Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa.

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Serval ID
serval:BIB_29E186913C08
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa.
Journal
Human Mutation
Author(s)
Callewaert B., Su C.T., Van Damme T., Vlummens P., Malfait F., Vanakker O., Schulz B., Mac Neal M., Davis E.C., Lee J.G., Salhi A., Unger S., Heimdal K., De Almeida S., Kornak U., Gaspar H., Bresson J.L., Prescott K., Gosendi M.E., Mansour S., Piérard G.E., Madan-Khetarpal S., Sciurba F.C., Symoens S., Coucke P.J., Van Maldergem L., Urban Z., De Paepe A.
ISSN
1098-1004 (Electronic)
ISSN-L
1059-7794
Publication state
Published
Issued date
2013
Volume
34
Number
1
Pages
111-121
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov'tPublication Status: ppublish. PDF type: Research article
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.
Pubmed
Web of science
Create date
21/03/2013 16:48
Last modification date
20/08/2019 13:09
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