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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., Straub, V., McCann, L.J., Seelow, D., Varon, R., Barresi, R., Schulze, A., Lucke, B., Luetzkendorf, S., Karbasiyan, M., Bachmann, S., 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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