Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia

Abstract

BackgroundFoveal 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.MethodsFundus 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.ResultsWe 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.ConclusionOur results demonstrate a novel use for OCT‐angiography in confirming FH, and also uncover genotype–phenotype correlations of FH‐linked SLC38A8 mutations.

Missense mutation in SLIT2 associated with congenital myopia, anisometropia, connective tissue abnormalities, and obesity

“…We performed computer-based structural modeling to gain insight into the pathogenicity of our patient’s SLIT2 mutation [ 35 – 37 ]. SLIT2 gene encodes a 1529 amino acid extracellular protein which contains no transmembrane sequence [ 6 , 7 ].…”

Amino Acid Transport Defects in Human Inherited Metabolic Disorders

“…This disorder's molecular basis is not known. Isolated foveal hypoplasia (in the absence of albinism, aniridia, microphthalmia, or achromatopsia) is exceedingly rare [190]. SLC38A8 encodes a sodium-coupled neutral amino acid transporter (SNAT8) that is expressed predominantly in the central nervous system and retina with a preference for glutamate as a substrate [190].…”

“…Isolated foveal hypoplasia (in the absence of albinism, aniridia, microphthalmia, or achromatopsia) is exceedingly rare [190]. SLC38A8 encodes a sodium-coupled neutral amino acid transporter (SNAT8) that is expressed predominantly in the central nervous system and retina with a preference for glutamate as a substrate [190]. Biallelic mutations in SLC38A8 have been linked to a rare autosomal recessive form of foveal hypoplasia (foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis).…”

“…Biallelic mutations in SLC38A8 have been linked to a rare autosomal recessive form of foveal hypoplasia (foveal hypoplasia 2, with or without optic nerve misrouting and/or anterior segment dysgenesis). Clinical manifestations are limited to ophthalmologic symptoms, including low vision and secondary nystagmus [190][191][192][193].…”

In trans variant calling reveals enrichment for compound heterozygous variants in genes involved in neuronal development and growth.

“…Charges and hydrogen atoms were added to the wild-type and mutant FGR models using PDB2PQR (Dolinsky et al, 2004). Electrostatic potentials were calculated using APBS (Konecny et al, 2012) as described previously (Moshfegh et al, 2016;Cox et al, 2017;Toral et al, 2017). Protein and solvent dielectric constants were set to 2.0 and 78.0, respectively.…”