Title
New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations
Author
Faculty/Department
Faculty of Medicine and Health Sciences
Publication type
article
Publication
New York, N.Y. ,
Subject
Human medicine
Source (journal)
Human mutation. - New York, N.Y.
Volume/pages
32(2011) :4 , p. 445-455
ISSN
1059-7794
ISI
000288464100017
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
Autosomal dominant cutis laxa (ADCL) is characterized by a typical facial appearance and generalized loose skin folds, occasionally associated with aortic root dilatation and emphysema. We sequenced exons 28-34 of the ELN gene in five probands with ADCL features and found five de novo heterozygous mutations: c.2296_2299dupGCAG (CL-1), c.2333delC (CL-2), c.2137delG (CL-3), c.2262delA (monozygotic twin CL-4 and CL-5), and c.2124del25 (CL-6). Four probands (CL-1, -2, -3, -6) presented with progressive aortic root dilatation. CL-2 and CL-3 also had bicuspid aortic valves. CL-2 presented with severe emphysema. Electron microscopy revealed elastic fiber fragmentation and diminished dermal elastin deposition. RT-PCR studies showed stable mutant mRNA in all patients. Exon 32 skipping explains a milder phenotype in patients with exon 32 mutations. Mutant protein expression in fibroblast cultures impaired deposition of tropoelastin onto microfibril-containing fibers, and enhanced tropoelastin coacervation and globule formation leading to lower amounts of mature, insoluble elastin. Mutation-specific effects also included endoplasmic reticulum stress and increased apoptosis. Increased pSMAD2 staining in ADCL fibroblasts indicated enhanced transforming growth factor beta (TGF-beta) signaling. We conclude that ADCL is a systemic disease with cardiovascular and pulmonary complications, associated with increased TGF-beta signaling and mutation-specific differences in endoplasmic reticulum stress and apoptosis. Hum Mutat 32: 445-455, 2011. (C) 2011 Wiley-Liss, Inc.
E-info
https://repository.uantwerpen.be/docman/iruaauth/a141ba/0256360.pdf
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