colocalization of transgenic and endogenous elastin by immunostaining. CL mice showed increased static lung compliance and decreased stiffness of lung tissue. In addition, markers of transforming growth factor-β (TGFβ) signaling and the unfolded protein response (UPR) were elevated together with increased apoptosis in the lungs of CL animals. We conclude that the synthesis of mutant elastin in CL activates multiple downstream disease pathways by triggering a UPR, altered mechanical signaling, increased release of TGFβ and apoptosis. We propose that the combined effects of these processes lead to the development of an emphysematous pulmonary phenotype in CL.

Topics: Animals; Apoptosis; Cutis Laxa; Desmosine; Disease Models, Animal; Elastic Modulus; Elastin; Eukaryotic Initiation Factor-2; Frameshift Mutation; Gene Expression; Genes, Reporter; Genetic Vectors; Green Fluorescent Proteins; Humans; Lung; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phosphorylation; Pulmonary Emphysema; Respiratory Mechanics; Smad2 Protein; Transforming Growth Factor beta; Tropoelastin; Unfolded Protein Response

Cutis laxa (CL) is a heterogeneous group of connective tissue disorders characterized by loose, sagging skin and variable involvement of other organs. Autosomal-dominant forms are relatively mild, and may be caused by mutations in the elastin gene, whereas the more severe recessive forms have been associated with mutations in the fibulin 4 and fibulin 5 genes, as well as in a vesicular ATPase subunit. We describe here a previously unreported autosomal-recessive form of CL caused by homozygous recessive mutations in exon 12 of the elastin gene (p.P211S) in three patients from two related consanguineous Syrian families. Furthermore, we found that the presence of a polymorphism in the fibulin 5 gene in one of the patients seems to modify the phenotype, producing more severe symptoms. This polymorphism (p.L301M) was associated with mild symptoms in the mother of the patient, who was heterozygous for both the elastin and fibulin 5 mutations. To our knowledge, autosomal-recessive CL owing to homozygous mutations in the elastin gene has not been reported previously.

Topics: Child; Child, Preschool; Cutis Laxa; Elastin; Exons; Extracellular Matrix Proteins; Family Health; Female; Genes, Recessive; Glycosylation; Heterozygote; Homozygote; Humans; Infant; Male; Phenotype; Polymorphism, Genetic; Severity of Illness Index; Sialoglycoproteins; Syria; Transferrin

Autosomal dominant congenital cutis laxa (ADCL) is genetically heterogeneous and shows clinical variability. Only seven ADCL families with mutations in the elastin gene (ELN) have been described previously. We present morphological and molecular genetic studies in a cutis laxa kindred with a previously undescribed highly variable phenotype caused by a novel ELN mutation c.1621 C > T. The proband presented with severe cutis laxa, severe congenital lung disease previously undescribed in ADCL and pulmonary artery disease, which is often seen in ARCL but rare in ADCL. He also developed infantile spasms (OMIM 308350; West syndrome), which we consider a coincidental association although recessive cutis laxa or even digenic inheritance cannot be excluded. Electron microscopy of the proband's dermis revealed only mild rarefication of elastic fibers (in contrast to most recessive cutis laxa types). Apart from mild elastic fiber fragmentation, dermal morphology of the proband's father was within normal range. Molecular analysis of the ELN gene using genomic DNA from blood and RNA from cultured skin fibroblasts indicated a novel splice site mutation in the proband and his clinically healthy father. Analysis of ELN expression in fibroblasts provided evidence for a dominant-negative effect in the child, while due to an unknown mechanism, the father showed haploinsufficiency which might explain the significant clinical variability.

Topics: Adult; Cells, Cultured; Cutis Laxa; Dermis; Elastin; Fibroblasts; Genes, Dominant; Genetic Predisposition to Disease; Humans; Infant; Male; Microscopy, Electron; Mutation; RNA Splicing

A 49-year-old man presented with a 20-year history of an asymptomatic reticular eruption on his upper trunk. On examination, there were well-demarcated orange-red patches with reticular margins and irregular central atrophy on the lateral chest and proximal upper limbs. Skin biopsies showed histological evidence of elastophagocytosis with scant lymphocytic inflammation. Elastin stains demonstrated focal loss of elastic fibers in the reticular dermis, consistent with mid-dermal elastolysis. Mid-dermal elastolysis is a rare disorder characterized by focal loss of elastic tissue in the mid-dermis. The etiology remains obscure. Reticular presentations of mid-dermal elastolysis have rarely been described and extend the clinical spectrum of dermal elastolytic disorders.

Topics: Biopsy; Cutis Laxa; Dermis; Diagnosis, Differential; Elastic Tissue; Elastin; Humans; Male; Middle Aged; Phagocytosis; Reticulin

Diseases linked to the elastin gene arise from loss-of-function mutations leading to protein insufficiency (supravalvular aortic stenosis) or from missense mutations that alter the properties of the elastin protein (dominant cutis laxa). Modeling these diseases in mice is problematic because of structural differences between the human and mouse genes. To address this problem, we developed a humanized elastin mouse with elastin production being controlled by the human elastin gene in a bacterial artificial chromosome. The temporal and spatial expression pattern of the human transgene mirrors the endogenous murine gene, and the human gene accurately recapitulates the alternative-splicing pattern found in humans. Human elastin protein interacts with mouse elastin to form functional elastic fibers and when expressed in the elastin haploinsufficient background reverses the hypertension and cardiovascular changes associated with that phenotype. Elastin from the human transgene also rescues the perinatal lethality associated with the null phenotype. The results of this study confirm that reestablishing normal elastin levels is a logical objective for treating diseases of elastin insufficiency such as supravalvular aortic stenosis. This study also illustrates how differences in gene structure and alternative splicing present unique problems for modeling human diseases in mice.

Topics: Alternative Splicing; Animals; Aorta; Aortic Stenosis, Subvalvular; Chromosomes, Artificial, Bacterial; Cutis Laxa; Disease Models, Animal; DNA; Elastin; Female; Gene Expression Regulation; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phenotype

Cutis laxa is an acquired or inherited condition characterized by redundant, pendulous and inelastic skin. Autosomal dominant cutis laxa has been described as a benign disease with minor systemic involvement.. To report a family with autosomal dominant cutis laxa and a young girl with sporadic cutis laxa, both with variable expression of an aortic aneurysmal phenotype ranging from mild dilatation to severe aneurysm or aortic rupture.. Histological evaluation of aortic aneurysmal specimens indicated classical hallmarks of medial degeneration, paucity of elastic fibres, and an absence of inflammatory or atherosclerotic lesions. Electron microscopy showed extracellular elastin deposits lacking microfibrillar elements. Direct sequencing of genomic amplimers detected defects in exon 30 of the elastin gene in affected individuals, but did not in 121 normal controls. The expression of mutant elastin mRNA forms was demonstrated by reverse transcriptase polymerase chain reaction analysis of cutis laxa fibroblasts. These mRNAs coded for multiple mutant tropoelastins, including C-terminally truncated and extended forms as well as for molecules lacking the constitutive exon 30.. ELN mutations may cause severe aortic disease in patients with cutis laxa. Thus regular cardiac monitoring is necessary in this disease to avert fatal aortic rupture.

Topics: Adult; Aortic Aneurysm; Child, Preschool; Cutis Laxa; Elastin; Female; Humans; Male; Mutation

Cutis laxa (CL) is a condition characterized by redundant, pendulous, and inelastic skin. Acquired CL has been reported in patients with inflammatory diseases. The goal of this study was to investigate whether genetic lesions predispose patients to the development of acquired CL. We report a patient who developed CL following a Toxocara canis parasitism. He later had an aortic root aneurysm that required surgical correction. Histological evaluation showed inflammation followed by destruction of elastic fibers in both the skin and the aorta. Mutational analysis showed that the patient was heterozygous for an inherited fibulin-5 (FBLN5) allele G202R and compound heterozygous for elastin (ELN) alleles A55V and G773D. Western blotting indicated abnormal proteolytic processing of tropoelastin (TE) in patient fibroblasts. The FBLN5 202R allele on the other hand led to increased interaction of FBLN5 and TE and increased deposition of insoluble ELN partially rescuing the deficiency conferred by ELN mutation G773D. We demonstrated that the interaction of ELN and FBLN5 alleles results in elastic fibers susceptible to inflammatory destruction. These results suggest that the pathogenesis of acquired CL involves an underlying genetic susceptibility and highlight the importance of molecular genetic analysis in patients with idiopathic connective tissue disorders.

Topics: Adult; Alleles; Amino Acid Sequence; Animals; Aorta; Base Sequence; Cells, Cultured; Child; Cutis Laxa; Dermatitis; Elastic Tissue; Elastin; Extracellular Matrix Proteins; Genetic Predisposition to Disease; Humans; Male; Molecular Sequence Data; Mutation, Missense; Recombinant Proteins; Toxocara canis; Toxocariasis

Topics: Abnormalities, Multiple; Calcium-Binding Proteins; Child; Child, Preschool; Cleft Palate; Contractile Proteins; Cutis Laxa; Elastin; Extracellular Matrix Proteins; Face; Family Health; Fatal Outcome; Female; Genetic Linkage; Haplotypes; Humans; Infant; Infant, Newborn; Intellectual Disability; Male; Microsatellite Repeats; Pedigree; Protein-Lysine 6-Oxidase; Skin; Syndrome

Inherited cutis laxa is a connective tissue disorder characterized by loose skin and variable internal organ involvement, resulting from paucity of elastic fibers. Elsewhere, frameshift mutations in the elastin gene have been reported in three families with autosomal dominant inheritance, and a family with autosomal recessive cutis laxa was recently reported to have a homozygous missense mutation in the fibulin-5 gene. In the present study, we analyzed the gene expression of elastin and fibulins 1-5 in fibroblasts from five patients with cutis laxa. One patient was found to express both normal (2.2 kb) and mutant (2.7 kb) fibulin-5 mRNA transcripts. The larger transcript contains an internal duplication of 483 nucleotides, which resulted in the synthesis and secretion of a mutant fibulin-5 protein with four additional tandem calcium-binding epidermal growth factor-like motifs. The mutation arose from a 22-kb tandem gene duplication, encompassing the sequence from intron 4 to exon 9. No fibulin-5 or elastin mutations were detected in the other patients. The results demonstrate that a heterozygous mutation in fibulin-5 can cause cutis laxa and also suggest that fibulin-5 and elastin gene mutations are not the exclusive cause of the disease.

Topics: Amino Acid Sequence; Base Sequence; Calcium-Binding Proteins; Cutis Laxa; DNA Primers; Elastin; Exons; Extracellular Matrix Proteins; Female; Gene Duplication; Genes, Recessive; Humans; Male; Molecular Sequence Data; Recombinant Proteins; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; Sequence Alignment; Sequence Homology, Amino Acid; Transcription, Genetic

Cutis laxa (CL) is a rare disorder in which the skin hangs in loose fields, so that affected individuals appear to be prematurely aged. The changes are more evident when effect the face with a prematurely-aged appearance. The acute form follows an inflammatory skin lesions. Its aetiology is not well known. We report a case of a head acute CL of a 17 years patient, secondary to a generalized skin eruption. The prematurely-aged appearance concern especially forehead, ear lobes and nasolabial folds. A two stages surgical treatment has associated: a forehead lifting associated to a Coleman lipofilling and an ear lobe reduction, a secondary Coleman lipofilling of the nasolabial folds. The skin biopsy confirm the diagnosis. The correction is stable and satisfactory after one year. The confrontation of our findings to those previously described confirm complexity of diagnosis and histological observations of this rare disorder.

Topics: Adolescent; Cutis Laxa; Elastin; Humans; Male; Plastic Surgery Procedures; Skin; Urticaria

The elastic fibre system has a principal role in the structure and function of various types of organs that require elasticity, such as large arteries, lung and skin. Although elastic fibres are known to be composed of microfibril proteins (for example, fibrillins and latent transforming growth factor (TGF)-beta-binding proteins) and polymerized elastin, the mechanism of their assembly and development is not well understood. Here we report that fibulin-5 (also known as DANCE), a recently discovered integrin ligand, is an essential determinant of elastic fibre organization. fibulin-5-/- mice generated by gene targeting exhibit a severely disorganized elastic fibre system throughout the body. fibulin-5-/- mice survive to adulthood, but have a tortuous aorta with loss of compliance, severe emphysema, and loose skin (cutis laxa). These tissues contain fragmented elastin without an increase of elastase activity, indicating defective development of elastic fibres. Fibulin-5 interacts directly with elastic fibres in vitro, and serves as a ligand for cell surface integrins alphavbeta3, alphavbeta5 and alpha9beta1 through its amino-terminal domain. Thus, fibulin-5 may provide anchorage of elastic fibres to cells, thereby acting to stabilize and organize elastic fibres in the skin, lung and vasculature.

Topics: Animals; Aorta; Cells, Cultured; CHO Cells; Cricetinae; Cutis Laxa; Elastic Tissue; Elastin; Emphysema; Extracellular Matrix Proteins; Humans; Integrins; Lung; Mice; Mice, Inbred C57BL; Recombinant Proteins

Topics: Connective Tissue Diseases; Cutis Laxa; Dermis; Elastic Tissue; Elastin; Humans; Multidrug Resistance-Associated Proteins; Mutation; Pseudoxanthoma Elasticum; Williams Syndrome

Congenital cutis laxa, a rare syndrome with marked skin laxity and pulmonary and cardiovascular compromise, is due to defective elastic fiber formation. In several cases, skin fibroblast tropoelastin production is markedly reduced yet reversed in vitro by transforming growth factor-beta treatment. We previously showed that this reversal was due to elastin mRNA stabilization in one cell strain, and here this behavior was confirmed in skin fibroblasts from two generations of a second family. cDNA sequencing and heteroduplex analysis of elastin gene transcripts from three fibroblast strains in two kindreds now identify two frameshift mutations (2012DeltaG and 2039DeltaC) in elastin gene exon 30, thus leading to missense C termini. No other mutations were present in the ELN cDNA sequences of all three affected individuals. Transcripts from both alleles in each kindred were unstable and responsive to transforming growth factor-beta. Exons 22, 23, 26A, and 32 were always absent. Since exon 30 underwent alternative splicing in fibroblasts, we speculate that a differential splicing pattern could conceivably lead to phenotypic rescue. These two dominant-acting, apparently de novo mutations in the elastin gene appear to be responsible for qualitative and quantitative defects in elastin, resulting in the cutis laxa phenotype.

Topics: Alleles; Base Sequence; Cutis Laxa; DNA Primers; Elastin; Exons; Frameshift Mutation; Humans; Infant, Newborn; Male; Molecular Sequence Data; RNA Splicing; RNA, Messenger

Elastin is the protein responsible for the characteristic elastic properties of many tissues including the skin, lungs and large blood vessels. Loss-of-function mutations in the elastin gene are known to cause the heart defect supravalvular aortic stenosis (SVAS). We and others have identified deletions, nonsense mutations and splice site mutations in SVAS patients that abolish the function of one elastin gene. We have now identified an elastin mutation in a patient with a completely different phenotype, the rare autosomal dominant condition cutis laxa. A frameshift mutation in exon 32 of the elastin gene is predicted to replace 37 amino acids at the C-terminus of elastin by a novel sequence of 62 amino acids. mRNA and immunoprecipitation studies show that the mutant allele is expressed. Electron microscopy of skin sections shows abnormal branching and fragmentation in the amorphous elastin component, and immunocytochemistry shows reduced elastin deposition in the elastic fibres and fewer microfibrils in the dermis. These findings suggest that the mutant tropoelastin protein is synthesized, secreted and incorporated into the elastic matrix, where it alters the architecture of elastic fibres. Interference with cross-linking would reduce elastic recoil in affected tissues and explain the cutis laxa phenotype.

Topics: Adult; Amino Acid Sequence; Base Sequence; Cutis Laxa; DNA; DNA Mutational Analysis; Elastic Tissue; Elasticity; Elastin; Female; Frameshift Mutation; Gene Expression; Genes, Dominant; Humans; Molecular Sequence Data; Protein Conformation; Skin; Tropoelastin

Two sisters with inherited generalized cutis laxa and a young man with possible acquired cutis laxa are presented.

Topics: Adolescent; Adult; Aging, Premature; Consanguinity; Cutis Laxa; Elastin; Female; Fibroblasts; Humans; Male; Pedigree

A 31-year-old man had cutis laxa after an urticarial eruption. He had no systemic manifestations. In urticarial lesions, elastolysis occurred only within the inflammatory infiltrate of neutrophils around the vessels and between the collagen bundles. In lax skin, elastolysis occurred throughout the entire dermis. Electron microscopic study showed a markedly decreased number of elastic fibers, with elastolysis most predominant near the inflammatory cells. These findings suggest that the neutrophil plays a significant role in the destruction of elastic fibers and subsequent development of cutis laxa.

Topics: Adult; Biopsy; Chronic Disease; Cutis Laxa; Elastic Tissue; Elastin; Epidermis; Fibroblasts; Humans; Male; Microscopy, Electron; Neck; Skin; Thorax; Urticaria

Skin fibroblasts from two cases of autosomal recessive cutis laxa (CL), having insignificant elastin production and mRNA levels, were challenged with transforming growth factor beta-1 (TGF-beta 1). Elastin production was brought from undetectable values to amounts typical of normal human skin fibroblasts in a dose-dependent fashion. Basic fibroblast growth factor (100 ng/ml) alone or in combination with TGF-beta 1 reduced elastin production and mRNA expression in CL skin fibroblasts more extensively than in normal cells. In situ hybridization showed that these effects were at the transcript level. One of the CL strains was examined in detail. Transcription rates for elastin were similar in normal and CL and unchanged by TGF-beta 1 or TGF-beta 2 (10 ng/ml), while in CL elastin mRNA half-life was increased > 10-fold by TGF-beta 2 and reduced 6-fold after TGF-beta 2 withdrawal, as compared with a control strain. Cycloheximide partially reversed elastin mRNA instability. These data are consistent with a defect in elastin mRNA stability that requires synthesis of labile factors or intact translational machinery, resulting in an extremely low steady state level of mRNA present in this strain of CL. Furthermore, TGF-beta can relieve elastin mRNA instability in at least one CL strain and elastin production defects in both CL strains.

Topics: Cells, Cultured; Child; Child, Preschool; Cutis Laxa; Elastin; Fibroblasts; Gene Expression Regulation; Half-Life; Humans; In Situ Hybridization; RNA, Messenger; Transcription, Genetic; Transforming Growth Factor beta; Tropoelastin

A case of cutis laxa acquisita was studied with the aim of defining the molecular defects involved and comparing them with those of an inherited form of cutis laxa. In the acquisita form of cutis laxa ultrastructural and biochemical observations confirmed a dramatic reduction of dermal elastin, whereas collagen content was normal. Elastin mRNA expression as well as tropoelastin production by dermal fibroblasts, in vitro, were normal compared with control cells, as revealed by in situ hybridization and enzyme-linked immunosorbent assay, respectively. Lysyl oxidase activity, measured on cultured fibroblasts, was reduced to 60% compared with age-matched control subjects. Unlike control skin fibroblasts or fibroblasts from inherited cutis laxa, the affected skin cells from cutis laxa acquisita predominantly expressed an elastolytic activity identified as cathepsin G. Patient serum also has reduced elastase inhibitory capacity and reduced levels of alpha 1-antiproteinase inhibitor (alpha 1-antitrypsin). Although cutis laxa acquisita is a heterogeneous group of disorders, findings in this patient were consistent with excessive loss of cutaneous elastin due to the combined effects of several factors, such as low lysyl oxidase activity together with high levels of cathepsin G and reduction of circulating proteinase inhibitor(s).

Topics: Adult; Biopsy; Cells, Cultured; Child, Preschool; Chromatography, High Pressure Liquid; Cutis Laxa; Elastin; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Humans; Male; Pancreatic Elastase; Skin; Tropoelastin

Degeneration of elastic tissue in acquired cutis laxa has been previously described, but microfibrils have not been adequately studied.. We determined whether the microfibrillar component of elastic tissue is affected in skin of a patient with acquired cutis laxa.. Lesional skin was examined with indirect immunofluorescence and immunoelectron microscopy with antibodies to fibrillin.. Indirect immunofluorescence showed a reduction in the distribution of fibrillin in the papillary dermis, where there was loss of the usual pattern of microfibrils perpendicular to the epidermis. Immunoelectron microscopy showed a typical distribution of elastic microfibrils around elastin of normal skin. In skin affected by cutis laxa microfibrils appeared morphologically normal but appeared less frequently in selected sites.. The microfibrillar component of elastic fibers was reduced in the papillary dermis of this patient with acquired cutis laxa.

Topics: Actin Cytoskeleton; Adult; Cutis Laxa; Elastic Tissue; Elastin; Epidermis; Facial Dermatoses; Female; Fibrillins; Fluorescent Antibody Technique; Humans; Microfilament Proteins; Microscopy, Immunoelectron

Abnormalities in the amount of skin elastin occur in several cutaneous disorders. The number of elastic fibers is increased in elastotic disorders such as pseudoxanthoma elasticum (PXE) and cutis rhomboidalis nuchae (actinic elastosis, AE) and is decreased in elastolytic disorders such as cutis laxa (CL). We describe a procedure to quantify desmosines and elastin in small amounts of skin using high-performance liquid chromatography (HPLC). Biopsies were obtained from normal, nonsolar exposed skin and from the lesional skin of patients with PXE, cutis rhomboidalis nuchae, and CL. Specimens were subjected to hot alkali treatment and the desmosines were released by acid hydrolysis and quantified by HPLC. The mean value for normal skin was 252 +/- 28 ng desmosines per milligram wet weight (SD, n = 5). The disorders of elastosis (PXE and AE) demonstrated a two- to fivefold increased content of desmosines. In contrast, the elastolytic disorder (CL) had only 20% of the normal content of desmosines. Furthermore, PXE and normal skin elastins had the same amount of desmosines per milligram purified elastin. This method could be used to evaluate the extent of elastosis or elastolysis in a particular lesion.

Topics: Adult; Aged; Amino Acids; Chromatography, High Pressure Liquid; Cutis Laxa; Desmosine; Elastin; Humans; Isodesmosine; Middle Aged; Pseudoxanthoma Elasticum; Skin; Skin Diseases

Several lines of evidence suggest that elastic fibers provide resilience to normal human skin, and that abnormalities in elastin may be the primary event leading to the clinical appearance of aged skin. Innately aged skin exhibits a paucity and fragmentation of elastic fibers, while actinically damaged skin consists of an abnormal accumulation of elastotic material within the dermis. Cutis laxa and elastoderma are two cutaneous diseases that manifest as selective alterations in elastic fibers. Clinical and histopathologic findings in these diseases are similar to those found in cutaneous aging. Thus, it appears that alterations in the quantity and/or quality of the elastic fibers may contribute to age-associated cutaneous changes.

Topics: Adolescent; Aging; Cutis Laxa; Elastic Tissue; Elastin; Humans; Male; Skin; Sunlight

Cutis laxa is a genetically heterogeneous connective tissue disease that occurs in both inherited and acquired forms. The most apparent defect is loose, redundant, nonresilient skin, but systemic connective tissue abnormalities exist, especially in conjunction with the early onset or autosomal recessive variety. The elastic fiber shows morphologic alterations. We studied dermal skin biopsies and cultured skin fibroblasts from 6 patients with congenital forms of cutis laxa in an effort to correlate alterations in elastin morphology and metabolism. In general, ultrastructural analysis revealed occasional variance in collagen fiber diameter, whereas elastic tissue varied in content, appearance, and the proportion and manner by which elastin and microfibrillar component associated. Fibroblast cell lines comprised of normal donors from a similar age group produced an average of 35 +/- 10 X 10(3) tropoelastin molecular equivalents per cell per hour, as measured by an ELISA. Three of six cutis laxa cell strains were markedly (5-20-fold) reduced in tropoelastin production. Two of these cell strains had specifically reduced levels of tropoelastin production relative to total protein synthesis. Analysis of elastin specific messenger RNA levels indicated this reduced expression of tropoelastin was regulated at a pretranslational level. In other strains, diminished production of elastin did not appear to be the primary defect, underscoring the heterogeneous nature of cutis laxa at both the biochemical and ultrastructural levels.

Topics: Blotting, Northern; Child, Preschool; Cutis Laxa; Elastin; Fibroblasts; Humans; Infant; Infant, Newborn; RNA, Messenger; Skin; Tropoelastin

Topics: Cations, Divalent; Cells, Cultured; Cutis Laxa; Elastin; Fibroblasts; Humans; Keratosis; Oligopeptides; Pancreatic Elastase; Pseudoxanthoma Elasticum; Skin

Fibroblast cultures were established from six patients with cutis laxa, and elastin gene expression was analyzed by RNA hybridizations with a 2.5-kilobase human elastin cDNA or an exon 1-specific 35-base oligomer. Northern analyses using either probe detected mRNA transcripts of approximately 3.5 kilobases, and no qualitative difference between the control and cutis laxa mRNAs was detected. However, quantitation of the elastin mRNA abundance by slot blot hybridizations revealed markedly reduced levels in all cutis laxa cell strains. Assuming equal translational activity of the control and cutis laxa mRNAs, the reduced mRNA levels could result in diminished elastin production, providing an explanation for the paucity of elastic fibers in the skin and other tissues in cutis laxa.

Topics: Base Sequence; Cells, Cultured; Cutis Laxa; DNA; Elastin; Exons; Fibroblasts; Genes; Humans; Nucleic Acid Hybridization; Reference Values; RNA, Messenger; Skin

Topics: Aging; Cutis Laxa; Elastic Tissue; Elastin; Humans; Pancreatic Elastase; Skin Diseases

Topics: Adult; Cutis Laxa; Elastic Tissue; Elastin; Female; Humans; Skin

Cutis laxa summarizes a heterogeneous group of diseases which are characterized by loose skin. An additional to the clinical variants of cutis laxa, a brief review of the elastin pathway is given and possible defects in cutis laxa are discussed.

Topics: Adult; Collagen; Connective Tissue; Cutis Laxa; Diagnosis, Differential; Elastic Tissue; Elastin; Female; Genes, Dominant; Genes, Recessive; Humans; Infant; Male; Sex Chromosome Aberrations; X Chromosome

Topics: Collagen; Cutis Laxa; Elastic Tissue; Elastin; Female; Genes, Dominant; Genes, Recessive; Humans; Infant; Microscopy, Electron; Skin

Previous morphologic observations have suggested abnormalities in the elastic fibers in a number of both inherited and acquired diseases. Recent progress made in understanding of the normal biology of elastin has allowed us to examine these diseases by biochemical means. In this review we are discussing the current status of the research on the elastin diseases with particular emphasis on clinical conditions affecting skin, as for example, cutis laxa, pseudoxanthoma elasticum, and the Buschke-Ollendorff syndrome. In addition, we present new data which appears to be the first demonstration of an elastin abnormality in the Marfan syndrome.

Topics: Connective Tissue Diseases; Cutis Laxa; Elastin; Humans; Marfan Syndrome; Menkes Kinky Hair Syndrome; Pseudoxanthoma Elasticum; Skin; Skin Diseases

We report a patient who has congenital cutis laxa and exocrine pancreatic insufficiency. Collagen analysis has provided evidence for defective elastin cross linking, possibly related to a mild copper deficiency. Connective tissue anomalies, in the presence of poor growth and/or symptoms of malabsorption should alert the physician to investigate pancreatic function. Adequate replacement of pancreatic enzymes will result in normal growth and development.

Topics: Adolescent; Collagen Diseases; Copper; Cutis Laxa; Elastin; Exocrine Pancreatic Insufficiency; Humans; Male

Topics: Animals; Arteriosclerosis; Collagen Diseases; Cutis Laxa; Elastin; Humans; Lathyrism; Models, Chemical; Rabbits; Rats; Structure-Activity Relationship

Specimens from one case each of acquired and congenital cutis laxa were examined by electron microscopy. Elastic flbers of the dermis and subcutaneous arteries and veins were found to have similar changes. Elastin was diminished and microfilaments were visible throughout the entire fiber. Electron-dense, amorphous or granular layers that alternate with relatively electron-light layers were deficient. This electron-dense substance was unevenly aggregated within or in the vicinity of elastic fiber. In the congenital case, the aggregation and deposition fo the electron-dense substance was often pronounced. In the vein, deficient deposition of elastin and admixture of microfilaments and amorphous substance were also found. Such admixture was often encircled by fibroblasts or smooth muscle cells. In the artery, multiplication of basal lamina was seen. Collagen fibers and anchoring fibrils of the skin were normal.

Topics: Arteries; Biopsy; Collagen; Cutis Laxa; Elastin; Female; Histocytochemistry; Humans; Infant; Male; Microscopy, Electron; Middle Aged; Skin; Wounds and Injuries

Topics: Adolescent; Adult; Child; Collagen; Cutis Laxa; Elasticity; Elastin; Female; Humans; Male; Skin; Skinfold Thickness