Glaucoma 3, Primary Congenital, E

A number sign (#) is used with this entry because of evidence that primary congenital glaucoma-3E (GLC3E) is caused by heterozygous mutation in the TEK gene (600221) on chromosome 9p21.

For a general phenotypic description and discussion of genetic heterogeneity of primary congenital glaucoma, see GLC3A (231300).

Clinical Features

Souma et al. (2016) studied a multiethnic cohort of 189 unrelated families with primary congenital glaucoma (PCG) in which affected individuals had onset of disease before 3 years of age; exhibited an increased corneal diameter greater than 10 mm, accompanied by corneal edema and/or Haab striae; and had intraocular pressures (IOPs) greater than 21 mm Hg and/or optic nerve cupping greater than 0.4. Of the 10 families with a mutation in the TEK gene, disease was unilateral in 5 families and bilateral in the other 5 families. Souma et al. (2016) noted a high frequency of carriers without a typical early-onset PCG phenotype, observed in 8 (36%) of 22 mutation carriers. The authors stated that because of the geographic and historic nature of some of the samples, it was impossible to examine parents of probands carefully for evidence of glaucoma or elevated IOP, and thus it was difficult to distinguish variable expressivity clearly from reduced penetrance. However, given the high frequency of unilateral involvement, and the development of glaucoma in later decades in 2 mutation carriers, Souma et al. (2016) proposed an autosomal dominant model with variable expressivity.

Molecular Genetics

In a multiethnic cohort of 189 unrelated families with primary congenital glaucoma, all of which were negative for mutation in known PCG-associated genes, Souma et al. (2016) performed exome sequencing and identified 10 heterozygous loss-of-function mutations in the TEK gene (see, e.g., 600221.0005 and 600221.0006) in 10 of the families.

Animal Model

Souma et al. (2016) generated Tek hemizygous and conditional knockout mice and analyzed their aqueous humor outflow pathways. Confocal microscopy revealed that Tek-haploinsufficient mice developed a severely hypomorphic canal with convolutions and focal narrowing, whereas the Schlemm canal was completely absent in Tek-knockout mice, consistent with a requirement for TEK as well as gene-dosage sensitivity during Schlemm canal development. Serial histologic sections of the iridocorneal region in Tek-haploinsufficient mice showed a hypoplastic Schlemm canal and trabecular meshwork, and analysis of IOPs by rebound tonometry showed a 25% elevation compared to control mice. Souma et al. (2016) concluded that reduced TEK signaling causes developmental defects of aqueous humor outflow structures and correlates with elevated IOP.