Homozygotes carrying an autosomal dominant TIGR mutation do not manifest glaucoma

• Published in: Nature genetics Vol. 19; no. 4; pp. 319 - 321
• Main Authors: Clépet, Christian, Nguyen, Thai, Moisan, Steve, Amyot, Marcel, Dubois, Stéphane, Polansky, Jon, Anctil, Jean-Louis, Côté, Gilles, Falardeau, Pierre, Plante, Micheline, Winstall, Eric, Vermeeren, Diana, Raymond, Vincent, Morissette, Jean
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01-08-1998
• Subjects: Adult; Amino Acid Sequence; Cytoskeletal Proteins; Eye Proteins - genetics; Female; Genes, Dominant - genetics; Glaucoma, Open-Angle - genetics; Glycoproteins - genetics; Heterozygote; Homozygote; Humans; Life Sciences; Male; Middle Aged; Molecular Sequence Data; Mutation - genetics; Pedigree; Penetrance; Phenotype; Quebec; Quebec
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/1203

Autosomal dominant disorders typically result in more severe clinical manifestations in mutant homozygotes than in heterozygotes. Huntington disease is the only reported non-neoplastic human pathology in which no phenotypic variance has been detected between these two types of carriers, and where the mutant allele is truly dominant over its wild-type counterpart. Primary open-angle glaucoma (POAG), a leading cause of blindness worldwide, is characterized by progressive degeneration of the optic nerve and is usually associated with intraocular hypertension (OHT). Several loci involved in glaucoma have been localized. Recently, mutations in the trabecular meshwork-inducible glucocorticoid response (TIGR) gene, also known as myocilin, mapping to the GLC1A locus at 1q23-q25, were identified in families affected by autosomal dominant POAG. We investigated a French-Canadian family, pedigree GV-001, in which POAG was transmitted as an autosomal dominant trait linked to the GLC1A locus. The large size of this kindred and its relative isolation in eastern Quebec allowed us to assess the effects of a TIGR mutation present in double dosage in four adult homozygotes. These individuals were asymptomatic for the disorder, with POAG affecting only the heterozygotes. The pedigree currently contains 622 individuals, of which 83 manifested either juvenile-onset (JOAG), a subset of POAG that has an early age at onset, or adult-onset POAG. Ten individuals also displayed OHT, which often preceded POAG by several years. A marriage in branch GV-510 between two affected second-degree cousins, mother V-1 and her spouse, father V-2, resulted in 10 children, now 33-50 years of age.