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

Abstract

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.

• Authors: Helen J Kuht, Jinu Han, Gail D E 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
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 29 Issue 18 Pg. 2989-3002 (11 04 2020) ISSN: 1460-2083 [Electronic] England
• PMID: 32744312 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press.

Chemical References

• Amino Acid Transport Systems, Neutral
• PAX6 Transcription Factor
• PAX6 protein, human
• Slc38a8 protein, human

Topics

• Adolescent
• Adult
• Amino Acid Transport Systems, Neutral (genetics)
• Anterior Eye Segment (abnormalities, diagnostic imaging, pathology)
• Cell Differentiation (genetics)
• Child
• Child, Preschool
• Eye Abnormalities (diagnostic imaging, genetics, pathology)
• Female
• Fovea Centralis (abnormalities, diagnostic imaging, pathology)
• Genetic Predisposition to Disease
• High-Throughput Nucleotide Sequencing
• Humans
• Infant
• Male
• Mutation (genetics)
• Nystagmus, Congenital (genetics, pathology)
• PAX6 Transcription Factor (genetics)
• Pedigree
• Retina (growth & development, pathology)
• Retinal Cone Photoreceptor Cells (pathology)
• Tomography, Optical Coherence
• Visual Acuity (genetics, physiology)
• Young Adult