title: New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
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-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.
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Bert
authors.initials: B
authors.lastname: Callewaert
authors.forename: Marjolijn
authors.initials: M
authors.lastname: Renard
authors.forename: Vishwanathan
authors.initials: V
authors.lastname: Hucthagowder
authors.forename: Beate
authors.initials: B
authors.lastname: Albrecht
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hausser
authors.forename: Edward
authors.initials: E
authors.lastname: Blair
authors.forename: Cristina
authors.initials: C
authors.lastname: Dias
authors.forename: Alice
authors.initials: A
authors.lastname: Albino
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wachi
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Sato
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mecham
authors.forename: Bart
authors.initials: B
authors.lastname: Loeys
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coucke
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Urban
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D025063:Chromosome Disorders; D003483:Cutis Laxa / Q000235:genetics* / Q000473:pathology; D004547:Elastic Tissue / Q000378:metabolism / Q000473:pathology; D004549:Elastin / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014333:Tropoelastin / Q000235:genetics / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D014333:Tropoelastin; D004549:Elastin