Comprehensive Clinical and Molecular Analysis of 12 Families with Type 1 Recessive Cutis Laxa. Issue 1 (13th August 2012)

• Record Type: Journal Article
• Authors: Callewaert, Bert; Su, Chi‐Ting; Van Damme, Tim; Vlummens, Philip; Malfait, Fransiska; Vanakker, Olivier; Schulz, Bianca; Mac Neal, Meghan; Davis, Elaine C.; Lee, Joseph G.H.; Salhi, Aicha; Unger, Sheila; Heimdal, Ketil; De Almeida, Salome; Kornak, Uwe; Gaspar, Harald; Bresson, Jean‐Luc; Prescott, Katrina; Gosendi, Maria E.; Mansour, Sahar; Piérard, Gérald E.; Madan‐Khetarpal, Suneeta; Sciurba, Frank C.; Symoens, Sofie; Coucke, Paul J; Van Maldergem, Lionel; Urban, Zsolt; De Paepe, Anne
• Is Part Of: Human mutation. Volume 34:Issue 1(2013:Jan.)
• Page Start: 111
• Page End: 121
• Publication Date: 2012-08-13
• Subjects: Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.22165
• Languages: English
• ISSNs: 1059-7794

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>FBLN4</italic> or <italic>FBLN5</italic>. Recently, <italic>LTBP4</italic> mutations have been implicated in a similar phenotype. Studying <italic>FBLN4</italic>, <italic>FBLN5</italic>, and <italic>LTBP4</italic> in 12 families with ARCL type I, we found bi‐allelic <italic>FBLN5</italic> mutations in two probands, whereas nine probands harbored biallelic mutations in <italic>LTBP4</italic>. <italic>FBLN5</italic> and <italic>LTBP4</italic> 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 <italic>LTBP4</italic> mutations. Functional studies showed that most premature termination mutations in <italic>LTBP4</italic> 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<sup>*</sup>27) showed reduced colocalization with fibronectin, leading to an abnormal morphology of microfibrils in fibroblast cultures, while retaining normal TGFβ activity. We conclude that <italic>LTBP4</italic> mutations cause disease through both loss of function and gain of function mechanisms.</p> </abstract>