Recurrent mutation in the crystallin alpha A gene associated with inherited paediatric cataract

Abstract

Background: Cataract is a major cause of childhood blindness worldwide. The purpose of this study was to determine the genetic cause of paediatric cataract in a South Australian family with a bilateral lamellar paediatric cataract displaying variable phenotypes.

Case presentation: Fifty-one genes implicated in congenital cataract in human or mouse were sequenced in an affected individual from an Australian (Caucasian) family using a custom Ampliseq library on the Ion Torrent Personal Genome Machine. Reads were mapped against the human genome (hg19) and variants called with the Torrent Suite software. Variants were annotated to dbSNP 137 using Ion Reporter (IR 1.6.2) and were prioritised for validation if they were novel or rare and were predicted to be protein changing. We identified a previously reported oligomerization disrupting mutation, c.62G > A (p.R21Q), in the Crystallin alpha A (CRYAA) gene segregating in this three generation family. No other novel or rare coding mutations were detected in the known cataract genes sequenced. Microsatellite markers were used to compare the haplotypes between the family reported here and a previously published family with the same segregating mutation. Haplotype analysis indicated a potential common ancestry between the two South Australian families with this mutation. The work strengthens the genotype-phenotype correlations between this functional mutation in the crystallin alpha A (CRYAA) gene and paediatric cataract.

Conclusion: The p.R21Q mutation is the most likely cause of paediatric cataract in this family. The recurrence of this mutation in paediatric cataract families is likely due to a familial relationship.

Fig. 1

Pedigree of family CSA110 with mutation in CRYAA. Individuals with ID numbers were examined by an ophthalmologist. Solid circles indicate affected females and solid squares indicate affected males. Plus sign indicates mutant allele and minus sign indicates wild type allele. Diagonal lines indicate the individual is deceased

Fig. 2

Phenotype of cataract in CSA110.05 showing lamellar and cortical cataract with white spokes

Fig. 3

Sequence chromatogram of all examined individuals at the c.62G > A mutation. All affected family members are heterozygous, as is an unaffected individual CSA110.02

Fig. 4

Haplotype analysis in two families with congenital cataract and the same mutation in Crystallin alpha A (CRYAA) a: CSA110 (reported in this study) and b: CSA91 (previously reported family). Solid circles indicate affected females and solid squares indicate affected males. Only individuals with IDs were available for study. Marker and gene order is D21S1260, CRYAA, D21S1890 and D21S1912 (marker names are indicated on each pedigree). Alleles at each marker are presented as the size of the PCR product detected. Plus sign indicates Crystallin alpha A (CRYAA) mutation carrier. The segregating haplotype is boxed and is the same in both families. A recombination event between D21S1260 and CRYAA was observed in CSA91.05

Fig. 5

Protein sequence alignments demonstrating the conservation of the altered amino acid (underlined). The figure shows the alignments of crystallin alpha A protein sequence of the region of interest from seven species to the human crystallin alpha A (CRYAA) protein. Both mutated and normal human protein sequences are shown beside sequences from Pan troglodytes (chimpanzee), Felis catus (cat), Mus musculus (mouse), Gallus gallus (rooster), Takifugu rubripes (fish), Danio rerio (zebrafish) and Xenopus tropicalis (Frog)