Autosomal Dominant Nuclear Cataract Research Articles

Mutation Analysis of Families with Autosomal Dominant Congenital Cataract: A Recurrent Mutation in the CRYBA1/A3 Gene Causing Congenital Nuclear Cataract

ABSTRACTPurpose: To identify the CRYBA1/A3 mutation spectrum and analyze the genotype-phenotype correlations in Chinese families with congenital cataract.Methods: Family history and clinical data of 47 unrelated families with autosomal dominant congenital cataract (ADCC) were recorded. CRYBA1/A3 gene sequencing was applied to identify the causative mutation. Haplotypes were constructed using closely linked microsatellite markers and intragenic single-nucleotide polymorphisms (SNPs) to compare the affected haplotype in three families.Results: Nuclear cataract was the most common type of ADCC in Chinese families, accounting for 42.6% (20/47). A recurrent CRYBA1/A3 deletion mutation (ΔG91) was identified in three families (6.4%) with nonprogressive nuclear congenital cataract. Different haplotypes segregated with the mutation in each family.Conclusions: A recurrent ΔG91CRYBA1/A3 mutation occurs independently in 6.4% of the Chinese families with autosomal dominant nuclear cataracts and most likely represents a mutational hot spot, which underscores the relations between nonprogressive nuclear cataract and CRYBA1/A3.

A R54L Mutation of CRYAA Associated with Autosomal Dominant Nuclear Cataracts in a Chinese Family

Purpose: To identify the genetic defect in a three-generation Chinese family with congenital cataracts.Methods: The phenotype of a three-generation Chinese family with congenital cataract was recruited. Detailed family history and clinical data of the family were recorded. Candidate genes sequencing was performed to screen out the disease-causing mutation. Bioinformatics analysis was performed to predict the function of mutant gene.Results: The phenotype of the family was identified as nuclear cataract. Direct sequencing revealed a c.161 G > T transversion in exon 1 of crystallin alpha-A (CRYAA). This mutation co-segregated with all affected individuals in the family and was not found in unaffected family members nor in the 100 unrelated controls. Bioinformatics analysis indicated that the 54th amino acid position was highly conserved and the mutation R54L caused an increase of local hydrophobicity around the substitution site.Conclusions: This study identified a novel disease-causing mutation c.161 G > T (p.R54L) in CRYAA in a Chinese family with autosomal dominant nuclear cataracts, this is the first report relating a G > T mutation in CRYAA leading to congenital nuclear cataract.

A Novel Mutation in the Connexin 50 Gene (GJA8) Associated with Autosomal Dominant Congenital Nuclear Cataract in a Chinese Family

Purpose: To identify the genetic defect in a four-generation Chinese family with autosomal dominant congenital nuclear cataract.Methods: Family history data were recorded. Clinical and ophthalmologic examinations were performed on family members. All the members were genotyped with microsatellite markers at loci associated with cataracts. Linkage analysis was performed after genotyping. Candidate genes were screened for mutation using direct sequencing.Results: Linkage analysis was obtained at markers D1S1653 (LOD score [Z] = 1.50, recombination fraction [θ] = 0.0) and D1S498 (LOD score Z = 0.90, recombination fraction [θ] = 0.0), which encompasses the connexin 50 gene (GJA8). Sequencing the coding regions of GJA8 revealed a novel, heterozygous c.773C>T transition that resulted in the substitution of a highly conserved serine by phenylalanine at codon 258 (S258F). Bioinformatics analysis showed that the mutation altered the hydrophobicity and secondary structure of the protein. This mutation co-segregated with the disease phenotype in all affected individuals and was not found in the unaffected family members or in 100 normal unrelated individuals.Conclusions: This study has identified a novel missense mutation located in the carboxyl terminus of GJA8 (S258F) associated with autosomal dominant nuclear cataract.

Autosomal Dominant Congenital Nuclear Cataracts Caused by a CRYAA Gene Mutation

Purpose: We sought to identify the genetic defect in a four-generation Chinese family with autosomal dominant congenital nuclear cataracts, examine the clinical features in detail and demonstrate the functional analysis of a candidate gene in the family.Methods: Family history data were recorded. Clinical and ophthalmological examinations were performed on affected and unaffected family members. All the members were genotyped with microsatellite markers at loci considered to be associated with cataracts. Two-point LOD scores were calculated using the LINKAGE program package after genotyping. A mutation was detected by dilff521229rect sequencing and verified by denaturing high-performance liquid chromatography (DHPLC). Wild-type and mutant proteins were analyzed with online softwares.Results: All affected members of this family had nuclear cataracts. Genetic analysis revealed a heterozygous previously described Arg116Cys mutation in the CRYAA gene in all of the affected members of the family but not in unaffected or 100 normal, unrelated individuals. Data generated with online software revealed that the different amino acid side chain, impact the aa116 interaction with other amino acids, thereby affecting the proteins secondary structure.Conclusions: This study identified a mutation in the CRYAA gene causing autosomal dominant nuclear cataracts and some patients show nystagmus or small blepharophimosis clinical features. These results provide evidence that CRYAA is a pathogenic gene for congenital cataracts, congenital cataracts are a clinically and genetically heterogeneous lens condition; at the same time, demonstrates a possible mechanism of action for the mutant gene.