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J. Biol. Chem., Vol. 281, Issue 42, 31854-31862, October 20, 2006

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Marfan Syndrome-causing Mutations in Fibrillin-1 Result in Gross Morphological Alterations and Highlight the Structural Importance of the Second Hybrid Domain^*

Kieran T. Mellody, Lyle J. Freeman, Clair Baldock¹, Thomas A. Jowitt, Veronique Siegler², Bertrand D. E. Raynal, Stuart A. Cain, Tim J. Wess², C. Adrian Shuttleworth, and Cay M. Kielty³

From the Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom and the School of Optometry and Vision Sciences, Redwood Building, King Edward VIII Avenue, University of Cardiff, CF10 3NB, United Kingdom

Mutations in fibrillin-1 result in Marfan syndrome, which affects the cardiovascular, skeletal and ocular systems. The multiorgan involvement and wide spectrum of associated phenotypes highlights the complex pathogenesis underlying Marfan syndrome. To elucidate the genotype to phenotype correlations, we engineered four Marfan syndrome causing mutations into a fibrillin-1 fragment encoded by exons 18-25, a region known to interact with tropoelastin. Biophysical and biochemical approaches, including small angle x-ray scattering, analytical ultracentrifugation, and circular dichroism, were used to study the impact of these mutations upon the structure and function of the protein. Mutations G880S, C862R, and C908R, situated within the second hybrid domain, disrupted the ratio of -helix to -sheet leading to a more compact conformation. These data clearly demonstrate the importance of the previously uncharacterized hybrid domain in fibrillin-1 structure. In contrast, mutation K1023N situated within the linker region between the third eight cysteine motif and cbEGF 11 markedly extended the length of the fragment. However, none of the mutations affected tropoelastin binding. The profound effects of all four mutations on fragment conformation suggest that they contribute to the pathogenesis of Marfan syndrome by disrupting protein folding and its assembly into fibrillin-rich microfibrils.

Received for publication, March 23, 2006 , and in revised form, July 11, 2006.

^* This work was funded in part by the British Heart Foundation, Medical Research Council (UK) and EU Grant LSHM-CT-2005-018960. 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 Recipient of a Royal Society Olga Kennard research fellowship.

² Recipient of Biotechnology and Biological Sciences Research Council Grant 98/S15326.

³ A Royal Society-Wolfson Research Merit Award holder. To whom correspondence should be addressed: Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT. Tel.: 44-161-275-5739; Fax: 44-161-275-5082; E-mail: cay.kielty{at}manchester.ac.uk.

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