Erythromelalgia caused by the missense mutation p.Arg220Pro in an alternatively spliced exon of SCN9A (NaV1.7).

Autor:	Deuis JR; Institute for Molecular Bioscience, 306 Carmody Road, The University of Queensland, St Lucia, QLD 4072, Australia., Kumble S; Murdoch Children's Research Institute, 50 Flemington Road, Royal Children's Hospital, Parkville, VIC 3052, Australia.; Department of Paediatrics, The University of Melbourne, 50 Flemington Road, Parkville, VIC 3052, Australia., Keramidas A; Institute for Molecular Bioscience, 306 Carmody Road, The University of Queensland, St Lucia, QLD 4072, Australia., Ragnarsson L; Institute for Molecular Bioscience, 306 Carmody Road, The University of Queensland, St Lucia, QLD 4072, Australia., Simons C; Murdoch Children's Research Institute, 50 Flemington Road, Royal Children's Hospital, Parkville, VIC 3052, Australia., Pais L; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, United States., White SM; Department of Paediatrics, The University of Melbourne, 50 Flemington Road, Parkville, VIC 3052, Australia.; Victorian Clinical Genetics Services, Royal Children's Hospital, 50 Flemington Road, Parkville, VIC 3052, Australia., Vetter I; Institute for Molecular Bioscience, 306 Carmody Road, The University of Queensland, St Lucia, QLD 4072, Australia.; School of Pharmacy, 20 Cornwall Street, The University of Queensland, Woolloongabba, QLD 4102, Australia.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2024 Jan 07; Vol. 33 (2), pp. 103-109.
DOI:	10.1093/hmg/ddad152
Abstrakt:	Erythromelalgia (EM), is a familial pain syndrome characterized by episodic 'burning' pain, warmth, and erythema. EM is caused by monoallelic variants in SCN9A, which encodes the voltage-gated sodium channel (NaV) NaV1.7. Over 25 different SCN9A mutations attributed to EM have been described to date, all identified in the SCN9A transcript utilizing exon 6N. Here we report a novel SCN9A missense variant identified in seven related individuals with stereotypic episodes of bilateral lower limb pain presenting in childhood. The variant, XM_011511617.3:c.659G>C;p.(Arg220Pro), resides in the exon 6A of SCN9A, an exon previously shown to be selectively incorporated by developmentally regulated alternative splicing. The mutation is located in the voltage-sensing S4 segment of domain I, which is important for regulating channel activation. Functional analysis showed the p.Arg220Pro mutation altered voltage-dependent activation and delayed channel inactivation, consistent with a NaV1.7 gain-of-function molecular phenotype. These results demonstrate that alternatively spliced isoforms of SCN9A should be included in all genomic testing of EM. (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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