Myocilin gene implicated in primary congenital glaucoma

Abstract

Primary congenital glaucoma (PCG) has been associated with CYP1B1 gene (2p21), with a predominantly autosomal recessive mode of inheritance. Our earlier studies attributed CYP1B1 mutations to only 40% of Indian PCG cases. In this study, we included 72 such PCG cases where CYP1B1 mutations were detected in only 12 patients in heterozygous condition, implying involvement of other gene(s). On screening these patients for mutations in myocilin (MYOC), another glaucoma-associated gene, using denaturing high-performance liquid chromatography followed by sequencing, we identified a patient who was double heterozygous at CYP1B1 (c.1103G>A; Arg368His) and MYOC (c.144G>T; Gln48His) loci, suggesting a digenic mode of inheritance of PCG. In addition, we identified the same MYOC mutation, implicated for primary open angle glaucoma, in three additional PCG patients who did not harbor any mutation in CYP1B1. These observations suggest a possible role of MYOC in PCG, which might be mediated via digenic interaction with CYP1B1 and/or an yet unidentified locus associated with the disease.

Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity

“…PCG occurs in all ethnic groups, but the disease incidence varies according to ethnic background, ranging from 1:1,250 in inbred populations to 1:30,000 in populations with heterogeneous ethnicity (6,(8)(9)(10)(11)(12). Families can exhibit autosomal recessive or dominant inheritance, although the majority of cases appear to be sporadic (5,6,(10)(11)(12)(13)(14).…”

“…The molecular etiology of PCG is only partially understood, as only a few genes responsible for PCG have been identified (6,(10)(11)(12)(13)(14). Mutations in CYP1B1, which encodes a cytochrome P450 enzyme, is the most common cause of autosomal recessive PCG worldwide, accounting for up to 87% of familial cases in some inbred populations but only 25%-27% in populations with heterogeneous ethnicity (5, 9, 15-18).…”

Rare FOXC1 variants in congenital glaucoma: identification of translation regulatory sequences

“…1 Interestingly, the existence of incomplete penetrance, variable expressivity and the fact that a significant proportion of patients carry nondominant heterozygous CYP1B1 mutations 1 suggest that more than one gene can be involved in PCG inheritance. Mutations in LTBP2, 2 MYOCILIN (MYOC, MIM# 601652) 3,4 and forkhead box C1 (FOXC1 MIM# 601090) have also been found in a small number of Indian PCG cases. 5 FOXC1 mutations have been found to be involved in several dominant ocular defects, including Axenfeld-Rieger syndrome type 3 (ARS; MIM# 602482), a disease that is associated with increased glaucoma risk and variability in iris and extraocular abnormalities.…”

Primary congenital glaucoma including next-generation sequencing-based approaches: clinical utility gene card

“…MYOC (NM_000261.1), located on chromosome 1q24 (3 exons), also codes for the myocilin/ trabecular meshwork-induced glucocorticoid response protein and MYOC variants account for 5.5% of PCG cases [12]. A further chromosomal locus has been identified at position 1p36 (GLC3B) but no gene has been identified as yet [13].…”