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. 2017 Feb 26;5(3):202-209.
doi: 10.1002/mgg3.266. eCollection 2017 May.

Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia

Marcus A Toral  1   2   3 , Gabriel Velez  1   2   3 , Katherine Boudreault  4 , Kellie A Schaefer  1   2 , Yu Xu  4 , Norman Saffra  5 , Alexander G Bassuk  6 , Stephen H Tsang  7   8 , Vinit B Mahajan  1   2
Affiliations

Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia

Marcus A Toral et al. Mol Genet Genomic Med. .

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.

Keywords: OCT‐angiography; SLC38A8; foveal hypoplasia; precision medicine; structural modeling.

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Figures

Figure 1
Figure 1
Clinical imaging. (A) Family pedigree shown. Exome sequencing revealed heterozygous mutation to SLC38A8 (OMIM #615585) in the mother, father, and homozygous mutations in the affected daughter (proband; indicated with arrow) and son. The variant was not present in either allele for the unaffected son. For clinical images, findings were similar bilaterally and best images, for either right eye (OD) or left eye (OS), were chosen. (B) OD Fundus imaging, autofluorescence, OCT, and OCT‐angiography shown for proband case (II:2). Region of OCT‐angiography indicated by white dotted‐line box. Note, the absence of foveal pit, fundus autofluorescence revealing an abnormal intensity of lipofusin and pigment in the macular region, and absence of the foveal avascular zone. Normal retinal architecture preserved. (C) OS imaging of affected son (II:1) reveals signs of foveal hypoplasia similar to proband (sister). OCT‐angiography could not be obtained due to severity of nystagmus. (D) OD imaging of unaffected son (II:3) shows normal retinal and foveal architecture and morphology. Foveal pit, foveal avascular zone, and normal foveal autofluorescence present.
Figure 2
Figure 2
Structural modeling of patient SCL38A8 mutations: (A) Sequence alignment showing the p.Asp283 position to be conserved across multiple species. (B) Membrane topological structure diagram predicts SLC38A8 to have 11 transmembrane helices and places the p.Asp283Ala mutation on the extracellular surface of the channel. (C) Our SLC38A8 model generated using the I‐TASSER program. (D) Known FHONDA‐associated mutations mapped onto our SLC38A8 model. (E) Mutations were introduced into our model using FoldX and predicted changes in total energy were calculated. Positive changes in total energy were predicted to be destabilizing. (F) Electrostatic potential surface of our SLC38A8 model shows a more positive potential surface at the site of the mutation near the opening of the channel pore. (G) Consurf coloring of the SLC38A8 model reveals the p.Asp283 residue to be 100% conserved across 103 homologous sequences.
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