Genome Scan of Maltese Families With Pseudoexfoliation Syndrome (PEX)

Abstract

Abstract: : Purpose: To map and clone the defective genes in 3 families with Pseudoexfoliation Syndrome (PEX) from the Mediterranean Island of Malta. Methods: Three multi–generational Maltese families with confirmed diagnosis of PEX were enrolled in the study. Families consisted of 41 (including 9 affected), 52 (7 affected) and 22 (5 affected) members. A genome–wide scan was carried out with 410 polymorphic DNA markers. Genotypic data exported to the CYRILLIC program and the most likely inherited haplotypes were constructed for each chromosome. Positive LOD scores were obtained with DNA markers on chromosomes 3, 6, 7, 8, 9, 13, 18, 19 and 21. Additional markers were genotyped by silver staining method and candidate genes were screened by direct DNA sequencing. Results: Construction and inspection of the inherited haplotypes in our 3 PEX families provided preliminary evidence of linkage only to chromosome 3q13–q24. Interestingly, an initially identified region between D3S4523 and D3S1744 broadly overlapped with the previously reported GLC1C locus for adult–onset primary open angle glaucoma (POAG) on 3q22–q23. However, saturation mapping with additional 20 DNA markers identified critical recombination that reduced this region significantly. Two of the PEX families showed consistent linkage from D3S4523 to D3S1765 and within a region of ∼4.3–Mb on 3q13–q21. The third PEX family only showed linkage consistent with the distal part of the GLC1C region. Of the 31 known genes currently residing within the PEX region on 3q13–q21, we already screened 7 and identified 18 different DNA variations in 6 of them. However, none of the observed sequence alterations were involved in the etiology of this condition. Conclusions: Genetic linkage analysis of Maltese families with PEX implies that a provisional locus may reside on 3q13–q21. Evaluation of linkage in other PEX families and mutation screening of additional candidate genes are now warranted. Support: NIH Grant EY09947.

Keywords: gene mapping • genetics • linkage analysis