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.
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Acknowledgments
We wish to thank the family members for their cooperation and participation in this study. G.B. was supported by the Deutsche Forschungsgemeinschaft (DFG; BO2985/3-1). This study was supported by the generous help of Ahmed Farooq Bazai, Vice Chancellor, BUITEMS, through faculty funds. We thank Dr. Sigrid Roters (Cologne, Germany) for ophthalmologic advice.
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439_2011_1062_MOESM2_ESM.tif
Supplementary Figure 1 Linkage of autosomal-recessive cataracts to chromosome 6p24 in family CA03. Schematic representation of genome-wide LOD score calculations in family CA03. LOD scores calculated with ALLEGRO are given along the y-axis relative to genomic positionin centi Morgan (cM) on the x-axis. Note a single significant peak (LOD score 3.01) located on chromosome 6. (DOC 1.45 MB)
439_2011_1062_MOESM3_ESM.tif
Supplementary Figure 2 Enrichment of the GCTN2 region on 6p24 for SINE repeats.Enrichment of SINE repeats in shifting windows of size 100kb on chromosome 6 (a) and around GCNT2 (b). See methods for details on the calculation of the enrichment score. (TIF 1.63 MB)
439_2011_1062_MOESM4_ESM.tif
Supplementary Figure 3 Individuals homozygous for the GCNT2 deletion have the adult i blood group.a Test tube results of anti-I typing in three members of families CA03 and CA05 each, showing that individuals affected by cataracts and homozygous for the GCNT2 deletion have the adult i blood group (I-negative) whereas unaffected family members have the common I blood group.b Test tube results of anti-I typing for two unrelated healthy Pakistani controls (control 1 and control 2) as well as a negative agglutination control (cord blood, I negative, i positive) and a positive agglutination control (adult donor blood, I positive, i negative). (TIF 3.11 MB)
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Borck, G., Kakar, N., Hoch, J. et al. An Alu repeat-mediated genomic GCNT2 deletion underlies congenital cataracts and adult i blood group. Hum Genet 131, 209–216 (2012). https://doi.org/10.1007/s00439-011-1062-1
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DOI: https://doi.org/10.1007/s00439-011-1062-1