TEK – TEK-related Primary Congenital Glaucoma

Primary congenital glaucoma (PCG) is a severe childhood disease characterized by developmental defects in aqueous humor outflow, leading to elevated intraocular pressure and optic nerve damage. In 10 of 189 unrelated PCG families, rare heterozygous TEK variants were identified and shown to result in protein haploinsufficiency via loss-of-function mechanisms in vitro (absence of normal protein, degradation, mislocalization) and in mice, hemizygosity for Tek caused a hypomorphic Schlemm’s canal with elevated IOP, demonstrating autosomal dominant inheritance with variable expressivity (PMID:27270174).

Subsequent cohorts expanded the genetic evidence: eight additional PCG families with TEK loss-of-function alleles were reported, and exon sequencing in 200 Chinese PCG patients identified TEK variants in 11 families with functional confirmation of four conserved-residue LoF mutations and one activating variant (PMID:33027505; PMID:34956319). Co-occurrence of TEK and CYP1B1 heterozygous alleles in five families suggested a digenic mode of inheritance, with perturbed TEK–CYP1B1 interaction and reduced ligand responsiveness (PMID:28620713). Overall, heterozygous TEK LoF variants account for ~5% of PCG across diverse populations.

Segregation analysis demonstrated parent-child transmission in two pedigrees (four additional affected relatives) supporting autosomal dominant inheritance and variable penetrance (PMID:33027505).

The TEK variant spectrum includes truncating (nonsense, frameshift, splice) and missense alleles with demonstrated loss of function. A representative allele is c.1753A>T (p.Lys585Ter), which abolishes receptor production and signaling (PMID:27270174).

Functional studies corroborate genetic findings: in vitro assays of TEK variants show defective auto-phosphorylation and ligand-induced activation, and Tek+/– mice recapitulate human PCG phenotypes with hypoplastic Schlemm’s canal and elevated IOP, confirming haploinsufficiency as the primary mechanism (PMID:27270174).

A targeted study in Chinese PCG patients highlighted five TEK variants without pathogenic effect, underscoring the need for functional validation to refine variant interpretation in clinical testing (PMID:34956319).

Collectively, extensive genetic and experimental data support a Strong ClinGen classification for TEK in PCG, with robust evidence for autosomal dominant haploinsufficiency and phenotypic concordance. TEK testing should be incorporated in genetic diagnostic panels for PCG, with functional assays guiding variant pathogenicity assessments.

Key Take-home: TEK haploinsufficiency is a validated, autosomal dominant cause of primary congenital glaucoma with variable expressivity, meriting routine clinical testing and functional follow-up.

References

• The Journal of Clinical Investigation | 2016 | Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity. PMID:27270174
• Investigative Ophthalmology & Visual Science | 2020 | SVEP1 as a Genetic Modifier of TEK-Related Primary Congenital Glaucoma. PMID:33027505
• Frontiers in Genetics | 2021 | Screening and Functional Analysis of TEK Mutations in Chinese Children With Primary Congenital Glaucoma. PMID:34956319
• Human Genetics | 2017 | Angiopoietin receptor TEK interacts with CYP1B1 in primary congenital glaucoma. PMID:28620713

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