title: A novel HSF4 gene mutation (p.R405X) causing autosomal recessive congenital cataracts in a large consanguineous family from Pakistan.
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 theta=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).
  
  
  CONCLUSIONS
  We identified the first nonsense mutation (p.R405X) in exon 11 of HSF4 in a large consanguineous Pakistani family with autosomal recessive cataract.
authors.affiliation: Faculty of Biotechnology and Informatics, BUITEMS, Quetta, Pakistan. naheedsaj@yahoo.com
authors.forename: Naheed
authors.initials: N
authors.lastname: Sajjad
authors.forename: Ingrid
authors.initials: I
authors.lastname: Goebel
authors.forename: Naseebullah
authors.initials: N
authors.lastname: Kakar
authors.forename: Abdul Majeed
authors.initials: AM
authors.lastname: Cheema
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.forename: Jamil
authors.initials: J
authors.lastname: Ahmad
mesh_terms: D000346:Afghanistan / Q000208:ethnology; D002386:Cataract / Q000151:congenital* / Q000235:genetics*; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D005260:Female; D005808:Genes, Recessive; D000076249:Heat Shock Transcription Factors; D006801:Humans; D008126:Lod Score; D008297:Male; D010154:Pakistan; D010375:Pedigree; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C102948:HSF4 protein, human; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors