OBJECTIVETo identify the genetic defect causing automosal dominant congenital cataracts (ADCC) with nuclear opacities in a Chinese pedigree.

METHODSLinkage analysis was carried out with the short tandem repeat polymorphisms flanking the candidate genes. Mutation analysis of the candidate gene in the critical region was performed to detect the potential mutation.

RESULTSThe cataract locus in this pedigree was mapped to 17q11.1-12, an 11.78 cM interval between markers D17S933 and D17S 1288. By means of sequencing the candiate gene, betaA1-crystallin (CRYBA1), a deletion mutation DeltaG91 in exon 4 was detected. This change cosegregated with the patients in the family but was not found in 50 normal unrelated individuals.

CONCLUSIONIt is a deletion mutation DeltaG91 of CRYBA1 gene that causes autosomal dominant congenital nuclear cataract. This is the first report of an autosomal dominant congenital nuclear cataract caused by the mutation in this gene.

Cataract ; congenital ; genetics ; Crystallins ; genetics ; Gene Deletion ; Genetic Linkage ; Humans ; Mutation ; Polymerase Chain Reaction ; beta-Crystallin A Chain

OBJECTIVETo identify the disease-causing gene mutations in three Chinese pedigrees affected with congenital inherited cataract, in ordre to provide genetic counseling and prenatal diagnosis.

METHODSUsing exons combined target region capture sequencing chip to screen the candidate disease-causing mutations, Sanger sequencing was used to confirm the disease-causing mutations.

RESULTSFamily 1 was polymorphic cataract, family 2 was cerulean cataract, family 3 was coralliform cataract. The inheritance mode of the three pedigrees consisted with autosomal dominant inheritance. In family 1, a nonsense mutation of CRYβB2 gene c.463C>T in exon 6 result in a p.Q155X amino acid change. In family 2, a missense mutation of of CRYGD gene c.43C>T in exon 2 result in a p.R14C amino acid change. In family 3, a missense mutation of CRYGD gene c.70C>A in exon 2 result in a p.P23T amino aid change. No above-mentioned mutations were found in normal individuals.

CONCLUSIONThe nonsense mutation c.463C>T (p.Q155X) of CRYβB2 gene, the heterozygous mutations c.43C>T(p.R14C) of CRYGD gene and c.70C>A( p.P23T) of CRYGD gene was the disease-causing gene mutation in family 1, 2 and 3 respectively, our results provid genetic counseling and prenatal diagnosis for these three families.

Cataract ; genetics ; Genetic Counseling ; Humans ; Mutation ; Pedigree ; Prenatal Diagnosis ; beta-Crystallin B Chain ; genetics ; gamma-Crystallins ; genetics

BACKGROUNDCongenital cataract is a highly heterogeneous disorder at both the genetic and phenotypic levels. This study was conducted to identify disease locus for autosomal dominant congenital cataracts in a four generation Chinese family.

METHODSFamily history and clinical data were recorded. All the members were genotyped with microsatellite markers which are close to the known genetic loci for autosomal congenital cataracts. Two-point Lod scores were obtained using the MLINK of the LINKAGE program package (ver 5.1). Candidate genes were amplified by polymerase chain reaction (PCR) and direct cycle sequencing.

RESULTSThe maximum Lod score of Zmax-2.11 was obtained with three microsatellite markers D22S258, D22S315, and D22S1163 at recombination fraction theta=0. Haplotype analysis showed that the disease gene was localized to a 18.5 Mbp region on chromosome 22 flanked by markers D22S1174 and D22S270, spanning the beta-crystallin gene cluster. A c.752T-->C mutation in exon 6 of CRYBB1 gene, which resulted in a heterozygous S228P mutation in predicted protein, was found to cosegregate with cataract in the family.

CONCLUSIONSThis study identified a novel mutation in CRYBB1 gene in a Chinese family with autosomal dominant congenital cataract. These results provide strong evidence that CRYBB1 is a pathogenic gene for congenital cataract.

Amino Acid Sequence ; Cataract ; congenital ; genetics ; Female ; Genes, Dominant ; Genetic Linkage ; Humans ; Male ; Molecular Sequence Data ; Mutation, Missense ; beta-Crystallin B Chain ; genetics

OBJECTIVETo perform mutation screening and prenatal diagnosis for a five-generation Chinese pedigree with autosomal dominant congenital nuclear cataract from Henan province by DNA sequencing.

METHODSBlood samples were taken from the family members. Four candidate genes (CRYBA1/A3, CRYBB1, CRYBB2 and CRYGD) were screened for mutations using direct sequencing. Prenatal genetic diagnosis was provided for a fetus at early gestation through chorionic villus sampling.

RESULTSA missense mutation, c.387C to A, was detected in exon 4 of the CRYBB1 gene in all of the patients. The mutation has resulted in a p.S129R transversion. The same mutation was not found in the fetus of the proband, who was confirmed to be healthy by one-year follow-up.

CONCLUSIONA missense mutation p.S129R of the CRYBB1 gene probably underlies the autosomal dominant congenital nuclear cataract in this pedigree. Detection of the mutation also facilitated prenatal genetic testing for the family.

Asian Continental Ancestry Group ; genetics ; Base Sequence ; Cataract ; congenital ; diagnosis ; genetics ; China ; DNA Mutational Analysis ; Female ; Genes, Dominant ; Genetic Counseling ; Genotype ; Humans ; Male ; Mutation ; Pedigree ; Pregnancy ; Prenatal Diagnosis ; Young Adult ; beta-Crystallin B Chain ; genetics

β/γ-Crystallins are predominant structural proteins in the cytoplasm of lens fiber cells and share a similar fold composing of four Greek-key motifs divided into two domains. Numerous cataract-causing mutations have been identified in various β/γ-crystallins, but the mechanisms underlying cataract caused by most mutations remains uncharacterized. The S228P mutation in βB1-crystallin has been linked to autosomal dominant congenital nuclear cataract. Here we found that the S228P mutant was prone to aggregate and degrade in both of the human and E. coli cells. The intracellular S228P aggregates could be redissolved by lanosterol. The S228P mutation modified the refolding pathway of βB1-crystallin by affecting the formation of the dimeric intermediate but not the monomeric intermediate. Compared with native βB1-crystallin, the refolded S228P protein had less packed structures, unquenched Trp fluorophores and increased hydrophobic exposure. The refolded S228P protein was prone to aggregate at the physiological temperature and decreased the protective effect of βB1-crystallin on βA3-crystallin. Molecular dynamic simulation studies indicated that the mutation decreased the subunit binding energy and modified the distribution of surface electrostatic potentials. More importantly, the mutation separated two interacting loops in the C-terminal domain, which shielded the hydrophobic core from solvent in native βB1-crystallin. These two interacting loops are highly conserved in both of the N- and C-terminal domains of all β/γ-crystallins. We propose that these two interacting loops play an important role in the folding and structural stability of β/γ-crystallin domains by protecting the hydrophobic core from solvent access.
Amino Acid Substitution ; Cataract ; genetics ; metabolism ; HeLa Cells ; Humans ; Molecular Dynamics Simulation ; Mutation, Missense ; Protein Aggregation, Pathological ; genetics ; metabolism ; Protein Domains ; Protein Structure, Secondary ; Proteolysis ; beta-Crystallin B Chain ; chemistry ; genetics ; metabolism