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X. Jiao, W. Yao, S. A. Riazuddin, T. Butt, A. Yasmeen, A. Li, Y. Zhang, S. Riazuddin, J. F. Hejtmancik; Mutations in ßB3-Crystallin, Galk1, Hsf4 Are Associated With Autosomal Recessive Cataract in Pakistani Families. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1336.
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© ARVO (1962-2015); The Authors (2016-present)
To identify the disease locus for autosomal recessive congenital cataracts in consanguineous Pakistani families.
Twenty five Pakistani families with autosomal recessive cataract were ascertained, patients were examined, blood samples were collected, and DNA was isolated. A genome wide scan was carried out with the ABI MD-10 microsatellite marker set and analyzed as fully penetrant autosomal recessive traits using the LINKAGE program package. Haplotypes were formed by inspection and candidate genes were sequenced. Mutations in ßB3-Crystallin, GALK1, and HSF4 were identified by PCR amplification and sequencing of exons and flanking sequences using fluorescent terminator technology in an ABI 3100 automated DNA sequencer.
In the genome-wide scan, a maximum lod score of 3.9 was obtained for family 60074 with both markers D16S503 and D16S3107. This region contains HSF4, which showed a G→C transition in exon4 resulting in a p.A145P in the protein. Maximum lod scores of 3.2 and 2.6 were obtained for families 60025 and 60063 respectively with both markers D22S1174 and D22S315. This interval contains the ßB3-Crystallin gene, which showed a G→C transition in exon 6 resulting in a p.G165R in the protein. Maximum lod scores of 4.8 and 5.5 for families 60055 and 60030 respectively were obtained for marker D17S785. This is near GALK1, which showed a T→C transition in exon3 resulting in a p.L138P in family 60055 and a single base pair deletion in exon3, c. 473delG, resulting in a frame shift and a premature termination in the galactokinase protein p.G137fsX163 in family 60030. No other families yielded a significant lod score.
These findings confirm that mutations in HSF4, ßB3-Crystallin and GALK1 genes result in autosomal recessive congenital cataract in Pakistan families and expand the spectrum of the mutations in these genes causing cataract. Identification of the specific mutations in these genes and correlation with the phenotype of the cataracts associated with these mutations will increase our understanding of lens biology at a molecular level.
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