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Mutations in fibrillin‐1 leading to classical and neonatal Marfan syndrome cause differential protease susceptibilities and protein function
Author(s) -
Hubmacher Dirk,
Kirschner Ryan,
Iyengar Garud,
Bromme Dieter,
Bartels Rainer,
Reinhardt Dieter P.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.480.4
Subject(s) - fibrillin , proteases , marfan syndrome , mutant , extracellular matrix , microfibril , mutation , biology , protease , cleavage (geology) , genetics , microbiology and biotechnology , medicine , gene , biochemistry , enzyme , cellulose , paleontology , fracture (geology)
Fibrillin‐1 constitutes the backbone of extracellular matrix microfibrils, which are crucial for regulating elastic fiber biogenesis and TGF‐beta bioavailability. Mutations in fibrillin‐1 give rise to the Marfan syndrome (MFS) characterized by vascular, skeletal and ocular symptoms. To investigate molecular consequences of mutations causing severe neonatal or the milder classical form of MFS, point mutations from each group were introduced in recombinant human fibrillin‐1 fragments. Proteolytic susceptibility was probed with physiological and non‐physiological proteases. The mutant proteins harboring neonatal mutations were typically more susceptible to proteolytic cleavage than those with classic mutations. The cleavage sites were found both in close proximity and distant to the mutations, indicating structural changes and the exposure of cryptic cleavage sites. The group of neonatal mutations more severely affected the ability of fibrillin‐1 to interact with heparin/heparan sulfate, which plays a role in microfibril assembly. Fibroblasts attached less efficiently to the neonatal as compared to the classical mutant proteins. These results suggest new molecular pathogenetic concepts for MFS. In most cases the neonatal mutations resulted in more severe effects, and the biochemical variability correlates with the clinical variability observed in MFS. The work was funded by the Canadian CIHR.