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

Publisher: Academic Press Country of Publication: England NLM ID: 0370707 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-0007 (Electronic) Linking ISSN: 00144835 NLM ISO Abbreviation: Exp Eye Res Subsets: MEDLINE

Publication: London : Academic Press
Original Publication: London.

Mutation, Missense*; Glaucoma, Angle-Closure/*genetics ; Hyperopia/*genetics ; Membrane Proteins/*genetics ; Microphthalmos/*genetics ; Vision Disorders/*genetics ; Visual Acuity/*physiology; Adult ; Aged, 80 and over ; Amino Acid Substitution ; Arginine ; Female ; Filtering Surgery ; Glaucoma, Angle-Closure/physiopathology ; Glaucoma, Angle-Closure/surgery ; Humans ; Hyperopia/physiopathology ; Hyperopia/surgery ; Lens Implantation, Intraocular ; Male ; Microphthalmos/physiopathology ; Microphthalmos/surgery ; Microscopy, Acoustic ; Middle Aged ; Pedigree ; Phacoemulsification ; Proline ; Protein Conformation, alpha-Helical/genetics ; Slit Lamp Microscopy ; Vision Disorders/physiopathology ; Exome Sequencing

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.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)

Keywords: Angle-closure glaucoma; Autosomal dominant; Blindness; Nanophthalmos; TMEM98

0 (Membrane Proteins)
0 (TMEM98 protein, human)
94ZLA3W45F (Arginine)
9DLQ4CIU6V (Proline)

Nanophthalmos 1

Date Created: 20210217 Date Completed: 20210903 Latest Revision: 20221207

20231215

10.1016/j.exer.2021.108497

33596443