Locus heterogeneity in autosomal recessive congenital cataracts: linkage to 9q and germline HSF4 mutations.
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.
Forshew
Tim
T
Section of Medical and Molecular Genetics, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
Johnson
Colin A
CA
Khaliq
Shagufta
S
Pasha
Shanaz
S
Willis
Catherine
C
Abbasi
Rashida
R
Tee
Louise
L
Smith
Ursula
U
Trembath
Richard C
RC
Mehdi
Syed Qasim
SQ
Moore
Anthony T
AT
Maher
Eamonn R
ER
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*
D004268:DNA-Binding Proteins; C102948:HSF4 protein, human; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors