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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 |
| ISSN: | 1553-7390 |
| Publisher: | Public Library of Science |
| Volume: | 6 |
| Number: | 3 |
| 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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