These two authors contributed equally to this work.
Comprehensive Clinical and Molecular Analysis of 12 Families with Type 1 Recessive Cutis Laxa
Article first published online: 13 AUG 2012
© 2012 Wiley Periodicals, Inc.
Volume 34, Issue 1, pages 111–121, January 2013
How to Cite
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.H., 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. and De Paepe, A. (2013), Comprehensive Clinical and Molecular Analysis of 12 Families with Type 1 Recessive Cutis Laxa. Hum. Mutat., 34: 111–121. doi: 10.1002/humu.22165
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.)
- Issue published online: 20 DEC 2012
- Article first published online: 13 AUG 2012
- Accepted manuscript online: 24 JUL 2012 09:11AM EST
- Manuscript Accepted: 6 JUL 2012
- Manuscript Received: 3 FEB 2012
- Ghent University. Grant Number: BOF 08/01M01108
- National Institutes of Health. Grant Numbers: RO1 HL090648, P50 HL 084948
- University of Pittsburgh Clinical and Translational Science Institute. Grant Number: UL1 RR024153
- Division of Nephrology
- Department of Internal Medicine
- National Taiwan University Hospital
- Urban–Rifkin–Davis syndrome;
- cutis laxa;
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.