Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4) due to PTRF-CAVIN mutations

• Published in: PLoS genetics Vol. 6; no. 3; p. e1000874
• Main Authors: Rajab, Anna, Straub, Volker, McCann, Liza J, Seelow, Dominik, Varon, Raymonda, Barresi, Rita, Schulze, Anne, Lucke, Barbara, Lützkendorf, Susanne, Karbasiyan, Mohsen, Bachmann, Sebastian, Spuler, Simone, Schuelke, Markus
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.03.2010; Public Library of Science (PLoS)
• Subjects: Adipose Tissue - pathology; Adolescent; Arrhythmias, Cardiac - complications; Arrhythmias, Cardiac - genetics; Base Sequence; Biosynthesis; Cardiac arrhythmia; Cardiovascular Disorders/Arrhythmias, Electrophysiology, and Pacing; Caveolae - pathology; Caveolae - ultrastructure; Cell Biology/Cell Signaling; Cell Biology/Gene Expression; Child; Development and progression; DNA Mutational Analysis; Family; Fatal Outcome; Female; Fibroblasts - pathology; Fibroblasts - ultrastructure; Gene mutations; Genes; Genetic aspects; Genetics and Genomics/Gene Function; Genetics and Genomics/Genetics of Disease; Genetics and Genomics/Medical Genetics; Homozygote; Humans; Identification and classification; Infant, Newborn; Lipodystrophy; Lipodystrophy, Congenital Generalized - complications; Lipodystrophy, Congenital Generalized - genetics; Lipodystrophy, Congenital Generalized - pathology; Long QT syndrome; Long QT Syndrome - complications; Long QT Syndrome - genetics; Male; Microscopy; Molecular Sequence Data; Muscles - pathology; Mutation - genetics; Oman; Patients; Pedigree; Phenotype; Proteins; RNA-Binding Proteins - genetics; Oman; Germany
• DOI: 10.1371/journal.pgen.1000874
• ISSN: 1553-7404; 1553-7390

We investigated eight families with a novel subtype of congenital generalized lipodystrophy (CGL4) of whom five members had died from sudden cardiac death during their teenage years. ECG studies revealed features of long-QT syndrome, bradycardia, as well as supraventricular and ventricular tachycardias. Further symptoms comprised myopathy with muscle rippling, skeletal as well as smooth-muscle hypertrophy, leading to impaired gastrointestinal motility and hypertrophic pyloric stenosis in some children. Additionally, we found impaired bone formation with osteopenia, osteoporosis, and atlanto-axial instability. Homozygosity mapping located the gene within 2 Mbp on chromosome 17. Prioritization of 74 candidate genes with GeneDistiller for high expression in muscle and adipocytes suggested PTRF-CAVIN (Polymerase I and transcript release factor/Cavin) as the most probable candidate leading to the detection of homozygous mutations (c.160delG, c.362dupT). PTRF-CAVIN is essential for caveolae biogenesis. These cholesterol-rich plasmalemmal vesicles are involved in signal-transduction and vesicular trafficking and reside primarily on adipocytes, myocytes, and osteoblasts. Absence of PTRF-CAVIN did not influence abundance of its binding partner caveolin-1 and caveolin-3. In patient fibroblasts, however, caveolin-1 failed to localize toward the cell surface and electron microscopy revealed reduction of caveolae to less than 3%. Transfection of full-length PTRF-CAVIN reestablished the presence of caveolae. The loss of caveolae was confirmed by Atomic Force Microscopy (AFM) in combination with fluorescent imaging. PTRF-CAVIN deficiency thus presents the phenotypic spectrum caused by a quintessential lack of functional caveolae.