PROBABLE EXCLUSION OF GLC1A AS A CANDIDATE GLAUCOMA GENE IN A FAMILY WITH MIDDLE-AGE-ONSET PRIMARY OPEN-ANGLE GLAUCOMA

Purpose: To determine whether an adult-onset variety of primary open-a ngle glaucoma in family UM:POAG1 is linked to the previously mapped GL C1A juvenile-onset primary open-angle glaucoma locus on chromosome Iq or whether linkage can be excluded. Methods: Microsatellite repeat mar kers from the 9 cM D1S196 to D1S218 interval containing the GLC1A gene were amplified by polymerase chain reaction from DNA samples collecte d from 11 members of one sibship in family UM:POAG1. Haplotype analysi s was carried out, including calculation of the probability that the o bserved data would have been obtained if the underlying cause of prima ry open-angle glaucoma in this family were a defect in a gene located in the tested interval. Linkage analysis was carried out under an auto somal dominant model for GLC1A glaucoma. Results: In family UM:POAG1, primary open-angle glaucoma was diagnosed in six surviving and one dec eased member of a sibship of 13 individuals during the fifth or sixth decade of life. Glaucoma in this family has a later average age at dia gnosis and significantly less elevation in intraocular pressure than G LC1A glaucoma so far described. Haplotype analysis, using a population prevalence up to 0.9%, shows that it is unlikely that the reported da ta would have been observed if primary open-angle glaucoma in this ped igree were due to the GLC1A locus on chromosome 1q21-q31. Linkage anal ysis under the juvenile glaucoma autosomal dominant model allowed excl usion of linkage across the entire GLC1A genetic inclusion interval, w ith a maximum lod score in the interval of -3.28. Conclusion: The most likely interpretation of these observations is that a defect in the G LC1A glaucoma gene is not responsible for adult-onset primary open-ang le glaucoma in family UM:POAG1. This suggests the existence of at leas t two primary open-angle glaucoma genes, the previously reported GLC1A gene on chromosome Iq and another gene located elsewhere in the genom e. Diagnosis of UM:POAG1 glaucoma between 42 and 57 years of age also raises questions regarding the relation of the glaucoma present in thi s family to the common later-age-onset form of the disease.