Mutation analysis in a German family identified a newcataract-causing allele in the CRYBB2 gene

[摘要] Purpose: The study demonstrates the functional candidate geneanalysis in a cataract family of German descent.Methods: We screened a German family, clinically documented to havecongenital cataracts, for mutation in the candidate genes CRYG (A toD) and CRYBB2 through polymerase chain reaction analyses andsequencing.Results: Congenital cataract was first observed in a daughter ofhealthy parents. Her two children (a boy and a girl) also suffer fromcongenital cataracts and have been operated within the first weeks ofbirth. Morphologically, the cataract is characterized as nuclear with anadditional ring-shaped cortical opacity. Molecular analysis revealed nocausative mutation in any of the CRYG genes. However, sequencing ofthe exons of the CRYBB2 gene identified a sequence variation in exon5 (383 A>T) with a substitution of Asp to Val at position 128. Allthree affected family members revealed this change but it was notobserved in any of the unaffected persons of the family. The putativemutation creates a restriction site for the enzyme TaiI. Thismutation was checked for in controls of randomly selected DNA samplesfrom ophthalmologically normal individuals from the population-basedKORA S4 study (n=96) and no mutation was observed. Moreover, the Asp atposition 128 is within a stretch of 12 amino acids, which are highlyconserved throughout the animal kingdom. For the mutant protein, theisoelectric point is raised from pH 6.50 to 6.75. Additionally, therandom coil structure of the protein between the amino acids 126-139 isinterrupted by a short extended strand structure. In addition, thisregion becomes hydrophobic (from neutral to +1) and the electrostaticpotential in the region surrounding the exchanged amino acid alters froma mainly negative potential to an enlarged positive potential.Conclusions: The D128V mutation segregates only in affected familymembers and is not seen in representative controls. It represents thefirst mutation outside exon 6 of the human CRYBB2 gene.

[学科分类] 生物化学/生物物理