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Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia
Journal article   Open access   Peer reviewed

Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia

Marcus A Toral, Gabriel Velez, Katherine Boudreault, Kellie A Schaefer, Yu Xu, Norman Saffra, Alexander G Bassuk, Stephen H Tsang and Vinit B Mahajan
Molecular genetics & genomic medicine, Vol.5(3), pp.202-209
05/2017
DOI: 10.1002/mgg3.266
PMCID: PMC5441399
PMID: 28546991
url
https://doi.org/10.1002/mgg3.266View
Published (Version of record) Open Access

Abstract

Background Foveal hypoplasia (FH) in the absence of albinism, aniridia, microphthalmia, or achromatopsia is exceedingly rare, and the molecular basis for the disorder remains unknown. FH is characterized by the absence of both the retinal foveal pit and avascular zone, but with preserved retinal architecture. SLC38A8 encodes a sodium‐coupled neutral amino acid transporter with a preference for glutamate as a substrate. SLC38A8 has been linked to FH. Here, we describe a novel mutation to SLC38A8 which causes FH, and report the novel use of OCT‐angiography to improve the precision of FH diagnosis. More so, we used computational modeling to explore possible functional effects of known SLC38A8 mutations. Methods Fundus autofluorescence, SD‐OCT, and OCT‐angiography were used to make the clinical diagnosis. Whole‐exome sequencing led to the identification of a novel disease‐causing variant in SLC38A8. Computational modeling approaches were used to visualize known SLC38A8 mutations, as well as to predict mutation effects on transporter structure and function. Results We identified a novel point mutation in SLC38A8 that causes FH. A conclusive diagnosis was made using OCT‐angiography, which more clearly revealed retinal vasculature penetrating into the foveal region. Structural modeling of the channel showed the mutation was near previously published mutations, clustered on an extracellular loop. Our modeling also predicted that the mutation destabilizes the protein by altering the electrostatic potential within the channel pore. Conclusion Our results demonstrate a novel use for OCT‐angiography in confirming FH, and also uncover genotype–phenotype correlations of FH‐linked SLC38A8 mutations. Here, we report identification by whole‐exome sequencing of a novel disease‐causing mutation to the gene SLC38A8, which encodes a sodium‐coupled neutral amino acid transporter protein and is linked to foveal hypoplasia (FH) of the retina. Through our novel use of OCT‐angiography in the diagnosis of FH, we were able to demonstrate improved diagnostic precision. Structural modeling approaches revealed that this mutation occurs on an extracellular loop of the protein, clustered near other known mutations, and that our mutation is predicted to destabilize the protein by altering the electrostatic potential within the channel pore.
 foveal hypoplasia OCT‐angiography precision medicine structural modeling SLC38A8

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