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

PLoS One. 2019 Dec 9;14(12):e0225010. doi: 10.1371/journal.pone.0225010. eCollection 2019.

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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cataract / congenital
  • Cataract / genetics*
  • Cataract / metabolism
  • Consanguinity
  • Female
  • Genes, Recessive
  • Genetic Linkage*
  • Heat Shock Transcription Factors / genetics*
  • Heat Shock Transcription Factors / metabolism
  • Humans
  • Lens, Crystalline / metabolism*
  • Lod Score
  • Male
  • Mice
  • Microsatellite Repeats*
  • Mutation, Missense*
  • Pakistan
  • Pedigree

Substances

  • HSF4 protein, human
  • Heat Shock Transcription Factors