RECURRENT MUTATIONS IN A SINGLE EXON ENCODING THE EVOLUTIONARILY CONSERVED OLFACTOMEDIN-HOMOLOGY DOMAIN OF TIGR IN FAMILIAL OPEN-ANGLE GLAUCOMA

Primary open-angle glaucoma (POAG) is a highly prevalent cause of irre versible blindness which associates cupping of the optic disc and alte ration of the visual field, elevation of intraocular pressure being a major risk factor, Provided diagnosis is made at an early stage, treat ments are available to prevent visual impairment, A locus, GLC1A, has been mapped on chromosome 1q23-q25 in several families affected with j uvenile-onset POAG (JOAG) and also in some families affected with juve nile and middle-age onset POAG. Recently, three mutations of the TIGR (Trabecular meshwork-induced Glucocorticoid Response) gene were shown to be responsible for the disease in several American families and in unrelated POAG patients, We now describe five new mutations in eight F rench families, All mutations known to date appear to concentrate in t he evolutionarily conserved C-terminal domain of TIGR which bears homo logy to frog olfactomedin, an extracellular matrix glycoprotein of the olfactory epithelium, to rat and human neuronal olfactomedin-related proteins and to F11C3.2, a protein from Caenorhabditis elegans. Moreov er this conserved domain of TIGR is encoded by a single exon to which mutation screening could be limited, Surprisingly, the TIGR message, w hich is abundantly transcribed in the trabecular meshwork and also in the ciliary body and the sclera, is not expressed in the optic nerve w hose degeneration is, however, the primary lesion of POAG.