title: Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa.
abstract: Autosomal recessive cutis laxa type I (ARCL type I) is characterized by generalized cutis laxa with pulmonary emphysema and/or vascular complications. Rarely, mutations can be identified in FBLN4 or FBLN5. Recently, LTBP4 mutations have been implicated in a similar phenotype. Studying FBLN4, FBLN5, and LTBP4 in 12 families with ARCL type I, we found bi-allelic FBLN5 mutations in two probands, whereas nine probands harbored biallelic mutations in LTBP4. FBLN5 and LTBP4 mutations cause a very similar phenotype associated with severe pulmonary emphysema, in the absence of vascular tortuosity or aneurysms. Gastrointestinal and genitourinary tract involvement seems to be more severe in patients with LTBP4 mutations. Functional studies showed that most premature termination mutations in LTBP4 result in severely reduced mRNA and protein levels. This correlated with increased transforming growth factor-beta (TGFβ) activity. However, one mutation, c.4127dupC, escaped nonsense-mediated decay. The corresponding mutant protein (p.Arg1377Alafs(*) 27) showed reduced colocalization with fibronectin, leading to an abnormal morphology of microfibrils in fibroblast cultures, while retaining normal TGFβ activity. We conclude that LTBP4 mutations cause disease through both loss of function and gain of function mechanisms.
authors: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Bert
authors: B
authors: Callewaert
authors: Chi-Ting
authors: CT
authors: Su
authors: Tim
authors: T
authors: Van Damme
authors: Philip
authors: P
authors: Vlummens
authors: Fransiska
authors: F
authors: Malfait
authors: Olivier
authors: O
authors: Vanakker
authors: Bianca
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authors: Schulz
authors: Meghan
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authors: Mac Neal
authors: Elaine C
authors: EC
authors: Davis
authors: Joseph G H
authors: JG
authors: Lee
authors: Aicha
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authors: Salhi
authors: Sheila
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authors: Unger
authors: Ketil
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authors: Heimdal
authors: Salome
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authors: De Almeida
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authors: Kornak
authors: Harald
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authors: Gaspar
authors: Jean-Luc
authors: JL
authors: Bresson
authors: Katrina
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authors: Prescott
authors: Maria E
authors: ME
authors: Gosendi
authors: Sahar
authors: S
authors: Mansour
authors: Gérald E
authors: GE
authors: Piérard
authors: Suneeta
authors: S
authors: Madan-Khetarpal
authors: Frank C
authors: FC
authors: Sciurba
authors: Sofie
authors: S
authors: Symoens
authors: Paul J
authors: PJ
authors: Coucke
authors: Lionel
authors: L
authors: Van Maldergem
authors: Zsolt
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authors: Urban
authors: Anne
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authors: De Paepe
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D003483:Cutis Laxa / Q000150:complications / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005192:Family Health; D005260:Female; D015870:Gene Expression; D006801:Humans; D007223:Infant; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron; D009154:Mutation; D010375:Pedigree; D011656:Pulmonary Emphysema / Q000150:complications; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D055815:Young Adult
chemical_list: C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins; C492373:FBLN5 protein, human; C509040:LTBP4 protein, human; D053779:Latent TGF-beta Binding Proteins