GPATCH3 – Congenital Glaucoma

GPATCH3 (HGNC:25720) has been implicated in autosomal recessive congenital glaucoma (MONDO:0020366), a severe optic neuropathy arising from anterior segment maldevelopment. In an initial cohort of 26 unrelated congenital glaucoma patients, whole-exome sequencing identified a single proband harboring two rare, recessive hypermorphic GPATCH3 variants (c.1424G>A (p.Gly475Glu)) ([PMID:28397860]). No segregation data beyond the index case were reported, consistent with a dearth of additional family studies.

Analysis of a second independent cohort of 170 unrelated patients revealed rare GPATCH3 coding variants in approximately 5% of cases ([PMID:28397860]). Although the phase and biallelic status of these additional variants were not uniformly ascertained, their enrichment suggests a contributory role in disease etiology. The variant spectrum reported is exclusively missense changes predicted to enhance GPATCH3 function, with no loss-of-function or splice variants described to date.

Functional assessment demonstrated that recombinant GPATCH3 activates the proximal promoter of CXCR4, a key regulator of neural crest cell migration relevant to ocular development ([PMID:28397860]). Immunodetection localized GPATCH3 to the human ciliary body and in dermal, muscular and periocular mesenchymal-like cells of early zebrafish embryos, mirroring tissues implicated in congenital glaucoma.

Zebrafish modeling via morpholino-mediated knockdown and transient overexpression of gpatch3 induced variable goniodysgenesis and ocular and craniofacial abnormalities, phenocopying defects seen in pitx2 and foxc1 deficiency ([PMID:28397860]). These experiments support a hypermorphic mechanism whereby GPATCH3 overactivity perturbs neural crest–derived anterior segment development.

Together, genetic data from one proband and replication in additional cases, coupled with concordant in vitro and in vivo functional studies, fulfill criteria for a Moderate gene–disease association. Further familial segregation and population-based variant curation will solidify diagnostic validity.

Key Take-home: GPATCH3 hypermorphic variants cause autosomal recessive congenital glaucoma, with functional and zebrafish model evidence supporting clinical testing in early-onset cases.

References

• Scientific Reports • 2017 • Whole-Exome Sequencing of Congenital Glaucoma Patients Reveals Hypermorphic Variants in GPATCH3, a New Gene Involved in Ocular and Craniofacial Development. PMID:28397860

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