Recurrent Mutations in a Single Exon Encoding the Evolutionarily Conserved Olfactomedin-Homology Domain of TIGR in Familial Open-Angle Glaucoma

Abstract

Primary open-angle glaucoma (POAG) is a highly prevalent cause of irreversible blindness which associates cupping of the optic disc and alteration of the visual field, elevation of intraocular pressure being a major risk factor. Provided diagnosis is made at an early stage, treatments are available to prevent visual impairment. A locus, GLC1A, has been mapped on chromosome 1q23-q25 in several families affected with juvenile-onset POAG (JOAG) and also in some families affected with juvenile 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 French families. All mutations known to date appear to concentrate in the evolutionarily conserved C-terminal domain of TIGR which bears homology 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 . Moreover, this conserved domain of TIGR is encoded by a single exon to which mutation screening could be limited. Surprisingly, the TIGR message, which is abundantly transcribed in the trabecular meshwork and also in the ciliary body and the sclera, is not expressed in the optic nerve whose degeneration is, however, the primary lesion of POAG.

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

“…The Gln368Stop mutation confers mild risk, 55 Thr377Met and Gly252Arg mutations intermediate risk, 56,57 and the Pro370Leu mutation severe risk. [58][59][60][61] …”

Regulation of human myocilin/TIGR gene transcription in trabecular meshwork cells and astrocytes: role of upstream stimulatory factor

“…Stone et al (Stone et al 1997) identi®ed three mutations in the gene for MYOC/TIGR, which lies within the interval on chromosome 1 that was originally associated with juvenile open angle-glaucoma (GLC1A) (Shef®eld et al 1993;Richards et al 1994;Wiggs et al 1994). Subsequently, mutations in the same gene of patients with GLC1A-linked juvenile open-angle glaucoma were also reported by other researchers (Adam et al 1997;Kee & Ahn 1997;Stoilova et al 1997;Suzuki et al 1997;Brezin et al 1998;Mansergh et al 1998;Michels-Rautenstrauss et al 1998). Juvenile open-angle glaucoma refers to a subset of POAG that has an earlier age of onset, a highly penetrant mode of inheritance and is usually associated with a high IOP requiring early surgical treatment (Wiggs et al 1995;Johnson et al 1996).…”

“…In addition to TM and retina, MYOC/TIGR is expressed in other ocular tissues such as the cornea, sclera, ciliary body, iris and optic nerve head (Adam et al 1997;Ortego et al 1997;Tomarev et al 1998;Karali et al 2000). The normal role of MYOC/TIGR and the mechanisms by which mutations in this gene cause glaucoma are unknown.…”

Optimedin induces expression of N-cadherin and stimulates aggregation of NGF-stimulated PC12 cells

“…Mutations in the olfactomedin domain may be deleterious for the functions of these proteins. For example, mutations in the olfactomedin domain of the human MYOCILIN gene may lead to juvenile open-angle glaucoma and in some cases to adult onset glaucoma [17][18][19][20].…”