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Human Molecular Genetics, 2002, Vol. 11, No. 18 2113-2118
© 2002 Oxford University Press

Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa

Bart Loeys1, Lionel Van Maldergem2, Geert Mortier1, Paul Coucke1, Sabine Gerniers3, Jean-Marie Naeyaert4 and Anne De Paepe1,*

1Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium, 2Centre de Genetique Humaine, Institut de Pathologie et de Genetique, Loverval, Belgium, 3Department of Pediatrics, Sint-Lucas Hospital, Ghent, Belgium and 4Department of Dermatology, Ghent University Hospital, Ghent, Belgium

Received April 16, 2002; Revised June 20, 2002; Accepted June 24, 2002

Hereditary cutis laxa comprises a heterogeneous group of connective tissue disorders characterized by loose skin and variable systemic involvement. Autosomal dominant and recessive as well as X-linked forms have been described. Some dominant forms are caused by mutations in the elastine gene (ELN). The X-linked form is now classified in the group of copper transport diseases. The genetic defect underlying the autosomal recessive (AR) forms of cutis laxa is not known. The phenotypic abnormalities recently observed in a fibulin-5 knockout mouse model are reminiscent of human AR cutis laxa type I. Both share cutis laxa, lung emphysema and arterial involvement. Molecular study of the fibulin-5 (FBLN5) gene in a large consanguineous Turkish family with four patients affected by AR cutis laxa type I demonstrated the presence of a homozygous missense mutation (T998C) in the FBLN5 gene resulting in a serine-to-proline (S227P) substitution in the fourth calcium-binding epidermal growth factor-like domain of fibulin-5 protein. This amino acid substitution is predicted to have important structural and functional consequences for normal elastogenesis. As such, we provide evidence that a genetic defect in fibulin-5 (FBLN5, also known as EVEC or DANCE) is responsible for a recessive form of cutis laxa in humans.

* To whom correspondence should be addressed at: Ghent University Hospital, Department of Medical Genetics, De Pintelaan 185, B-9000 Ghent, Belgium. Tel: +32 92403602; Fax: +32 92404970; Email: anne.depaepe{at}rug.ac.be


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