Genetic dissection of myocilin glaucoma

Abstract

Primary open-angle glaucoma (POAG) is a complex disease with unknown causes. However, in the past decade, POAG has been linked to six chromosomal regions, of which the gene MYOC encoding myocilin and the gene OPTN encoding optineurin have been identified to harbor causal mutations (disease-causing variants, DCV). POAG caused by DCV at MYOC has been termed "myocilin glaucoma". Clinically, DCV at MYOC may manifest as a typical POAG, normal tension glaucoma, or ocular hypertension without glaucoma. Individuals with the Arg46Stop mutation that almost knocks out the entire coding sequence may have severe glaucoma or no glaucoma. Genetically, myocilin glaucoma follows autosomal dominant, recessive or no pattern of inheritance. DCV at MYOC cause POAG in interaction with environmental factors and DCV at other loci. Most DCV at MYOC are relatively young, and the Gln368Stop mutation is exclusively European in origin. The overall frequency of DCV at MYOC is similar among African, Caucasian and Asian probands with POAG. Because of this fact and the higher prevalence of POAG in African descendants compared with Caucasians or Asians, the overall frequency of DCV at MYOC is several-fold higher in the general population of African descendants, which is in part responsible for their higher prevalence of POAG. Although the Arg46Stop mutation was often observed in normal controls, Arg46Stop carriers tend to have higher risk of developing POAG. Polymorphisms at several loci including MYOC are associated with POAG, and play an important role in the pathogenesis of POAG.

Primary open-angle glaucoma genes

“…Glaucoma-causing mutations in myocilin were first detected in linkage-based studies of large pedigrees with juvenile open angle glaucoma (JOAG). 7,27 Myocilin mutations have since been found in 3-4% of POAG patients 7,26 and a range of glaucoma-associated myocilin mutations have now been cataloged in review articles 28,29 and online at http://www.myocilin.com. In most cases, myocilin-associated glaucoma appears to be transmitted as an autosomal dominant trait and is associated with markedly elevated IOP.…”

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

“…50 MYOC glaucoma is the most common form of inherited glaucoma (2-4% of glaucoma worldwide). 51 Of note, it is particularly associated with high IOP in both the early and the later onset forms of the disease.…”

“…154 There are also gene mutations associated with POAG, which are not common in all populations. 50 New approaches may help identify these as yet unidentified genetic variations. One approach to the whole genome association mapping that exploits linkage disequilibrium generated by admixture between genetically distinct ancestral populations is called 'admixture mapping', 155 and can be an interesting and practical genetic approach in POAG.…”

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].…”