Autosomal recessive congenital cataracts linked to HSF4 in a consanguineous Pakistani family


Autoři: Xiaodong Jiao aff001;  Shahid Y. Khan aff002;  Haiba Kaul aff003;  Tariq Butt aff003;  Muhammad Asif Naeem aff003;  Sheikh Riazuddin aff003;  J. Fielding Hejtmancik aff001;  S. Amer Riazuddin aff002
Působiště autorů: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America aff001;  The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America aff002;  National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan aff003;  Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan aff004
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225010

Souhrn

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.

Klíčová slova:

Alleles – Cataracts – Eye lens – Missense mutation – Polymerase chain reaction – Substitution mutation – Transcription factors – Autosomal recessive traits


Zdroje

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2019 Číslo 12