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Kristina N Whisenhunt, Stuart W Tompson, Yasmin S Bradfield, Samuel J Huang, Nickie Stangel, Emily C Higuchi, Burton J Kushner, Terri L Young; A missense mutation in the intracellular protein kinase domain of TEK causes autosomal dominant PCG and non-ocular features. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2121. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Primary congenital glaucoma (PCG) accounts for 5% of childhood blindness worldwide. It can be caused by defects in the aqueous humor ocular outflow structures, leading to increased intraocular pressure (IOP), expanded globe size, and optic nerve damage with subsequent vision loss. Recently, we discovered that haploinsufficency for the tunica interna endothelial cell kinase gene, TEK, can cause PCG with variable age of onset and expressivity. In mice, hemizygosity for Tek led to the formation of a hypomorphic Schlemm’s canal and trabecular meshwork, resulting in increased IOP. Herein, we performed exome sequencing in a large multi-generational family with autosomal dominant (AD) PCG and uncovered non-ocular phenotypes associating with the disease.
After consent was obtained, medical histories were acquired from 14 members of a large Caucasian family; 6 individuals had PCG, 1 had juvenile-onset glaucoma, and 7 others had no clinical signs of glaucoma. However, Perthes disease, ovarian cysts, and gastroparesis were also noted in multiple family members. Exome sequencing (Nimblegen SeqCap EZ V3 capture kit, 100bp paired-end reads, Illumina HiSeq2000) was performed on 6 individuals (3 affected, 3 unaffected). Variants were filtered and analyzed using Golden Helix SVS software. Sanger sequencing validated the candidate variants and co-segregation analysis was performed on remaining family members.
Exome sequencing identified a rare heterozygous p.Ala841Val (c.2522C>T, NM_000459.3) missense variant within the intracellular protein tyrosine kinase (PTK) domain of TEK that was present in all individuals affected with glaucomatous disease. Additionally, Perthes disease and/or ovarian cysts were observed in 4 mutation carriers. FATHMM, SIFT, and Polyphen2 predicted the variant to be damaging. Protein sequence alignments showed the Ala-841 residue to have been conserved for 450 million years, since the common ancestor of humans and the Spotted Gar (primitive freshwater fish).
We provide further evidence for AD inheritance in TEK-related PCG, caused in this family by a missense mutation in the PTK domain previously only associated with systemic venous malformations. Our observations further suggest that this TEK mutation may be involved in the ovarian cyst and Perthes disease phenotypes, via vascular developmental mechanisms.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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