Abstract
Purposes: Recent studies have suggested that loss-of-function mutations of the tunica intima endothelial receptor tyrosine kinase (TEK) are responsible for approximately 5% of primary congenital glaucoma (PCG) cases in diverse populations. However, the causative role of TEK mutations has not been studied in Chinese PCG patients. Here, we report the mutation spectrum of TEK after screening a large cohort of PCG patients of Chinese Han origin and analyze the identified variants in functional assays. Methods: TEK-targeted next-generation sequencing (NGS) was performed in 200 PCG patients. Candidate variants were prioritized by mutation type and allele frequency in public datasets. Plasmids containing wild type and identified variants of TEK were constructed and used to assess protein expression, solubility, receptor auto-phosphorylation, and response to ligand stimulation in cell-based assays. Results: Ten missense and one nonsense heterozygous variants were detected by NGS in 11 families. The clinical features of TEK variants carriers were comparable to that of TEK-mutated patients identified in other populations and CYP1B1-mutated individuals from in-house database. Functional analysis confirmed four variants involving evolutionarily conserved residues to be loss-of-function, while one variant (p.R1003H) located in tyrosine kinase domain seemed to be an activating mutation. However, our results did not support the pathogenicity of the other five variants (p.H52R, p.M131I, p.M228V, p.H494Y, and p.L888P). Conclusion: We provide evidence for TEK variants to be causative in Chinese PCG patients for the first time. Attention needs to be paid to TEK mutations in future genetic testing.
Highlights
In healthy eyes, the intraocular pressure (IOP) is maintained by dynamic balance between aqueous humor production via ciliary body and drainage through trabecular and uveoscleral pathway (Johnson et al, 2017)
The diagnosis of primary congenital glaucoma (PCG) must agree with the following criteria: (1) expansion of corneal diameter, corneal clouding, or Haab’s striae; (2) IOP >21 mm Hg; (3) optic nerve cupping or asymmetric cupto-disc ratio; and (4) disease onset before age 3
44 TEK variants were detected in 199 samples
Summary
The intraocular pressure (IOP) is maintained by dynamic balance between aqueous humor production via ciliary body and drainage through trabecular and uveoscleral pathway (Johnson et al, 2017). Mutations of CYP1B1, LTBP2, MYOC, FOXC1, TEK, and ANGPT1 have been implicated in PCG patients from diverse populations (Stoilov et al, 1997; Kaur et al, 2005; Ali et al, 2009; Chakrabarti et al, 2009; Souma et al, 2016; Thomson et al, 2017). The molecular basis of PCG remains largely unrevealed, especially for patients of Chinese Han origin with CYP1B1 heterozygous and homozygous mutations accounting for only 17.2% of cases and no mutations of LTBP2 being identified (Chen et al, 2008; Chen et al, 2016)
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