Further corroboration of distinct functional features in SCN2A variants causing intellectual disability or epileptic phenotypes

Molecular Medicine

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[1] 0000 0001 0726 4330, grid.412341.1, Division of Child Neurology, University Children’s Hospital Zurich, 8032, Zurich, Switzerland;0000 0001 2107 3311, grid.5330.5, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany;0000 0001 2235 3868, grid.419749.6, Children’s department, Swiss Epilepsy Centre, Clinic Lengg, 8008, Zurich, Switzerland;0000 0004 0472 0371, grid.277151.7, Service de génétique médicale, CHU Nantes, 44093, Nantes, France;0000 0004 0618 9684, grid.419174.e, National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, 420-8688, Shizuoka, Japan;0000 0004 1937 0650, grid.7400.3, Institute of Medical Genetics, University of Zurich, 8952, Schlieren, Zurich, Switzerland;0000 0004 1937 0650, grid.7400.3, Institute of Medical Genetics, University of Zurich, 8952, Schlieren, Zurich, Switzerland;0000 0004 1937 0650, grid.7400.3, radiz—Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases, University of Zurich, 8006, Zurich, Switzerland;0000 0004 1937 0650, grid.7400.3, Institute of Medical Genetics, University of Zurich, 8952, Schlieren, Zurich, Switzerland;0000 0004 1937 0650, grid.7400.3, radiz—Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases, University of Zurich, 8006, Zurich, Switzerland;0000 0004 1937 0650, grid.7400.3, Neuroscience Center Zurich, University of Zurich and ETH Zurich, 8057, Zurich, Switzerland;0000 0004 1937 0650, grid.7400.3, Zurich Center for Integrative Human Physiology, University of Zurich, 8057, Zurich, Switzerland;0000 0004 1937 0650, grid.7400.3, radiz—Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases, University of Zurich, 8006, Zurich, Switzerland;0000 0001 0726 4330, grid.412341.1, Division of Child Neurology, University Children’s Hospital Zurich, 8032, Zurich, Switzerland;0000 0004 1937 0650, grid.7400.3, radiz—Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases, University of Zurich, 8006, Zurich, Switzerland;0000 0001 0726 4330, grid.412341.1, Division of Child Neurology, University Children’s Hospital Zurich, 8032, Zurich, Switzerland;0000 0000 8988 2476, grid.11598.34, Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, 8036, Graz, Austria;0000 0004 1937 0650, grid.7400.3, radiz—Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases, University of Zurich, 8006, Zurich, Switzerland;0000 0004 1937 0650, grid.7400.3, Institute of Pharmacology and Toxicology, University of Zurich, 8057, Zurich, Switzerland;0000 0004 1937 0650, grid.7400.3, radiz—Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases, University of Zurich, 8006, Zurich, Switzerland;0000 0004 1937 0650, grid.7400.3, Institute of Pharmacology and Toxicology, University of Zurich, 8057, Zurich, Switzerland;0000 0001 2156 2780, grid.5801.c, Institute of Pharmaceutical Sciences, ETH Zurich, 8093, Zürich, Switzerland;0000 0004 1937 0650, grid.7400.3, Neuroscience Center Zurich, University of Zurich and ETH Zurich, 8057, Zurich, Switzerland;grid.474690.8, Laboratory for Neurogenetics, RIKEN Center for Brain Science, Wako-shi, 351-0198, Saitama, Japan;

关键词: SCN2A;    Nav1.2;    Channelopathy;    Patch-clamp;    Epilepsy;    Epileptic encephalopathy;    Intellectual disability;    Structural modelling;    Electrophysiology;   

DOI  :  10.1186/s10020-019-0073-6

来源: publisher

【 摘 要 】

BackgroundDeleterious variants in the voltage-gated sodium channel type 2 (Nav1.2) lead to a broad spectrum of phenotypes ranging from benign familial neonatal-infantile epilepsy (BFNIE), severe developmental and epileptic encephalopathy (DEE) and intellectual disability (ID) to autism spectrum disorders (ASD). Yet, the underlying mechanisms are still incompletely understood.MethodsTo further elucidate the genotype-phenotype correlation of SCN2A variants we investigated the functional effects of six variants representing the phenotypic spectrum by whole-cell patch-clamp studies in transfected HEK293T cells and in-silico structural modeling.ResultsThe two variants p.L1342P and p.E1803G detected in patients with early onset epileptic encephalopathy (EE) showed profound and complex changes in channel gating, whereas the BFNIE variant p.L1563V exhibited only a small gain of channel function. The three variants identified in ID patients without seizures, p.R937C, p.L611Vfs*35 and p.W1716*, did not produce measurable currents. Homology modeling of the missense variants predicted structural impairments consistent with the electrophysiological findings.ConclusionsOur findings support the hypothesis that complete loss-of-function variants lead to ID without seizures, small gain-of-function variants cause BFNIE and EE variants exhibit variable but profound Nav1.2 gating changes. Moreover, structural modeling was able to predict the severity of the variant impact, supporting a potential role of structural modeling as a prognostic tool. Our study on the functional consequences of SCN2A variants causing the distinct phenotypes of EE, BFNIE and ID contributes to the elucidation of mechanisms underlying the broad phenotypic variability reported for SCN2A variants.

【 授权许可】

CC BY