Confirmation of a Locus for Primary Congenital Glaucoma (PCG) on Chromosome 14q24 in a Pakistani Pedigree

Abstract

Purpose: : Primary congenital glaucoma (PCG) has been linked to two loci, 2p21 (GLC3A) where the responsible gene is CYP1B1, and 1p36 (GLC3B) for which the gene involved remains to be identified. In addition a third locus was described on chromosome 14q24 (GLC3C) in a Turkish family (Stoilov and Sarfarazi, IOVS, 2002, E-Abstract 3015), but this finding has not yet been confirmed in a peer-reviewed paper. PCG is inherited as an autosomal recessive disease and is particularly prevalent in communities where marriage to a relative is a common practice. The purpose of this study was to investigate the genetic basis and phenotype of PCG in a consanguineous Pakistani pedigree.

Methods: : A three generation, consanguineous family from the Punjab province of Northern Pakistan was investigated. Four affected and six unaffected members from two generations underwent ophthalmic examination. DNA was extracted from venous blood samples. A mixed sample containing DNA from the four affected individuals was analysed on a single Affymetrix SNP array and the results were examined for large regions of homozygosity. Linkage was confirmed using highly informative microsatellite markers genotyped on ABI 3130 DNA Analyser.

Results: : Affected family members showed the typical findings of PCG, namely tearing and photophobia from birth, significantly raised IOP at presentation (up to 56mmHg), and buphthalmos (corneal diameters up to 15mmHg). Most had undergone multiple surgeries but had been left with visual acuities of Count Fingers at best.SNP analysis excluded linkage to either GLC3A or GLC3B. However, homozygosity on chromosome 14q24 implicated the GLC3C locus. Microsatellite markers confirmed linkage with a lod score of > 4, with markers D14S277, D14S1047, D14S61, D14S53 and D14S983 all homozygous. A proximal crossover was detected at D14S258.

Conclusions: : These findings confirm the existence of a third locus for PCG on 14q24 (GLC3C) in a second family. The different ethnic origins of the two linked families suggest different mutations will be involved in each. Candidate gene screening is now being performed in order to identify the responsible gene.

Keywords: gene mapping • genetics