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Title
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New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations
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Author
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Abstract
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| 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. |
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Language
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English
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Source (journal)
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Human mutation. - New York, N.Y.
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Publication
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New York, N.Y.
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2011
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ISSN
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1059-7794
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DOI
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10.1002/HUMU.21462
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Volume/pages
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32
:4
(2011)
, p. 445-455
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ISI
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000288464100017
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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