Comprehensive Clinical and Molecular Analysis of 12 Families with Type 1 Recessive Cutis Laxa


  • Communicated by Peter H. Byers

  • Contract grant sponsors: Methusalem grant from the Ghent University (BOF 08/01M01108 to A.D.P.); National Institutes of Health (RO1 HL090648 to Z.U., P50 HL 084948 to F.C.S., and UL1 RR024153 to the University of Pittsburgh Clinical and Translational Science Institute); Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin branch, Taiwan (to C.T.S.); Fund for Scientific Research—Flanders (postdoctoral fellowship to B.C. and F.M.); BOF research fellowship from the Ghent University (to O.V.)

Correspondence to: Bert Callewaert, Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. E-mail:


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.