Missense mutations of conserved glycine residues in fibrillin-1 highlight a potential subtype of cb-EGF-like domains

Khau Van Kien, P.; Baux, D.; Pallares-Ruiz, N.; Baudoin, C.; Plancke, Aélie.; Chassaing, N.; Collignon, P.; Drouin-Garraud, Vérie.; Hovnanian, A.; Martin-Coignard, D.; Collod-Béroud, Gëlle.; Béroud, C.; Roux, A-Françoise.; Claustres, M.

Human mutation 31(1): E1021-E1042

2010


ISSN/ISBN: 1098-1004
PMID: 19802897
DOI: 10.1002/humu.21131
Accession: 054400112

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Abstract
In six index cases/families referred for Marfan syndrome (MFS) molecular diagnosis, we identified six novel mutations in the FBN1 gene: c.1753G>C (p.Gly585Arg), c.2456G>A (p.Gly819Glu), c.4981G>A (p.Gly1661Arg), c.5339G>A (p.Gly1780Glu), c.6418G>A (p.Gly2140Arg) and c.6419G>A (p.Gly2140Glu). These variants, predicted to result in Glycine substitutions are located at the third position of a 4 amino acids loop-region of calcium-binding Epidermal Growth Factor-like (cb-EGF) fibrillin-1 domains 5, 9, 24, 25 and 32. Familial segregation studies showing cosegregation with MFS manifestations or de novo inheritance in addition to in silico analyses (conservation, 3D modeling) suggest evidence for a crucial role of the respective Glycine positions. Extending these analyses to all Glycine residue at position 3 of this 4 residues loop in fibrillin-1 cb-EGF with the UMD predictor tool and alignment of 2038 available related sequences strongly support a steric strain that only allows Glycine or even Alanine residues for domain structure maintenance and for the fibrillin functions. Our data compared with those of the literature strongly suggest the existence of a cb-EGF domain subtype with implications for related diseases.

Missense mutations of conserved glycine residues in fibrillin-1 highlight a potential subtype of cb-EGF-like domains