Genes Associated With Human Glaucoma

Introduction

For many years a family history of glaucoma has been recognized as an important disease risk factor. Some forms of glaucoma are inherited as mendelian dominant or recessive traits, including juvenile open-angle glaucoma, congenital glaucoma, developmental glaucomas (Rieger’s syndrome and aniridia), and pigmentary glaucoma. Other types of glaucoma, such as adult primary open-angle glaucoma (POAG), have a heritable susceptibility. At least one gene has been identified for most types of glaucoma ( Table 10.31.1 ).

The identification of genes that contribute to glaucoma and characterization of the normal and abnormal biological function of the protein products of these genes can provide important new information about the pathophysiology of the disease. Current treatment for glaucoma is directed toward the regulation of aqueous humor formation by the ciliary body and increased outflow of aqueous humor through the trabecular meshwork or alternative pathways created by surgical procedures. Current therapy does not actually treat the cause of the disease because the molecular and cellular basis of disease in most cases is unknown. Identifying genes responsible for glaucoma and determining the functions of the normal and abnormal protein products will define the underlying molecular processes contributing to disease. This information could lead to the development of novel treatments, including gene-based therapies. The isolation of genes responsible for glaucoma will also lead to new methods for diagnosis based on the DNA sequence changes that result in defective genes and protein products. Such DNA-based diagnostic tests can identify individuals at risk for the disease before any visual deterioration has occurred.

Congenital Glaucoma

Congenital glaucoma can be inherited as an autosomal recessive or autosomal dominant trait. Two genes responsible for autosomal recessive disease have been identified: CYP1B1 , coding for cytochrome P4501B1 , and LTBP2 , coding for latent transforming growth factor-beta (TGF-β)–binding protein 2. Subsequently, mutations in CYP1B1 have been identified in patients worldwide, whereas LTBP2 appears to be more localized to specific populations where consanguineous marriages are common. Glaucoma-associated CYP1B1 mutations disrupt protein functional domains, implying that loss of function (LOF) of the protein results in the phenotype. Variability in the phenotypic expression of mutant forms of CYP1B1 has led to the suggestion that modifier genes may also influence the severity of the disease resulting from mutations in this gene. One study indicated that patients carrying MYOC mutations in addition to CYP1B1 mutations have more severe disease, suggesting that the proteins of these two genes may interact in the same biochemical pathways. Disease severity has also been shown to be modified by tyrosinase in a CYP1B1 knockout model; however, tyrosinase does not appear to be a major modifier gene in humans with CYP1B1 mutations.

TIE2 (TEK) LOF mutations can cause congenital glaucoma with autosomal dominant inheritance and variable expressivity. Homozygous Tie2 knockout mice without functional TEK (tunica interna endothelial cell kinase) have high intraocular pressure (IOP) and buphthalmos secondary to absence of Schlemm’s canal. Humans with heterozygous LOF TIE2 mutations have a range of glaucoma phenotypes extending from congenital onset to adult onset. A similar phenotype is caused by mutations in the gene coding for Angiopoietin-1 (ANGPT1) , a TEK/TIE2 ligand. It is not clear what underlies the variable disease phenotype, although modifier genes and variable development of Schlemm’s canal are possible explanations.

Developmental Glaucoma

In humans, primarily four genes— PITX2 , FOXC1 , PAX6 , and CPAMD8— have been associated with abnormal anterior segment development and glaucoma. Mutations in PITX2 located on chromosome 4q25 cause Rieger's syndrome, which is an autosomal dominant disorder of morphogenesis that results in abnormal development of the anterior segment of the eye. Typical clinical findings may include posterior embryotoxon, iris hypoplasia, iridocorneal adhesions, and corectopia. Approximately 50% of affected individuals develop high-IOP glaucoma associated with severe optic nerve disease. Although the elevation of IOP is likely to result from abnormal development of the anterior structures of the eye, a direct correlation between the severity of the anterior segment dysgenesis and the incidence of glaucoma has not been observed. Presumably the structures that are involved in the elevation of IOP in these patients are not readily visible clinically. PITX2 is a bicoid homeobox transcription factor that plays an important role in ocular development. Mutations responsible for Rieger’s syndrome are LOF mutations and missense changes that interfere with critical protein domains. Interestingly, among family members carrying the same mutations, there can be extensive variation in the severity of the phenotype. The underlying mechanism responsible for this phenotypic variability is not known.

FOXC1 , a member of the forkhead family of regulatory proteins, is located on chromosome 6p25. Mutations in this gene are associated with iris hypoplasia and glaucoma, as well as cardiovascular developmental abnormalities. FOXC1 gene dosage is important for normal function, because both deletions and duplications can result in abnormal phenotypes. The importance of the FOXC1 gene in ocular development is demonstrated by a mouse knockout model that lacks the FOXC1 gene product and has abnormal development of the anterior segment of the eye. Various anterior segment structures are abnormally formed in the FOXC1 -deficient mouse, including the iris and Schlemm’s canal.

PAX6 is a member of the paired box homeodomain proteins, and mutations in this gene have been reported to cause aniridia, Peters’ anomaly, and anterior stromal keratitis. Aniridia and Peters' anomaly are both associated with glaucoma, presumably as a result of abnormal development of aqueous humor drainage structures.

Recently, biallelic CPAMD8 mutations have been identified in individuals with an atypical form of anterior segment dysgenesis characterized by bilateral iris hypoplasia, ectopia lentis, corectopia, ectropion uveae, and cataracts. CPAMD8 (C3 and PZP-like α ₂ -macroglobulin domain-containing protein 8) is a protein of unknown function that may have a role in innate immunity and TGF-β activation. CPAMD8 biallelic mutations have subsequently been identified in patients with congenital glaucoma.