Infrequent SCN9A mutations in congenital insensitivity to pain and erythromelalgia.
Infrequent SCN9A mutations in congenital insensitivity to pain and erythromelalgia.
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先天性对疼痛和红细胞毛的不敏感性中的SCN9A突变很少发生。
DOI：
10.1136/jnnp-2012-303719
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发表时间：
2013-04
期刊：
影响因子：
--
通讯作者：
Dyck PJ
中科院分区：
文献类型：
--
作者：
Klein CJ;Wu Y;Kilfoyle DH;Sandroni P;Davis MD;Gavrilova RH;Low PA;Dyck PJ
已报道的SCN9A突变有：(1)先天性疼痛不敏感(CIP)；(2)原发性红斑痛；(3)阵发性极度疼痛障碍；(4)热性惊厥和最近的(5)小纤维感觉神经病。我们试图在一组临床特征良好的CIP和红斑性肢痛症患者中调查SCN9A突变。我们对19例临床研究良好的病例进行了SCN9A的全部外显子测序，其中包括6例CIP和13例红斑性肢痛症(9例有家族史，10例有小纤维神经病)。在数据库SNP135、1K基因组、NHLBI-Exome测序计划(5400-exome)数据库和768条正常染色体中对识别出的突变体进行了评估。在红斑性肢痛症7例中，我们发现了一种新的Q10>；K突变。在CIP病例6中，我们发现了一个新的新的剪接突变(IVS8-2A>；G)；该剪接突变与一个无义突变(R523>；X)复合，与他未受影响的父亲相比，几乎完全取消了SCN9A的mRNA表达。在CIP病例5中，我们发现了一个变异(P610>；T)，以前被认为是红斑性肢痛症的原因，支持最近提出的对其因果性质的怀疑。我们还在所有19名患者中发现了一个剪接连接变异(IVS24-7delGTTT)，这种剪接变异以前被认为是CIP的偶然变量，但实际上IVS24-7delGTTT是高加索人群中的主要等位基因。已鉴定出两个新的SCN9A突变，但经常发现可能在疼痛调制中提供易感因素的多态变异。CIP和红斑性肢痛症被定义为遗传异质性，一些以前被认为是原因的SCN9A变异可能只是修饰因素。
Mutations in SCN9A have been reported in (1) congenital insensitivity to pain (CIP); (2) primary erythromelalgia; (3) paroxysmal extreme pain disorder; (4) febrile seizures and recently (5) small fibre sensory neuropathy. We sought to investigate for SCN9A mutations in a clinically well-characterised cohort of patients with CIP and erythromelalgia. We sequenced all exons of SCN9A in 19 clinically well-studied cases including 6 CIP and 13 erythromelalgia (9 with family history, 10 with small-fibre neuropathy). The identified variants were assessed in dbSNP135, 1K genome, NHLBI-Exome Sequencing Project (5400-exomes) databases, and 768 normal chromosomes. In erythromelalgia case 7, we identified a novel Q10>K mutation. In CIP case 6, we identified a novel, de novo splicing mutation (IVS8-2A>G); this splicing mutation compounded with a nonsense mutation (R523>X) and abolished SCN9A mRNA expression almost completely compared with his unaffected father. In CIP case 5, we found a variant (P610>T) previously considered causal for erythromelalgia, supporting recently raised doubt on its causal nature. We also found a splicing junction variant (IVS24-7delGTTT) in all 19 patients, this splicing variant was previously considered casual for CIP, but IVS24-7delGTTT was in fact the major allele in Caucasian populations. Two novel SCN9A mutations were identified, but frequently polymorphism variants are found which may provide susceptibility factors in pain modulation. CIP and erythromelalgia are defined as genetically heterogeneous, and some SCN9A variants previously considered causal may only be modifying factors.
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