title: An Alu repeat-mediated genomic GCNT2 deletion underlies congenital cataracts and adult i blood group.
abstract: We performed homozygosity mapping in a consanguineous Pakistani family segregating autosomal-recessive congenital cataracts and identified linkage to a 3.03 Mb locus on chromosome 6p24 containing the GCNT2 gene. GCNT2 encodes glucosaminyl (N-acetyl) transferase 2, an enzyme responsible for the formation of the blood group I antigen. Rare biallelic GCNT2 mutations have been shown to cause the association of congenital cataracts and the adult i blood group, making GCNT2 the prime candidate gene for the observed phenotype. Indeed, we identified a homozygous deletion segregating with cataracts that encompasses exons 1B, 1C, 2 and 3 of GCNT2. Long-range polymerase chain reaction and breakpoint sequencing revealed that affected individuals in this and in a second, apparently unrelated Pakistani family segregating congenital cataracts are homozygous for the same 93 kb deletion. The deletion is flanked by Alu repeats of the AluS family on both sides and microsatellite genotyping suggested that its occurrence in the two families was the product of recurrent Alu-Alu repeat-mediated nonhomologous recombinations or an old founder effect. Subsequently, we showed that cataract-affected individuals in both families have the adult i blood group, whereas unaffected individuals have blood group I as the vast majority of the population. Because the GCNT2 locus is rich in Short INterspersed Elements (SINE repeats) and thus likely prone to genomic rearrangements, microdeletions or microduplications at this locus might cause a larger than currently anticipated fraction of apparently isolated autosomal-recessive cataracts.
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany. guntram.borck@uni-ulm.de
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
authors.forename: Naseebullah
authors.initials: N
authors.lastname: Kakar
authors.forename: Jochen
authors.initials: J
authors.lastname: Hoch
authors.forename: Katrin
authors.initials: K
authors.lastname: Friedrich
authors.forename: Jan
authors.initials: J
authors.lastname: Freudenberg
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Rüstem
authors.initials: R
authors.lastname: Yilmaz
authors.forename: Shakeela
authors.initials: S
authors.lastname: Daud
authors.forename: Dost Muhammad
authors.initials: DM
authors.lastname: Baloch
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
authors.forename: Jamil
authors.initials: J
authors.lastname: Ahmad
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
mesh_terms: D020087:Alu Elements; D001483:Base Sequence; D001789:Blood Group Antigens / Q000235:genetics*; D002386:Cataract / Q000151:congenital* / Q000235:genetics*; D003241:Consanguinity; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: D001789:Blood Group Antigens; D017351:N-Acetylglucosaminyltransferases; C063312:beta-1,3-galactosyl-0-glycosyl-glycoprotein beta-1,3-N-acetylglucosaminyltransferase