1. Autosomal recessive congenital cataracts linked to HSF4 in a consanguineous Pakistani family.
- Author
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Jiao X, Khan SY, Kaul H, Butt T, Naeem MA, Riazuddin S, Hejtmancik JF, and Riazuddin SA
- Subjects
- Animals, Cataract congenital, Cataract metabolism, Consanguinity, Female, Genes, Recessive, Heat Shock Transcription Factors metabolism, Humans, Lod Score, Male, Mice, Pakistan, Pedigree, Cataract genetics, Genetic Linkage, Heat Shock Transcription Factors genetics, Lens, Crystalline metabolism, Microsatellite Repeats, Mutation, Missense
- Abstract
Purpose: To investigate the genetic basis of autosomal recessive congenital cataracts (arCC) in a large consanguineous Pakistani family., Methods: All participating members of family, PKCC074 underwent an ophthalmic examination. Slit-lamp photographs were ascertained for affected individuals that have not been operated for the removal of the cataractous lens. A small aliquot of the blood sample was collected from all participating individuals and genomic DNAs were extracted. A genome-wide scan was performed with polymorphic short tandem repeat (STR) markers and the logarithm of odds (LOD) scores were calculated. All coding exons and exon-intron boundaries of HSF4 were sequenced and expression of Hsf4 in mouse ocular lens was investigated. The C-terminal FLAG-tagged wild-type and mutant HSF4b constructs were prepared to examine the nuclear localization pattern of the mutant protein., Results: The ophthalmological examinations suggested that nuclear cataracts are present in affected individuals. Genome-wide linkage analyses localized the critical interval to a 10.95 cM (14.17 Mb) interval on chromosome 16q with a maximum two-point LOD score of 4.51 at θ = 0. Sanger sequencing identified a novel missense mutation: c.433G>C (p.Ala145Pro) that segregated with the disease phenotype in the family and was not present in ethnically matched controls. Real-time PCR analysis identified the expression of HSF4 in mouse lens as early as embryonic day 15 with a steady level of expression thereafter. The immunofluorescence tracking confirmed that both wild-type and mutant HSF4 (p.Ala145Pro) proteins localized to the nucleus., Conclusion: Here, we report a novel missense mutation in HSF4 associated with arCC in a familial case of Pakistani descent., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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