elastin and Metabolism--Inborn-Errors

Pseudoxanthoma elasticum (PXE) is a relatively rare heritable disorder affecting the skin, eyes and cardiovascular system, with considerable morbidity and mortality. The disease affects the elastic fibers of affected organs, which become progressively calcified. Thus, PXE has been considered as a prototypic heritable connective tissue disorder affecting the elastic fiber system. Recently, PXE has been linked to mutations in the MRP6/ABCC6 gene, a member of the ABC transporter family, expressed primarily in the liver and the kidneys. This information, together with clinical observations suggesting environmental, hormonal and/or dietary modulation of the disease, raises the intriguing possibility that PXE is a primary metabolic disorder at the environment-genome interface.

Topics: Age of Onset; ATP-Binding Cassette Transporters; Biological Transport, Active; Cardiovascular System; Elastin; Environmental Exposure; Eye; Female; Genetic Predisposition to Disease; Humans; Kidney; Liver; Male; Metabolism, Inborn Errors; Multidrug Resistance-Associated Proteins; Phenotype; Pseudoxanthoma Elasticum; Sex Factors; Skin

Topics: 2-Aminoadipic Acid; Animals; Basement Membrane; Cells, Cultured; Chemical Phenomena; Chemistry; Collagen; Connective Tissue Diseases; Cross-Linking Reagents; Elastin; Histidine; Humans; Metabolism, Inborn Errors; Models, Molecular; Protein-Lysine 6-Oxidase; Pyridines; Rats

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

Topics: Amino Acid Sequence; Amino Acids; Aminopropionitrile; Animals; Chemical Phenomena; Chemistry; Collagen; Copper; Desmosine; Elastin; Humans; Hydroxylysine; Lysine; Metabolism, Inborn Errors; Nutrition Disorders; Nutritional Physiological Phenomena; Penicillamine; Protein-Lysine 6-Oxidase; Tropocollagen

Topics: Animals; Basement Membrane; Cattle; Collagen; Connective Tissue; Ehlers-Danlos Syndrome; Elastin; Epidermolysis Bullosa; Fibroblasts; Glycopeptides; Humans; Keloid; Lysine; Marfan Syndrome; Metabolism, Inborn Errors; Microbial Collagenase; Mixed Function Oxygenases; Progeria; Protein Biosynthesis; Pseudoxanthoma Elasticum; Wound Healing

Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the last step in proline synthesis. Deficiency of PYCR1, caused by a defect in PYCR1, was recently described in patients with cutis laxa, intrauterine growth retardation, developmental dysplasia of the hips and mental retardation. In this paper, we describe additional six patients (ages ranging from 4 months to 55 years) from four Iranian families with clinical manifestations of a wrinkly skin disorder. All patients have distinct facial features comprising triangular face, loss of adipose tissue and thin pointed nose. Additional features are short stature, wrinkling over dorsum of hand and feet, visible veins over the chest and hyperextensible joints. Three of the patients from a large consanguineous family do not have mental retardation, while the remaining three patients from three unrelated families have mental and developmental delay. Mutation analysis revealed the presence of disease-causing variants in PYCR1, including a novel deletion of the entire PYCR1 gene in one family, and in each of the other patients the homozygous missense mutations c.616G > A (p.Gly206Arg), c.89T > A (p.Ile30Lys) and c.572G > A (p.Gly191Glu) respectively, the latter two of which are novel. Light- and electron microscopy investigations of skin biopsies showed smaller and fragmented elastic fibres, abnormal morphology of the mitochondria and their cristae, and slightly abnormal collagen fibril diameters with irregular outline and variable size. In conclusion, this study adds information on the natural course of PYCR1 deficiency and sheds light on the pathophysiology of this disorder. However, the exact pathogenesis of this new disorder and the role of proline in the development of the clinical phenotype remain to be fully explained.

Topics: Abnormalities, Multiple; Adolescent; Adult; Child; Child, Preschool; Collagen; delta-1-Pyrroline-5-Carboxylate Reductase; DNA Mutational Analysis; Elastin; Family; Female; Humans; Infant; Male; Metabolism, Inborn Errors; Middle Aged; Models, Biological; Mutation, Missense; Phenotype; Proline; Pyrroles; Pyrroline Carboxylate Reductases; Young Adult

Topics: Acetaldehyde; Amino Acid Oxidoreductases; Aminopropionitrile; Animals; Carbon Isotopes; Collagen; Collagen Diseases; Cyanides; Elastin; Lathyrism; Lysine; Metabolism, Inborn Errors; Protein Binding; Protein Denaturation; Rats

Topics: Agar; Elastin; Fluoresceins; Humans; Immunodiffusion; Metabolism, Inborn Errors; Pancreatic Elastase; Trypsin Inhibitors

Topics: Adult; Elastin; Emphysema; Enzyme Repression; Humans; Leukocytes; Metabolism, Inborn Errors; Pancreatic Elastase; Peptide Hydrolases; Trypsin Inhibitors; Ventilation-Perfusion Ratio