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SLC38A8 mutations result in arrested retinal development with loss of cone photoreceptor specialisation.

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journal contribution
posted on 27.11.2020, 12:31 by Helen J Kuht, Jinu Han, Gail DE Maconachie, Sung Eun Park, Seung-Tae Lee, Rebecca McLean, Viral Sheth, Michael Hisaund, Basu Dawar, Nicolas Sylvius, Usman Mahmood, Frank A Proudlock, Irene Gottlob, Hyun Taek Lim, Mervyn G Thomas
Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosomal recessive disorder arising from SLC38A8 mutations. SLC38A8 is a putative glutamine transporter with strong expression within the photoreceptor layer in the retina. Previous studies have been limited due to lack of quantitative data on retinal development and nystagmus characteristics. In this multi-centre study, a custom-targeted next generation sequencing (NGS) gene panel was used to identify SLC38A8 mutations from a cohort of 511 nystagmus patients. We report 16 novel SLC38A8 mutations. The sixth transmembrane domain is most frequently disrupted by missense SLC38A8 mutations. Ninety percent of our cases were initially misdiagnosed as PAX6-related phenotype or ocular albinism prior to NGS. We characterized the retinal development in vivo in patients with SLC38A8 mutations using high-resolution optical coherence tomography. All patients had severe grades of arrested retinal development with lack of a foveal pit and no cone photoreceptor outer segment lengthening. Loss of foveal specialization features such as outer segment lengthening implies reduced foveal cone density, which contributes to reduced visual acuity. Unlike other disorders (such as albinism or PAX6 mutations) which exhibit a spectrum of foveal hypoplasia, SLC38A8 mutations have arrest of retinal development at an earlier stage resulting in a more under-developed retina and severe phenotype.

Funding

This work was supported by Ulverscroft Foundation, Fight for Sight (grant ref: 5009/5010 and 24NN181), the Medical Research Council (MRC), London, UK (grant number: MR/J004189/1, MRC/N004566/1 and MC_PC_17171), a fund (#2018-ER6902-00) from the Research of Korea Centers for Disease Control and Prevention and a grant (No. 2019IL0366) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea. B.D. is supported by the National Institute of Health Research (NIHR) (ACF-2019-11-003). M.G.T. is supported by the NIHR (CL-2017-11-003).

History

Citation

Human Molecular Genetics, Volume 29, Issue 18, 15 September 2020, Pages 2989–3002, https://doi.org/10.1093/hmg/ddaa166

Version

VoR (Version of Record)

Published in

Human Molecular Genetics

Volume

29

Issue

18

Pagination

2989 - 3002

Publisher

Oxford University Press (OUP)

issn

0964-6906

eissn

1460-2083

Acceptance date

10/07/2020

Copyright date

2020

Available date

03/08/2020

Spatial coverage

England

Language

eng