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Clinical comparison and functional study of the L703P: a recurrent mutation in human SCN4A that causes sodium channel myotonia

Published:August 16, 2022DOI:https://doi.org/10.1016/j.nmd.2022.08.004

      Highlights

      • We identified a SCN4A mutation (p.L703P) in a Chinese family with non-dystrophic myotonias (NDM).
      • Characterization of mutant channel revealed both gain-of-function and loss-of-function changes in gating properties.
      • Literature search results in two independent case reports of NDM patients carrying L703P mutation in Nav1.4 channels.
      • The L703P is a recurrent mutation associated with NDM.

      Abstract

      The non-dystrophic myotonias are inherited skeletal muscle disorders characterized by skeletal muscle stiffness after voluntary contraction, without muscle atrophy. Based on their clinical features, non-dystrophic myotonias are classified into myotonia congenita, paramyotonia congenita, and sodium channel myotonia. Using whole-exome next-generation sequencing, we identified a L703P mutation (c.2108T>C, p.L703P) in SCN4A in a Chinese family diagnosed with non-dystrophic myotonias. The clinical findings of patients in this family included muscle stiffness and hypertrophy. The biophysical properties of wildtype and mutant channels were investigated using whole-cell patch clamp. L703P causes both gain-of-function and loss-of-function changes in Nav1.4 properties, including decreased current density, impaired recovery, enhanced activation and slow inactivation. Our study demonstrates that L703P is a pathogenic variant for myotonia, and provides additional electrophysiological information for understanding the pathogenic mechanism of SCN4A-associated channelopathies.

      Keywords

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      References

        • Desaphy J.F.
        • Altamura C.
        • Vicart S.
        • Fontaine B.
        Targeted therapies for skeletal muscle ion channelopathies: systematic review and steps towards precision medicine.
        J Neuromuscul. 2021; 8: 357-381https://doi.org/10.3233/JND-200582
        • Morales F.
        • Pusch M.
        An up-to-date overview of the complexity of genotype-phenotype relationships in myotonic channelopathies.
        Front Neurol. 2020; 10: 1404https://doi.org/10.3389/fneur.2019.01404
        • Horga A.
        • Raja Rayan D.L.
        • Matthews E.
        • Sud R.
        • Fialho D.
        • Durran S.C.
        • et al.
        Prevalence study of genetically defined skeletal muscle channelopathies in England.
        Neurology. 2013; 80: 1472-1475https://doi.org/10.1212/WNL.0b013e31828cf8d0
        • Matthews E.
        • Holmes S.
        • Fialho D.
        Skeletal muscle channelopathies: a guide to diagnosis and management.
        Pract Neurol. 2021; 21: 196-204https://doi.org/10.1136/practneurol-2020-002576
        • Cannon S.C.
        Sodium channelopathies of skeletal muscle.
        Handb Exp Pharmacol. 2018; 246: 309-330https://doi.org/10.1007/164_2017_52
        • Grundy D.
        Principles and standards for reporting animal experiments in the Journal of Physiology and Experimental Physiology.
        J. Physiol. (Lond.). 2015; 593: 2547-2549https://doi.org/10.1113/JP270818
        • Fournier E.
        • Arzel M.
        • Sternberg D.
        • Vicart S.
        • Laforet P.
        • Eymard B.
        • et al.
        Electromyography guides toward subgroups of mutations in muscle channelopathies.
        Ann Neurol. 2004; 56: 650-661https://doi.org/10.1002/ana.20241
        • Fournier E.
        • Viala K.
        • Gervais H.
        • Sternberg D.
        • Arzel-Hezode M.
        • Laforet P.
        • et al.
        Cold extends electromyography distinction between ion channel mutations causing myotonia.
        Ann Neurol. 2006; 60: 356-365https://doi.org/10.1002/ana.20905
        • Richards S.
        • Aziz N.
        • Bale S.
        • Bick D.
        • Das S.
        • Gastier-Foster J.
        • et al.
        Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
        Genet Med. 2015; 17: 405-424https://doi.org/10.1038/gim.2015.30
        • Ke Q.
        • Ye J.
        • Tang S.
        • Wang J.
        • Luo B.
        • Ji F.
        • et al.
        N1366S mutation of human skeletal muscle sodium channel causes paramyotonia congenita.
        J. Physiol. (Lond.). 2017; 595: 6837-6850https://doi.org/10.1113/JP274877
        • Li Y.
        • Zhu T.
        • Yang H.
        • Dib-Hajj S.D.
        • Waxman S.G.
        • Yu Y.
        • et al.
        Nav1.7 is phosphorylated by Fyn tyrosine kinase which modulates channel expression and gating in a cell type-dependent manner.
        Mol Pain. 2018; 141744806918782229https://doi.org/10.1177/1744806918782229
        • Markhorst J.M.
        • Stunnenberg B.C.
        • Ginjaar I.B.
        • Drost G.
        • Erasmus C.E.
        • Sie L.T.
        Clinical experience with long-term acetazolamide treatment in children with nondystrophic myotonias: a three-case report.
        Pediatr Neurol. 2014; 51: 537-541https://doi.org/10.1016/j.pediatrneurol
        • Orstavik K.
        • Wallace S.C.
        • Torbergsen T.
        • Abicht A.
        • Erik Tangsrud S.
        • Kerty E.
        • et al.
        A de novo mutation in the SCN4A gene causing sodium channel myotonia.
        J Neuromuscul Dis. 2015; 2: 181-184https://doi.org/10.3233/JND-150069
        • Farinato A.
        • Altamura C.
        • Imbrici P.
        • Maggi L.
        • Bernasconi P.
        • Mantegazza R.
        • et al.
        Pharmacogenetics of myotonic hNav1.4 sodium channel variants situated near the fast inactivation gate.
        Pharmacol Res. 2019; 141: 224-235https://doi.org/10.1016/j.phrs.2019.01.004
        • Wagnon J.L.
        • Meisler M.H.
        Recurrent and non-recurrent mutations of SCN8A in epileptic encephalopathy.
        Front Neurol. 2015; 6: 104https://doi.org/10.3389/fneur.2015.00104
        • Catterall W.A.
        • Goldin A.L.
        • Waxman S.G.
        International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels.
        Pharmacol Rev. 2005; 57: 397-409https://doi.org/10.1124/pr.57.4.4
        • Pan X.
        • Li Z.
        • Zhou Q.
        • Shen H.
        • Wu K.
        • Huang X.
        • et al.
        Structure of the human voltage-gated sodium channel Nav1.4 in complex with beta1.
        Science. 2018; 362: eaau2486https://doi.org/10.1126/science.aau2486
        • Beam K.G.
        • Caldwell J.H.
        • Campbell D.T.
        Na channels in skeletal muscle concentrated near the neuromuscular junction.
        Nature. 1985; 313: 588-590https://doi.org/10.1038/313588a0
        • Sampaio F.
        • Soares S.
        • Pereira S.
        • Lemos J.A.
        • Mota A.
        Sodium channel myotonia and a novel Gly701Asp mutation in the SCN4A gene: from an ophthalmological symptom to a familial disease.
        Neuroophthalmology. 2020; 45: 41-44https://doi.org/10.1080/01658107.2020.1779316
        • Brancati F.
        • Valente E.M.
        • Davies N.P.
        • Sarkozy A.
        • Sweeney M.G.
        • LoMonaco M.
        • et al.
        Severe infantile hyperkalaemic periodic paralysis and paramyotonia congenita: broadening the clinical spectrum associated with the T704M mutation in SCN4A.
        J Neurol Neurosurg Psychiatry. 2003; 74: 1339-1341https://doi.org/10.1136/jnnp.74.9.1339
        • Kim J.
        • Hahn Y.
        • Sohn E.H.
        • Lee Y.J.
        • Yun J.H.
        • Kim J.M.
        • et al.
        Phenotypic variation of a Thr704Met mutation in skeletal sodium channel gene in a family with paralysis periodica paramyotonica.
        J Neurol Neurosurg Psychiatry. 2001; 70: 618-623https://doi.org/10.1136/jnnp.70.5.618
        • Bendahhou S.
        • Cummins T.R.
        • Tawil R.
        • Waxman S.G.
        • Ptacek L.J.
        Activation and inactivation of the voltage-gated sodium channel: role of segment S5 revealed by a novel hyperkalaemic periodic paralysis mutation.
        J Neurosci. 1999; 19: 4762-4771https://doi.org/10.1523/JNEUROSCI.19-12-04762.1999
        • Zaharieva I.T.
        • Thor M.G.
        • Oates E.C.
        • van Karnebeek C.
        • Hendson G.
        • Blom E.
        • et al.
        Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy.
        Brain. 2016; 139: 674-691https://doi.org/10.1093/brain/awv352
        • Arnold W.D.
        • Feldman D.H.
        • Ramirez S.
        • He L.
        • Kassar D.
        • Quick A.
        • et al.
        Defective fast inactivation recovery of Nav 1.4 in congenital myasthenic syndrome.
        Ann Neurol. 2015; 77: 840-850https://doi.org/10.1002/ana.24389
        • Habbout K.
        • Poulin H.
        • Rivier F.
        • Giuliano S.
        • Sternberg D.
        • Fontaine B.
        • et al.
        A recessive Nav1.4 mutation underlies congenital myasthenic syndrome with periodic paralysis.
        Neurology. 2016; 86: 161-169https://doi.org/10.1212/WNL.0000000000002264
        • Cannon S.C.
        When all is lost...a severe myopathy with hypotonia from sodium channel mutations.
        Brain. 2016; 139: 642-644https://doi.org/10.1093/brain/awv400
        • Novak K.R.
        • Norman J.
        • Mitchell J.R.
        • Pinter M.J.
        • Rich M.M.
        Sodium channel slow inactivation as a therapeutic target for myotonia congenita.
        Ann Neurol. 2015; 77: 320-332https://doi.org/10.1002/ana.24331
        • Takahashi M.P.
        • Cannon S.C.
        Enhanced slow inactivation by V445M: a sodium channel mutation associated with myotonia.
        Biophys J. 1999; 76: 861-868https://doi.org/10.1016/S0006-3495(99)77249-8
        • Webb J.
        • Wu F.F.
        • Cannon S.C.
        Slow inactivation of the NaV1.4 sodium channel in mammalian cells is impeded by co-expression of the beta1 subunit.
        Pflugers Arch. 2009; 457: 1253-1263https://doi.org/10.1007/s00424-008-0600-8
        • Lee S.C.
        • Kim H.S.
        • Park Y.E.
        • Choi Y.C.
        • Park K.H.
        • Kim D.S.
        Clinical diversity of SCN4A-mutation-associated skeletal muscle sodium channelopathy.
        J Clin Neurol. 2009; 5: 186-191https://doi.org/10.3988/jcn.2009.5.4.186