Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy.

TitleBiallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy.
Publication TypeJournal Article
Year of Publication2022
AuthorsMarafi, D, Fatih, JM, Kaiyrzhanov, R, Ferla, MP, Gijavanekar, C, Al-Maraghi, A, Liu, N, Sites, E, Alsaif, HS, Al-Owain, M, Zakkariah, M, El-Anany, E, Guliyeva, U, Guliyeva, S, Gaba, C, Haseeb, A, Alhashem, AM, Danish, E, Karageorgou, V, Beetz, C, Subhi, AA, Mullegama, SV, Torti, E, Sebastin, M, Breilyn, MSheck, Duberstein, S, Abdel-Hamid, MS, Mitani, T, Du, H, Rosenfeld, JA, Jhangiani, SN, Akdemir, ZCoban, Gibbs, RA, Taylor, JC, Fakhro, KA, Hunter, JV, Pehlivan, D, Zaki, MS, Gleeson, JG, Maroofian, R, Houlden, H, Posey, JE, V Sutton, R, Alkuraya, FS, Elsea, SH, Lupski, JR
Date Published2022 Apr 29
KeywordsEpilepsy, Generalized, Glutamine, Histidine, Humans, Metabolome, Nitrogen, Sodium-Calcium Exchanger

The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: are associated with rare Mendelian disorders including developmental and epileptic encephalopathy and severe neurodevelopmental disorders. Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental disorders identified two siblings with developmental and epileptic encephalopathy and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar developmental and epileptic encephalopathy phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and CSF of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis.

Alternate JournalBrain
PubMed ID34605855
PubMed Central IDPMC9050560
Grant ListT32 GM007526 / GM / NIGMS NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
MR/S01165X/1 / MRC_ / Medical Research Council / United Kingdom
/ WT_ / Wellcome Trust / United Kingdom
UM1 HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States

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