A stop codon mutation in SCN9A causes lack of pain sensation
A stop codon mutation in SCN9A causes lack of pain sensation
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DOI：
10.1093/hmg/ddm160
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发表时间：
2007-09-01
影响因子：
3.5
通讯作者：
Krupp, Johannes J.
中科院分区：
文献类型：
--
作者：
Ahmad, Sultan;Dahllund, Leif;Krupp, Johannes J.
人类普遍缺乏疼痛体验是一种罕见的情况，这种表型的分子原因尚不清楚。在这里，我们研究了一个来自纽芬兰的加拿大家庭，其成员表现出先天无法体验疼痛的能力。我们已将该基因定位于染色体2q(2q24.3-2q31.1)上的13.7Mb区域。对该区域候选基因的筛选发现了编码电压门控钠通道Na(V)1.7的SCN9A蛋白截短突变。该突变是984位核苷酸的C-A颠换，将酪氨酸328的密码子转换为终止密码子。预测的产物缺少Na(V)1.7的所有成孔区。事实上，在细胞系中表达这种改变的基因不会产生功能反应，也不会在ND7/23细胞中表达时对内源性电压门控钠电流产生代偿作用。因为在小鼠中，Nav1.7的纯合敲除已被证明是致命的，所以我们探索了为什么Nav1.7的缺陷对人类不是致命的。在猴子、人类、小鼠和大鼠组织中的表达研究表明，Nav1.7的表达谱存在物种差异。在啮齿类动物中，该通道在下丘脑核团中有较强的表达，而在灵长类动物中，该通道在该区域仅有微弱的mRNA表达。此外，灵长类动物的脑垂体腺和肾上腺无信号，而啮齿类动物的这两个腺体为mRNA阳性。这种物种差异可能解释了在人类身上观察到的突变的非致命性。我们的数据进一步证明，Nav1.7是人类外周伤害性感受的关键因素。
The general lack of pain experience is a rare occurrence in humans, and the molecular causes for this phenotype are not well understood. Here we have studied a Canadian family from Newfoundland with members who exhibit a congenital inability to experience pain. We have mapped the locus to a 13.7 Mb region on chromosome 2q (2q24.3-2q31.1). Screening of candidate genes in this region identified a protein-truncating mutation in SCN9A, which encodes for the voltage-gated sodium channel Na(v)1.7. The mutation is a C-A transversion at nucleotide 984 transforming the codon for tyrosine 328 to a stop codon. The predicted product lacks all pore-forming regions of Na(v)1.7. Indeed, expression of this altered gene in a cell line did not produce functional responses, nor did it cause compensatory effects on endogenous voltage-gated sodium currents when expressed in ND7/23 cells. Because a homozygous knockout of Nav1.7 in mice has been shown to be lethal, we explored why a deficiency of Nav1.7 is non-lethal in humans. Expression studies in monkey, human, mouse and rat tissue indicated species-differences in the Nav1.7 expression profile. Whereas in rodents the channel was strongly expressed in hypothalamic nuclei, only weak mRNA levels were detected in this area in primates. Furthermore, primate pituitary and adrenal glands were devoid of signal, whereas these two glands were mRNA-positive in rodents. This species difference may explain the non-lethality of the observed mutation in humans. Our data further establish Nav1.7 as a critical element of peripheral nociception in humans.