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New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations

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 m...

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Main Authors: Callewaert, Bert (Author) , Renard, Marjolijn (Author) , Hucthagowder, Vishwanathan (Author) , Albrecht, Beate (Author) , Haußer-Siller, Ingrid (Author) , Blair, Edward (Author) , Dias, Cristina (Author) , Albino, Alice (Author) , Wachi, Hiroshi (Author) , Sato, Fumiaki (Author) , Mecham, Robert P. (Author) , Loeys, Bart (Author) , Coucke, Paul J. (Author) , De Paepe, Anne (Author) , Urban, Zsolt (Author)
Format: Article (Journal)
Language:English
Published: 01 February 2011
In: Human mutation
Year: 2011, Volume: 32, Issue: 4, Pages: 445-455
ISSN:1098-1004
DOI:10.1002/humu.21462
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1002/humu.21462
Verlag, lizenzpflichtig, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.21462
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Author Notes:Bert Callewaert, Marjolijn Renard, Vishwanathan Hucthagowder, Beate Albrecht, Ingrid Hausser, Edward Blair, Cristina Dias, Alice Albino, Hiroshi Wachi, Fumiaki Sato, Robert P. Mecham, Bart Loeys, Paul J. Coucke, Anne De Paepe, and Zsolt Urban
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Summary: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-β) signaling. We conclude that ADCL is a systemic disease with cardiovascular and pulmonary complications, associated with increased TGF-β signaling and mutation-specific differences in endoplasmic reticulum stress and apoptosis.
Item Description:Gesehen am 27.06.2022
Physical Description:Online Resource
ISSN:1098-1004
DOI:10.1002/humu.21462

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