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Subhabrata Chakrabarti, Sriparna Ganguly, Meha Kabra, Anil K Mandal, Sirisha Senthil, Inderjeet Kaur, Partha P Majumder; The LTBP2 Gene Exhibits a Limited Involvement in Primary Congenital Glaucoma. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3801.
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© ARVO (1962-2015); The Authors (2016-present)
Among the 4 chromosomal loci mapped in primary congenital glaucoma (PCG), two genes have been characterized to harbor mutations in CYP1B1 (GLC3A) and LTBP2 (GLC3D). While CYP1B1 exhibits a universal involvement in PCG worldwide, the same has not been true for LTBP2. In order to assess its involvement in classical PCG cases, we screened this gene in a large cohort of patients who were devoid of CYP1B1 mutations.
All the 36 coding exons of LTBP2 along with the intron-exon boundaries were screened in all the PCG cases (n=250) and unaffected normal controls (n=300) by resequencing with appropriate primers. The effect of individual variants on the protein were analysed by bioinformatic tools (SIFT scores). Haplotypes were generated at the LTBP2 locus by genotyping 44 intragenic and 20 flanking variants and analysed with the Haploview software (version 4.2) that uses the EM algorithm. Finally, the observed data was analyzed in conjunction with data from other populations.
Four mutations were observed in 6/250 PCG cases in LTBP2. Of these, a homozygous nonsense mutation in exon 4 (Gln329Stop) was observed in two cases. The remaining missense mutations were heterozygous across the 4 probands in exon 26 (Pro1291Thr), exon 32 (Val1543Ile) and exon 34 (Gly1660Trp) and were highly conserved across species (SIFT [p<0.05]). Twelve rare variants were distributed sparsely in the cohort (MAF<0.01 in the cohort), while a common polymorphism (rs2304707) was present in equal proportions in cases and controls. All the intragenic and flanking polymorphisms were in Hardy Weinberg equilibrium in the controls (p>0.05) and LD plot indicated six blocks across the 80 kb region at this locus. However, there were no association to any specific haplotypes with PCG (p>0.05) based on the permutation tests (n=10,000 iterations). The observed mutations did not indicate any genotype-phenotype correlation. These results were grossly different from the Balkan Gypsies and inbred populations from Iran and Pakistan that exhibited wide allelic homogeneity and founder effect on a uniform haplotype background.
Mutations in LTBP2 accounted for 1.6% (95%CI, 0.81%-3.12%) of all PCG cases, which was much lower to that observed in other populations with developmental glaucoma. The phenotypic heterogeneity associated with LTBP2 mutations is indicative of its involvement with multiple ocular phenotypes other than classical PCG.
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