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Human Molecular Genetics Advance Access published online on October 11, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl414
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received August 26, 2006
Revised October 9, 2006
Accepted October 9, 2006

Article

FIBULIN-5 MUTATIONS: MECHANISMS OF IMPAIRED ELASTIC FIBER FORMATION IN RECESSIVE CUTIS LAXA

Qirui Hu 1, Bart L. Loeys 2, Paul J. Coucke 2, Anne De Paepe 2, Robert P. Mecham 3, Jiwon Choi 4, Elaine C. Davis 4, and Zsolt Urban 5 *

1 Departments of Pediatrics
2 Departments of Center for Medical Genetics, Ghent University, Ghent, 9000, Belgium
3 Departments of Cell Biology and Physiology
4 Department of Anatomy and Cell Biology, McGill University, Montreal, H3A 2B2, Canada
5 Departments of Pediatrics and Genetics, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8208, St. Louis, MO 63110

* To whom correspondence should be addressed.
Zsolt Urban, E-mail: urban_z{at}kids.wustl.edu


  Abstract

To elucidate the molecular mechanisms of impaired elastic fiber formation in recessive cutis laxa, we have investigated two disease-causing missense substitutions in fibulin-5, C217R and S227P. Pulse-chase immunoprecipitation experiments indicated that S227P mutant fibulin-5 was synthesized and secreted by skin fibroblasts at a reduced rate compared to the wildtype protein. Both mutants failed to be incorporated into elastic fibers by transfected rat lung fibroblasts. Purified recombinant fibulin-5 with either mutation showed reduced affinity for tropoelastin in solid-phase binding assays. Furthermore, S227P mutant fibulin-5 also showed impaired association with fibrillin-1 microfibrils. The same mutation triggered an endoplasmic reticulum (ER) stress response as indicated by the strong colocalization of this mutant protein with folding chaperones in the ER, including calreticulin, immunoglobulin-binding protein (BiP), and protein disufide isomerase, and by increased rates of apoptosis in patient fibroblasts. Histological analysis of skin sections from a cutis laxa patient with a homozygous S227P mutation showed a lack of fibulin-5 in the extracellular matrix and a concomitant disorganization of dermal elastic fibers. By electron microscopy, elastic fibers in the skin of this patient showed a failure of elastin globules to fuse into a continuous elastic fiber core. We conclude that recessive cutis laxa mutations in fibulin-5 result in misfolding, decreased secretion, and a reduced interaction with elastin and fibrillin-1 leading to impaired elastic fiber development. These findings support the hypothesis that fibulin-5 is necessary for elastic fiber formation by facilitating the deposition of elastin onto a microfibrillar scaffold via direct molecular interactions.


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