Identification of the p. R116H mutation in a Chinese family with novel variable cataract phenotype: evidence for a mutational hot spot in αA-crystallin gene.
OBJECTIVE
To report the recurrent p.R116H mutation in the αA-crystallin gene (CRYAA) which causes a novel variable cataract phenotype, and to determine whether this mutation represents a mutational hot spot.


METHODS
Family history and clinical data were recorded. The genomic DNA was extracted from peripheral blood leukocytes. Microsatellite markers at loci considered to be associated with autosomal dominant cataracts were selected and genotyped for two-point linkage analysis. Direct sequencing was performed to identify the disease-causing mutation. Haplotype analysis was constructed to compare the affected haplotype in this family and in another Chinese family previously reported by us.


RESULTS
Clinical features of cataract in this family were asymmetric in two eyes of some affected subjects. Evidence of linkage was obtained with marker D21S1411 (logarithm of odds [LOD] score [Z] = 2.42, recombination fraction [θ] = 0.0). Sequencing of the candidate CRYAA gene revealed a single base alteration c.347 G > A in exon 3, which resulted in the substitution of highly conserved arginine by histidine at codon 116 (p.R116H). This mutation co-segregated with all affected individuals and was not observed in unaffected family members or 100 normal unrelated individuals. The comparative haplotype analysis showed that the affected haplotypes in the two families were different.


CONCLUSIONS
This study identified a novel cataract-microcornea phenotype caused by the recurrent mutation p.R116H in CRYAA, and suggested that this mutation site is not likely the consequence of a founder effect, but probably a result of a mutational hot spot.
National Research Institute for Family Planning, Beijing, China.
Binbin
B
Wang
Kai Jie
KJ
Wang
Si Quan
SQ
Zhu
Jing
J
Wang
Xu
X
Ma
D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics*; D002386:Cataract / Q000151:congenital / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D003315:Cornea / Q000002:abnormalities*; D003459:Crystallins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005124:Eye Abnormalities / Q000235:genetics* / Q000473:pathology; D005260:Female; D008040:Genetic Linkage; D060005:Genotyping Techniques; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation
C511246:CRYAA protein, human; D003459:Crystallins