Abstract
BackgroundHereditary 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.MethodsA 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.ResultsThe 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).ConclusionWe identified the first nonsense mutation (p.R405X) in exon 11 of HSF4 in a large consanguineous Pakistani family with autosomal recessive cataract.
Highlights
Hereditary cataracts are most frequently inherited as autosomal dominant traits, but can be inherited in an autosomal recessive or X-linked fashion
Nonsyndromic congenital cataracts tend to be highly penetrant as Mendelian traits with autosomal dominant more com
Out of 12 autosomal recessive loci, mutations in eight genes have been identified [516]. Of those families with inherited cataracts for whom the mutant gene is known, about half show mutations in genes encoding for crystallins, about a quarter have mutations in genes coding for connexins, with the remainder divided among the genes encoding the heat shock transcription factor-4 (HSF4), aquaporin-0 (AQP0, MIP), and beaded filament structural protein-2 (BFSP2) [3]
Summary
Hereditary cataracts are most frequently inherited as autosomal dominant traits, but can be inherited in an autosomal recessive or X-linked fashion. 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). Nonsyndromic congenital cataracts tend to be highly penetrant as Mendelian traits with autosomal dominant more com-. Loci for 28 autosomal dominant and 12 autosomal recessive forms of congenital cataracts have been mapped. Out of 12 autosomal recessive loci, mutations in eight genes have been identified [516] Of those families with inherited cataracts for whom the mutant gene is known, about half show mutations in genes encoding for crystallins, about a quarter have mutations in genes coding for connexins, with the remainder divided among the genes encoding the heat shock transcription factor-4 (HSF4), aquaporin-0 (AQP0, MIP), and beaded filament structural protein-2 (BFSP2) [3]
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