Genetic dissection of myocilin glaucoma

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.