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

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 tachycard...

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Published inPLoS 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
LanguageEnglish
Published United States Public Library of Science 01.03.2010
Public Library of Science (PLoS)
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Summary: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.
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Conceived and designed the experiments: VS RV RB SB SS MS. Performed the experiments: RB AS BL SL MK MS. Analyzed the data: VS DS RV RB AS BL SL SB SS MS. Contributed reagents/materials/analysis tools: AR LJM DS MS. Wrote the paper: VS MS. Recruited patients and performed the patient investigations: AR VS LJM MS. Performed the bioinformatic analysis: DS.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1000874