Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy

Abstract

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: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy (DEE) and severe neurodevelopmental disorders (NDDs). Exome sequencing and family-based rare variant analyses on a cohort with NDD identified two siblings with DEE 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 DEE 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 cerebrospinal fluid of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for DEE and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis.

De novo heterozygous variants in SLC30A7 are a candidate cause for Joubert syndrome

“…Null mutation of Slc30a7 in mice results in a lean phenotype that cannot be corrected by oral zinc (Huang & Tepaamorndech, 2013). Yet, loss of function of other ZnT paralogs has been established in other neurological conditions like epileptic encephalopathies and Alzheimer disease (Boone et al, 2011;Duan et al, 2021;Marafi, Fatih, Kaiyrzhanov, Ferla, & Gijavanekar, 2021).…”

Impact of Inhibition of Glutamine and Alanine Transport on Cerebellar Glial and Neuronal Metabolism

“…The impact of glutamine cycling on brain function has been highlighted by the recent discovery of rare biallelic variants in SLC38A3 [ 109 ], resulting in global developmental delay, microcephaly, epilepsy, absent speech and visual impairment. This underlines the importance of the astrocytic release of glutamine ( Figure 9 ) which, it would appear, is unable to be compensated adequately by other transporters.…”

Solute carrier transporter disease and developmental and epileptic encephalopathy

“…The disease caused by SLC38A3 pathogenic variants is currently classified as developmental and epileptic encephalopathy type 102 (OMIM 619881) and was first reported by Marafi et al ( 130 ). Currently, 10 patients were reported with DEE102 from six families, five of which had consanguineous marriages ( 130 ). All 10 patients had axial hypotonia, absent speech, and global developmental delay/mental retardation ( 130 ).…”