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J. Biol. Chem., Vol. 281, Issue 18, 12888-12895, May 5, 2006

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Murine Model of the Ehlers-Danlos Syndrome

col5a1 HAPLOINSUFFICIENCY DISRUPTS COLLAGEN FIBRIL ASSEMBLY AT MULTIPLE STAGES^*

Richard J. Wenstrup¹, Jane B. Florer, Jeffrey M. Davidson, Charlotte L. Phillips^¶, Brent J. Pfeiffer^¶, Diana W. Menezes^||, Inna Chervoneva^**, and David E. Birk^||

From the Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio 45229, Department of Laboratory Medicine, Vanderbilt University, Nashville, Tennessee 37232, ^¶Department of Biochemistry, University of Missouri-Columbia, Columbia, Missouri 65212, and the Departments of ^**Medicine and ^||Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

The most commonly identified mutations causing Ehlers-Danlos syndrome (EDS) classic type result in haploinsufficiency of pro1(V) chains of type V collagen, a quantitatively minor collagen that co-assembles with type I collagen as heterotypic fibrils. To determine the role(s) of type I/V collagen interactions in fibrillogenesis and elucidate the mechanism whereby half-reduction of type V collagen causes abnormal connective tissue biogenesis observed in EDS, we analyzed mice heterozygous for a targeted inactivating mutation in col5a1 that caused 50% reduction in col5a1 mRNA and collagen V. Comparable with EDS patients, they had decreased aortic stiffness and tensile strength and hyperextensible skin with decreased tensile strength of both normal and wounded skin. In dermis, 50% fewer fibrils were assembled with two subpopulations: relatively normal fibrils with periodic immunoreactivity for collagen V where type I/V interactions regulate nucleation of fibril assembly and abnormal fibrils, lacking collagen V, generated by unregulated sequestration of type I collagen. The presence of the aberrant fibril subpopulation disrupts the normal linear and lateral growth mediated by fibril fusion. Therefore, abnormal fibril nucleation and dysfunctional fibril growth with potential disruption of cell-directed fibril organization leads to the connective tissue dysfunction associated with EDS.

Received for publication, October 24, 2005 , and in revised form, January 23, 2006.

^* This work was supported in part by National Institutes of Health Grants AR47054 (to R. J. W.), AG19475 (to C. L. P.), and EY05129 (to D. E. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Human Genetics, Children's Hospital Research Foundation, 3333 Burnet Ave., ML 4006, Cincinnati, OH 45229-3039. Tel.: 513-636-7219; Fax: 513-636-2261; E-mail: richard.wenstrup{at}cchmc.org.

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