Age-dependent prevalence of mutations at the GLC1A locus in primary open-angle glaucoma

PURPOSE: To screen a population with primary open-angle glaucoma for mutati ons in the gene that encodes the trabecular meshwork inducible glucocortico id response protein (TIGR), also known as myocilin (MYOC). METHODS: Ophthalmologic information was collected for study subjects with p rimary open-angle glaucoma and their relatives. Mutation screening of 74 pr imary open-angle glaucoma probands was conducted by sequencing TIGR/MYOC co ding sequence and splice sites. RESULTS: In 23 families we detected 13 nonsynonymous sequence changes, nine of which appear to be mutations likely to cause or contribute to primary o pen-angle glaucoma. Two mutations, Arg272Gly and Ile499Ser, and one nonsyno nymous sequence variant, Asn57Asp, are novel. We found mutations in nine of 25 juvenile glaucoma probands (36%) and two of 49 adult-onset glaucoma pro bands (4%). Age classification of families rather than individual probands revealed mutations in three of nine families with strictly juvenile primary open-angle glaucoma (33%), and no mutations in 39 families with strictly a dult-onset primary open-angle glaucoma (0%). Tn families with mixed-onset p rimary open-angle glaucoma containing both juvenile primary open-angle glau coma and adult-onset primary open-angle glaucoma cases, we found mutations in eight of 26 families (31%). CONCLUSIONS: Our data suggest that Gly252Arg, Arg272Gly, Glu323Lys, Gln368S TOP, Pro370Leu, Thr377Met, Val42Phe, Ile477Asn, and Ile499Ser are likely to play roles that cause or contribute to the etiology of autosomal dominant primary open-angle glaucoma. Our finding of more TIGR/MYOC mutations in fam ilies with mixed-onset primary open-angle glaucoma than in the families wit h strictly adult-onset primary open-angle glaucoma implies that the presenc e of relatives with juvenile primary open-angle glaucoma in a family could be used as a basis for identifying a subset of the population with adult-on set primary open-angle glaucoma with higher prevalence of TIGR/MYOC mutatio ns. To address this issue, and to refine estimations of mutation prevalence in these age-defined subpopulations, prospective study of a larger populat ion ascertained entirely through adult-onset primary open-angle glaucoma pr obands will be needed. (C) 2000 by Elsevier Science Inc. All rights reserve d.