A novel proline substitution (Arg201Pro) in alpha helix 8 of TMEM98 causes autosomal dominant nanophthalmos-4, closed angle glaucoma and attenuated visual acuity. (April 2021)

• Record Type: Journal Article
• Authors: Koenighofer, Martin; Parzefall, Thomas; Frohne, Alexandra; Frei, Elisabeth; Waldstein, Sebastian M.; Mitulovic, Goran; Schoefer, Christian; Frei, Klemens; Lucas, Trevor
• Is Part Of: Experimental eye research. Volume 205(2021)
• Publication Date: 2021-04
• Subjects: Nanophthalmos -- TMEM98 -- Autosomal dominant -- Angle-closure glaucoma -- Blindness; NNO Nanophthalmos -- MCO Microphthalmia -- ACG Angle-closure glaucoma -- AR Autosomal recessive -- AD Autosomal dominant -- MYRF Myelin regulatory factor -- MFRP Membrane-type frizzled-related protein -- MCOP6 Microphthalmia, isolated 6 -- FRAT Frequently rearranged in advanced t-cell lymphomas -- BMPR1A Bone morphogenetic protein receptor, type IA -- BMP4 Bone morphogenetic protein 4 -- y/o Years of age -- GCIP Grap2 and cyclin-D-interacting protein 1; Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2021.108497
• Languages: English
• ISSNs: 0014-4835

Abstract

Abstract: Nanophthalmos-4 is a rare autosomal dominant disorder caused by two known variations in TMEM98 . An Austrian Caucasian pedigree was identified suffering from nanophthalmos and late onset angle-closure glaucoma and premature loss of visual acuity. Whole exome sequencing identified segregation of a c.602G > C transversion in TMEM98 (p.Arg201Pro) as potentially causative. A protein homology model generated showed a TMEM98 structure comprising α4, α5/6, α7 and α8 antiparallel helix bundles and two predicted transmembrane domains in α1 and α7 that have been confirmed in vitro . Both p.Arg201Pro and the two missense variations representing proline insertions identified previously to cause nanophthalmos-4 (p.Ala193Pro and p.His196Pro) are located in the charge polarized helix α8 (p.183-p210). Stability of the C-terminal alpha helical structure of TMEM98 is therefore essential to prevent the development of human nanophthalmos-4. Precise molecular diagnosis could lead to the development of tailored therapies for patients with orphan ocular disease.