Institute for Molecular Bioscience, 306 Carmody Road, The University of Queensland, St Lucia, QLD 4072, Australia.
Murdoch Children's Research Institute, 50 Flemington Road, Royal Children's Hospital, Parkville, VIC 3052, Australia.
Hum Mol Genet. 2024 Jan 7;33(2):103-109. doi: 10.1093/hmg/ddad152.
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.
红细胞增多性疼痛症（EM），是一种以阵发性“灼烧”样疼痛、发热和红斑为特征的家族性疼痛综合征。EM 是由 SCN9A 单等位基因变异引起的，该基因编码电压门控钠离子通道（NaV）NaV1.7。迄今为止，已经描述了超过 25 种不同的 SCN9A 突变与 EM 有关，所有这些突变都是在利用外显子 6N 的 SCN9A 转录本中发现的。在这里，我们报告了一种新的 SCN9A 错义突变，该突变在七个具有刻板双侧下肢疼痛发作的相关个体中被发现，这些疼痛发作发生在儿童时期。该变体，XM_011511617.3：c.659G>C；p.（Arg220Pro），位于 SCN9A 的外显子 6A 中，该外显子先前被证明可通过发育调节的选择性剪接选择性地包含。该突变位于域 I 的电压感应 S4 段中，该段对于调节通道激活非常重要。功能分析表明，p.Arg220Pro 突变改变了电压依赖性激活并延迟了通道失活，与 NaV1.7 功能获得分子表型一致。这些结果表明，在 EM 的所有基因组测试中都应包括 SCN9A 的选择性剪接异构体。
