title: Locus heterogeneity in autosomal recessive congenital cataracts: linkage to 9q and germline HSF4 mutations.
abstract: Isolated (non-syndromic) congenital cataract may be inherited as an autosomal dominant, autosomal recessive, or X-linked recessive trait. Considerable progress has been made in identifying genes and loci for dominantly inherited cataract, but the molecular basis for autosomal recessive disease is less well defined. Hence we undertook genetic linkage studies in four consanguineous Pakistani families with non-syndromic autosomal recessive congenital cataracts. In two families linkage to a 38 cM region 9q13-q22 was detected. Although a locus for recessive congenital cataracts had not been mapped previously to this region, the target interval encompasses the candidate region autosomal recessive adult-onset pulverulent cataracts (CAAR). The CAAR was mapped previously to 9q13-q22, and may therefore be allelic to non-syndromic autosomal recessive congenital cataracts. The other two families did not demonstrate linkage to 9q, but both had a region of homozygosity at 16q22 containing the heat shock transcription factor 4 (HSF4) gene. The HSF4 mutations have been reported in four families with autosomal dominant cataracts and, recently, in a single kindred with autosomal recessive congenital cataract. Mutation analysis of HSF4 revealed homozygous mutations (p.Arg175Pro and c.595_599delGGGCC, respectively) in the two families. These findings confirm that mutations in HSF4 may result in both autosomal dominant and autosomal recessive congenital cataract, and highlight the locus heterogeneity in autosomal recessive congenital cataract.
authors.affiliation: Section of Medical and Molecular Genetics, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Forshew
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.forename: Shagufta
authors.initials: S
authors.lastname: Khaliq
authors.forename: Shanaz
authors.initials: S
authors.lastname: Pasha
authors.forename: Catherine
authors.initials: C
authors.lastname: Willis
authors.forename: Rashida
authors.initials: R
authors.lastname: Abbasi
authors.forename: Louise
authors.initials: L
authors.lastname: Tee
authors.forename: Ursula
authors.initials: U
authors.lastname: Smith
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Syed Qasim
authors.initials: SQ
authors.lastname: Mehdi
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D001483:Base Sequence; D002386:Cataract / Q000151:congenital* / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D018095:Germ-Line Mutation; D000076249:Heat Shock Transcription Factors; D006801:Humans; D008126:Lod Score; D008297:Male; D010154:Pakistan; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C102948:HSF4 protein, human; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors