title: Whole exome sequencing identifies de novo heterozygous CAV1 mutations associated with a novel neonatal onset lipodystrophy syndrome.
abstract: Despite remarkable progress in identifying causal genes for many types of genetic lipodystrophies in the last decade, the molecular basis of many extremely rare lipodystrophy patients with distinctive phenotypes remains unclear. We conducted whole exome sequencing of the parents and probands from six pedigrees with neonatal onset of generalized loss of subcutaneous fat with additional distinctive phenotypic features and report de novo heterozygous null mutations, c.424C>T (p.Q142*) and c.479_480delTT (p.F160*), in CAV1 in a 7-year-old male and a 3-year-old female of European origin, respectively. Both the patients had generalized fat loss, thin mottled skin and progeroid features at birth. The male patient had cataracts requiring extraction at age 30 months and the female patient had pulmonary arterial hypertension. Dermal fibroblasts of the female patient revealed negligible CAV1 immunofluorescence staining compared to control but there were no differences in the number and morphology of caveolae upon electron microscopy examination. Based upon the similarities in the clinical features of these two patients, previous reports of CAV1 mutations in patients with lipodystrophies and pulmonary hypertension, and similar features seen in CAV1 null mice, we conclude that these variants are the most likely cause of one subtype of neonatal onset generalized lipodystrophy syndrome.
authors.affiliation: Department of Internal Medicine and the Center for Human Nutrition, Division of Nutrition and Metabolic Diseases, UT Southwestern Medical Center, Dallas, Texas.
authors.forename: Abhimanyu
authors.initials: A
authors.lastname: Garg
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington.
authors.forename: Martin
authors.initials: M
authors.lastname: Kircher
authors.affiliation: Division of Clinical and Molecular Genetics, Hospital Vall d'Hebron, Universitat Pompeu Fabra, CIBERER, Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Del Campo
authors.affiliation: Department of Pediatrics, Division of Genetics and Metabolism, University of Kentucky, Lexington, Kentucky.
authors.forename: R Stephen
authors.initials: RS
authors.lastname: Amato
authors.affiliation: Department of Internal Medicine and the Center for Human Nutrition, Division of Nutrition and Metabolic Diseases, UT Southwestern Medical Center, Dallas, Texas.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Agarwal
mesh_terms: D051242:Caveolin 1 / Q000235:genetics*; D002478:Cells, Cultured; D059472:Exome / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D008060:Lipodystrophy / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1
keywords: cataract; caveolin 1; lipodystrophy; progeroid syndrome; pulmonary hypertension