Research article

A novel HSF4 gene mutation (p.R405X) causing autosomal recessive congenital cataracts in a large consanguineous family from Pakistan

Naheed Sajjad¹, Ingrid Goebel^2,3, Naseebullah Kakar¹, Abdul M Cheema¹, Christian Kubisch^2,3 and Jamil Ahmad^1*

• * Corresponding author: Jamil Ahmad jamil_48@yahoo.co.in

Author Affiliations

¹ Faculty of Biotechnology and Informatics, BUITEMS, Quetta, Pakistan

² Institute of Human Genetics, University of Cologne, Cologne, Germany

³ Institute for Genetics, University of Cologne, Cologne, Germany

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BMC Medical Genetics 2008, 9:99 doi:10.1186/1471-2350-9-99

Published: 11 November 2008

Abstract

Background

Hereditary cataracts are most frequently inherited as autosomal dominant traits, but can also be inherited in an autosomal recessive or X-linked fashion. To date, 12 loci for autosomal recessive cataracts have been mapped including a locus on chromosome 16q22 containing the disease-causing gene HSF4 (Genbank accession number NM_001040667). Here, we describe a family from Pakistan with the first nonsense mutation in HSF4 thus expanding the mutational spectrum of this heat shock transcription factor gene.

Methods

A large consanguineous Pakistani family with autosomal recessive cataracts was collected from Quetta. Genetic linkage analysis was performed for the common known autosomal recessive cataracts loci and linkage to a locus containing HSF4 (OMIM 602438) was found. All exons and adjacent splice sites of the heat shock transcription factor 4 gene (HSF4) were sequenced. A mutation-specific restriction enzyme digest (HphI) was performed for all family members and unrelated controls.

Results

The disease phenotype perfectly co-segregated with markers flanking the known cataract gene HSF4, whereas other autosomal recessive loci were excluded. A maximum two-point LOD score with a Zmax = 5.6 at θ = 0 was obtained for D16S421. Direct sequencing of HSF4 revealed the nucleotide exchange c.1213C > T in this family predicting an arginine to stop codon exchange (p.R405X).

Conclusion

We identified the first nonsense mutation (p.R405X) in exon 11 of HSF4 in a large consanguineous Pakistani family with autosomal recessive cataract.