Current knowledge of SLC6A1-related neurodevelopmental disorders

Abstract

Advances in gene discovery have identified genetic variants in the solute carrier family 6 member 1 (SLC6A1) gene as a monogenic cause of neurodevelopmental disorders, including epilepsy with myoclonic atonic seizures, autism spectrum disorder, and intellectual disability. The SLC6A1 gene encodes for the GABA transporter protein type 1 (GAT1), which is responsible for the reuptake of the neurotransmitter GABA, the primary inhibitory neurotransmitter in the central nervous system, from the extracellular space. GABAergic inhibition is essential to counterbalance neuronal excitation, and when significantly disrupted, it negatively impacts brain development leading to developmental differences and seizures. Aggregation of patient variants and observed clinical manifestations expand understanding of the genotypic and phenotypic spectrum of this disorder. Here, we assess genetic and phenotypic features in 116 individuals with SLC6A1 variants, the vast majority of which are likely to lead to GAT1 loss-of-function. The knowledge acquired will guide therapeutic decisions and the development of targeted therapies that selectively enhance transporter function and may improve symptoms. We analyzed the longitudinal and cell type-specific expression of SLC6A1 in humans and localization of patient and control missense variants in a novel GAT1 protein structure model. In this update, we discuss the progress made in understanding and treating SLC6A1-related disorders thus far, through the concerted efforts of clinicians, scientists, and family support groups.

Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules

“…Genes such as KCNE5 [ 45 ], SHANK3 [ 46 ], CASQ2 [ 47 ], EDNRA (endothelin receptor type A) [ 48 ], EPHB4 [ 49 ], ALPK3 [ 50 ], WNT11 [ 51 ], IRAK2 [ 52 ], FBN1 [ 53 ], SFRP2 [ 54 ], CLCA2 [ 55 ], NEXN (nexilin F-actin binding protein) [ 56 ], PALLD (palladin, cytoskeletal associated protein) [ 57 ], DAB2 [ 58 ], NRP2 [ 59 ], THBS2 [ 60 ], CSF1R [ 61 ], KCNA2 [ 62 ], CACNA1C [ 63 ], F2R [ 64 ], UCHL1 [ 65 ], CCL18 [ 66 ], ITGB1BP2 [ 67 ] and FMOD (fibromodulin) [ 68 ] were reportedly involved in cardio vascular diseases, but these genes might be key for progression of obesity associated type 2 diabetes mellitus. Hu et al [ 69 ], Liu et al [ 70 ], Eltokhi et al [ 71 ], Cai et al [ 72 ], Pfeiffer et al [ 73 ], Lin et al [ 74 ], Royer-Zemmour et al [ 75 ], Pastor et al [ 76 ], Goodspeed et al [ 77 ], Zhang et al [ 78 ], Rogers et al [ 79 ], Su et al [ 80 ] and Foale et al [ 81 ] reported that NRXN1, CRHR1, SHANK2, PSEN2, CKB (creatine kinase B), CD200R1, SRPX2, PTPRZ1, SLC6A1, GABRB2, KCNA1, ASAH1 and LINGO1 were the genes expressed in progression of neuropsychiatric disorders, but these genes might be involved in advancement of obesity associated type 2 diabetes mellitus. Reports indicate that genes include SPHK2 [ 82 ], NPC1L1 [ 83 ], CNTFR (ciliaryneurotrophic factor receptor) [ 84 ], SLC2A4 [ 85 ], EDA (ectodysplasin A) [ 86 ], TGM2 [ 87 ], GCK (glucokinase) [ 88 ], FASN (fatty acid synthase) [ 89 ], FAP (fibroblast activation protein alpha) [ 90 ], PRNP (prion protein) [ 91 ], LYVE1 [ 92 ], SERPINE1 [ 93 ], TNF (tumor necrosis factor) [ 94 ], FASLG (Fas ligand) [ 95 ...…”

Investigation of Candidate Genes and Mechanisms Underlying Obesity Associated Type 2 Diabetes Mellitus Using Bioinformatics Analysis and Screening of Small Drug Molecules 

“…KCNE5 [45], SHANK3 [46], CASQ2 [47], EDNRA (endothelin receptor type A) [48], EPHB4 [49], ALPK3 [50], WNT11 [51], IRAK2 [52], FBN1 [53], SFRP2 [54], CLCA2 [55], NEXN (nexilin F-actin binding protein) [56], PALLD (palladin, cytoskeletal associated protein) [57], DAB2 [58], NRP2 [59], THBS2 [60], CSF1R [61], KCNA2 [62], CACNA1C [63], F2R [64], UCHL1 [65], CCL18 [66], ITGB1BP2 [67] and FMOD ( bromodulin) [68] were reportedly involved in cardio vascular diseases, but these genes might be key for progression of obesity associated type 2 diabetes mellitus. Hu et al [69], Liu et al [70], Eltokhi et al [71], Cai et al [72], Pfeiffer et al [73], Lin et al [74], Royer-Zemmour et al [75], Pastor et al [76], Goodspeed et al [77], Zhang et al [78], Rogers et al [79], Su et al [80] and Foale et al [81] reported that NRXN1, CRHR1, SHANK2, PSEN2, CKB (creatine kinase B), CD200R1, SRPX2, PTPRZ1, SLC6A1, GABRB2, KCNA1, ASAH1 and LINGO1 were linked with progression of neuropsychiatric disorders, but these genes might be involved in advancement of obesity associated type 2 diabetes mellitus. Reports indicate that SPHK2 [82], NPC1L1 [83], CNTFR (ciliaryneurotrophic factor receptor)…”

Gene Transfer Therapy for Neurodevelopmental Disorders

“…The prominent epilepsy syndrome was epilepsy with myoclonic-atonic seizure (24%), and many patients also had absence or atypical absence seizure (72%). On EEG, many patients have generalized epileptiform discharges, notably in the frequency of 3 Hz, as well as generalized background slowing [118, 119].…”

“…It was first described in 2015 among a cohort of patients with Doose syndrome [116], but the phenotype continues to expand as more patients are identified [117]. A recent compilation of 116 patients with SRD identified the core features of the disorder to include epilepsy (91%), developmental delay or cognitive impairment (82%), and autistic traits (23%) [118]. The prominent epilepsy syndrome was epilepsy with myoclonic-atonic seizure (24%), and many patients also had absence or atypical absence seizure (72%).…”