Identification and study of a FBN1 gene mutation in a Chinese family with ectopia lentis

To identify the mutation in the fibrillin-1 gene (FBN1) in a Chinese family with ectopia lentis (EL) and to predict the structural and functional consequences of the mutation.

Patients and family members were given complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from leukocytes of venous blood of three affected and three unaffected individuals in the family, and 100 healthy controls. All 65 coding exons and their flanking intronic boundaries of FBN1 were amplified in the proband by polymerase chain reaction, followed by direct sequencing. The mutation identified in the proband was screened for in other family members and 100 healthy controls by direct sequencing. Protein conservation analysis was performed in seven species using an online ClustalW tool. Protein structure was modeled based on the Protein data bank and mutated in PyMOL 1.1r1 to predict the structural and functional consequences of the mutation.

A heterozygous c.2262A>G change in exon 18 of FBN1 was detected in the proband, which resulted in the substitution of tyrosine by cysteine at codon 754 (p.Y754C). This mutation was also present in the affected family members, but absent in other unaffected family members and 100 healthy controls. The mutant residue, located in the calcium binding epidermal growth factor-like7 domain, was highly conserved among mammalian species. The mutation could probably affect the disulfide bond formation of the domain and calcium binding of the adjacent domain, which would induce a critical functional change of the domain itself and neighboring domains.

We indentified a p.Y754C mutation in FBN1, which is the causative mutation for EL in this family. This missense mutation introduced an additional cysteine residue by substitution of a highly conserved tyrosine residue within the cbEGF-like7 module.