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Primary congenital glaucoma (PCG) is a severe childhood blinding disorder caused by developmental defects in aqueous humor outflow through Schlemm’s canal and the trabecular meshwork. ANGPT1, encoding the ligand angiopoietin-1 for the TEK receptor tyrosine kinase, is critical for vascular morphogenesis and has been implicated in PCG pathogenesis through disrupted ANGPT/TIE2 signaling (ANGPT1; Primary congenital glaucoma).
Genetic analyses identified three unrelated PCG probands with heterozygous loss-of-function ANGPT1 variants, including truncating alleles c.706C>T (p.Gln236Ter) in an international cohort of 284 patients (PMID:29106382). No additional affected relatives segregating these alleles have been reported.
Functional studies demonstrate that Angpt1-knockout mice develop a severely hypomorphic Schlemm’s canal with elevated intraocular pressure, closely modeling the human disease phenotype. In vitro and in vivo assays of patient-derived ANGPT1 alleles confirm loss of receptor activation and multimerization, establishing a direct pathogenic mechanism (PMID:29106382).
The variant spectrum in PCG includes truncating changes c.706C>T (p.Gln236Ter) and c.1480C>T (p.Arg494Ter), as well as missense c.746A>G (p.Lys249Arg). These alleles disrupt the oligomerization domain required for TEK binding and signal transduction, consistent with a haploinsufficiency mechanism.
ANGPT1 deficiency impairs ANGPT/TIE2 signaling necessary for Schlemm’s canal morphogenesis, with concordant evidence from murine models and human functional assays. No studies to date dispute this association.
Together, genetic and experimental data support a moderate association between ANGPT1 and PCG, informing molecular diagnosis and highlighting ANGPT1/TIE2 as a therapeutic target. Key Take-home: ANGPT1 haploinsufficiency contributes to primary congenital glaucoma via disrupted Schlemm’s canal development.
Gene–Disease AssociationModerate3 unrelated probands with rare LOF ANGPT1 variants; murine knockout replicates canal dysgenesis Genetic EvidenceLimited3 probands harboring heterozygous ANGPT1 truncating variants with minimal segregation data Functional EvidenceModerateAngpt1-knockout mice exhibit hypomorphic Schlemm’s canal and elevated IOP; patient alleles demonstrate loss-of-function in vitro/in vivo |