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

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Item Type:Article
Title:Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4) due to PTRF-CAVIN mutations
Creators Name:Rajab, A. and Straub, V. and McCann, L.J. and Seelow, D. and Varon, R. and Barresi, R. and Schulze, A. and Lucke, B. and Luetzkendorf, S. and Karbasiyan, M. and Bachmann, S. and Spuler, S. and Schuelke, M.
Abstract: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.
Keywords:Adipose Tissue, Cardiac Arrhythmias, Base Sequence, Caveolae, DNA Mutational Analysis, Fatal Outcome, Fibroblasts, Homozygote, Congenital Generalized Lipodystrophy, Long QT Syndrome, Molecular Sequence Data, Muscles, Mutation, Oman, Pedigree, Phenotype, RNA-Binding Proteins
Source:PLoS Genetics
Publisher:Public Library of Science
Page Range:e1000874
Date:12 March 2010
Official Publication:https://doi.org/10.1371/journal.pgen.1000874
PubMed:View item in PubMed

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