elastin and Growth-Disorders

Topics: Animals; Cattle; Chick Embryo; Collagen; Connective Tissue; Elastin; Glucocorticoids; Growth Disorders; Humans; In Vitro Techniques; Osteoporosis; Vitamin A

Copper, as a component of numerous cuproenzymes, plays a vital role in many physiologic functions in man and animals. From the stand-point of human health there are at least three functional areas of prime importance. Copper is involved in the development and maintenance of cardiovascular and skeletal integrity, central nervous system structure and function, and erythropoietic function including iron metabolism. Although there is no evidence for widespread copper deficiency in the human population, it does occur, owing to genetic defects and other precipitating factors. A clear understanding of the functions of copper and its mechanisms of action could prove highly beneficial in the solution of present and unforeseen problems in medicine.

Topics: Anemia; Animals; Bone Diseases; Brain Diseases; Cardiovascular Diseases; Central Nervous System Diseases; Collagen; Copper; Deficiency Diseases; Elastin; Enzymes; Female; Growth Disorders; Hair; Humans; Infant; Infant, Newborn; Metalloproteins; Pigmentation Disorders; Pregnancy; Pregnancy Complications; Protein-Lysine 6-Oxidase

Topics: Aging; Amino Acids; Aneurysm; Animals; Arteriosclerosis; Brain Diseases; Copper; Deficiency Diseases; Elastic Tissue; Elastin; Endocardial Fibroelastosis; Growth Disorders; Hair; Humans; Inflammation; Lathyrism; Marfan Syndrome; Metabolic Diseases; Respiratory Tract Diseases; Skin Diseases

Topics: Abnormalities, Multiple; DNA; DNA Mutational Analysis; Elastin; Growth Disorders; Humans; Intellectual Disability; Polymorphism, Single-Stranded Conformational; Syndrome

Williams syndrome (WS) is a neurodevelopmental disorder with a variable phenotype. Molecular genetic studies have indicated that hemizygosity at the elastin locus (ELN) may account for the cardiac abnormalities seen in WS, but that mental retardation and hypercalcemia are likely caused by other genes flanking ELN. In this study, we defined the minimal critical deletion region in 63 patients using 10 microsatellite markers and 5 fluorescence in situ hybridization (FISH) probes on chromosome 7q, flanking ELN. The haplotype analyses showed the deleted cases to have deletions of consistent size, as did the FISH analyses using genomic probes for the known ends of the commonly deleted region defined by the satellite markers. In all informative cases deleted at ELN, the deletion extends from D7S489U to D7S1870. The genetic distance between these two markers is about 2 cM. Of the 51 informative patients with deletions, 29 were maternal and 22 were paternal in origin. There was no evidence for effects on stature by examining gender, ethnicity, cardiac status, or parental origin of the deletion. Heteroduplex analysis for LIMK1, a candidate gene previously implicated in the WS phenotype, did not show any mutations in our WS patients not deleted for ELN. LIMK1 deletions were found in all elastin-deletion cases who had WS. One case, who has isolated, supravalvular aortic stenosis and an elastin deletion, was not deleted for LIMK1. It remains to be determined if haploinsufficiency of LIMK1 is responsible in part for the WS phenotype or is simply deleted due to its close proximity to the elastin locus.

Topics: Chromosomes, Human, Pair 7; DNA; DNA Mutational Analysis; Elastin; Female; Growth Disorders; Heart Defects, Congenital; Humans; In Situ Hybridization, Fluorescence; Male; Sequence Deletion; Williams Syndrome

Williams syndrome (WS) is generally characterized by mental deficiency, gregarious personality, dysmorphic facies, supravalvular aortic stenosis, and idiopathic infantile hypercalcemia. Patients with WS show allelic loss of elastin (ELN), exhibiting a submicroscopic deletion, at 7q11.23, detectable by FISH. Hemizygosity is likely the cause of vascular abnormalities in WS patients. A series of 235 patients was studied, and molecular cytogenetic deletions were seen in 96% of patients with classic WS. Patients included 195 solicited through the Williams Syndrome Association (WSA), plus 40 clinical cytogenetics cases referred by primary-care physicians. Photographs and medical records of most WSA subjects were reviewed, and patients were identified as "classic" (n = 114) or "uncertain" (n = 39). An additional 42 WSA patients were evaluated without clinical information. FISH was performed with biotinylated ELN cosmids on metaphase cells from immortalized lymphoblastoid lines from WSA patients and after high-resolution banding analysis on clinical referral patients. An alpha-satellite probe for chromosome 7 was included in hybridizations, as an internal control. Ninety-six percent of the patients with classic WS showed a deletion in one ELN allele; four of these did not show a deletion. Of the uncertain WS patients, only 3 of 39 showed a deletion. Of the 42 who were not classified phenotypically, because of lack of clinical information, 25 patients (60%) showed a deletion. Thirty-eight percent (15/40) of clinical cytogenetics cases showed an ELN deletion and no cytogenetic deletion by banded analysis. These results support the usefulness of FISH for the detection of elastin deletions as an initial diagnostic assay for WS.

Topics: Abnormalities, Multiple; Child, Preschool; Chromosomes, Human, Pair 7; DNA Probes; Elastin; Face; Female; Gene Deletion; Growth Disorders; Heart Defects, Congenital; Humans; In Situ Hybridization, Fluorescence; Infant; Male; Phenotype; Syndrome

To investigate the frequency of deletions of the elastin gene in patients with Williams syndrome (WS), we screened 44 patients by both FISH and PCR amplification of a dinucleotide repeat polymorphism. FISH was performed using cosmids containing either the 5' or the 3' end of the elastin gene. PCR analysis was performed on the patients and their parents with a (CA)n repeat polymorphism found in intron 17 of the elastin locus. Of the 44 patients screened, 91% were shown to be deleted by FISH. Using the DNA polymorphism, both maternally (39%) and paternally (61%) derived deletions were found. Four patients were not deleted for elastin but have clinical features of WS. Since deletions of elastin cannot account for several features found in WS, these patients will be valuable in further delineation of the critical region responsible for the WS phenotype. Although PCR can be useful for determining the parental origin of the deletion, our results demonstrate that FISH analysis of the elastin locus provides a more rapid and informative test to confirm a clinical diagnosis of WS. The presence of two copies of the elastin locus in a patient does not, however, rule out WS as a diagnosis.

Topics: Abnormalities, Multiple; Aortic Valve Stenosis; Chromosomes, Human, Pair 7; Elastin; Face; Female; Gene Deletion; Growth Disorders; Humans; In Situ Hybridization, Fluorescence; Intellectual Disability; Karyotyping; Male; Polymerase Chain Reaction

The human calcitonin receptor (CTR) is a transmembrane peptide with dual action as a receptor for the hormone calcitonin and as an extracellular calcium sensor. Therefore, CTR dysfunction could lead to disorders of calcium metabolism associated with hypercalcemia, such as the Williams syndrome (WS). WS is a developmental disorder caused by a deletion at chromosome 7q11.23 that includes the elastin locus (ELN). We have mapped the CTR gene (CALCR) to chromosome band 7q21.3 by polymerase chain reaction and single-strand conformation analysis of somatic cell hybrids as well as fluorescence in situ hybridization (FISH) to metaphase chromosome spreads. Two-color FISH cohybridizing CTR and ELN probes confirmed that CALCR maps telomeric to ELN. Subsequent analysis of chromosome spreads from four WS patients revealed deletion of the ELN locus in all of them and normal hybridization of CTR probes to both chromosome 7 homologues, indicating that CALCR lies outside the deleted region.

Topics: Animals; Base Sequence; Chromosome Deletion; Chromosome Mapping; Chromosomes, Human, Pair 7; Cricetinae; Cricetulus; DNA Primers; Elastin; Genomic Library; Growth Disorders; Humans; Hybrid Cells; In Situ Hybridization, Fluorescence; Molecular Sequence Data; Receptors, Calcitonin; Syndrome

Topics: Animals; Ascorbic Acid; Collagen; Colorimetry; Diet; Elastin; Erythrocyte Count; FIGLU Test; Folic Acid Deficiency; Growth Disorders; Hematocrit; Hemoglobins; Hydroxylation; Hydroxyproline; Leukocyte Count; Male; Proline; Protein Biosynthesis; Rats; Skin; Trichloroacetic Acid; Tritium