Genetic variation in a human odorant receptor alters odour perception
Genetic variation in a human odorant receptor alters odour perception
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DOI：
10.1038/nature06162
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发表时间：
2007-09-27
期刊：
影响因子：
64.8
通讯作者：
Matsunami, Hiroaki
中科院分区：
文献类型：
--
作者：
Keller, Andreas;Zhuang, Hanyi;Matsunami, Hiroaki
人类的嗅觉在个体之间有很大的差异，在给定气味的强度和愉悦度上有很大的感知差异。例如，雄烯酮（5 α-雄甾-16-烯-3-酮），一种来自睾丸激素的有气味的类固醇，不同的人会不同地认为它是令人讨厌的（“出汗，小便”），令人愉快的（“甜，花香”）或无味的（1-3）。对于其他几种气味，观察到气味感知的类似变化（4-6）。个体之间气味感知变化的机制基础是未知的。我们调查了人类气味受体基因的遗传变异是否部分解释了个体之间气味感知的变化（7，8）。在这里，我们表明，一个人的气味受体，OR 7 D4，选择性激活雄烯酮和相关的气味类固醇androstadienone（androsta-4，16-dien-3-one）在体外，并不响应64其他气味和两种溶剂的面板。这种受体的一种常见变体（OR 7 D4 WM）含有两个非同义的单核苷酸多态性（SNP），导致两个氨基酸取代（R88 W，T133 M;因此是“RT”），严重损害体外功能。具有RT/WM或WM/WM基因型的人类受试者作为一组对雄烯酮和雄甾二烯酮不太敏感，并且发现这两种气味比RT/RT组更不令人愉快。OR 7 D4的基因型变异占这些类固醇气味感知的效价（愉快或不愉快）和强度变化的显着比例。我们的研究结果表明，第一个人类气味受体在体外的功能和气味感知之间的联系。
Human olfactory perception differs enormously between individuals, with large reported perceptual variations in the intensity and pleasantness of a given odour. For instance, androstenone (5 alpha-androst-16-en-3-one), an odorous steroid derived from testosterone, is variously perceived by different individuals as offensive ("sweaty, urinous''), pleasant ("sweet, floral'') or odourless(1-3). Similar variation in odour perception has been observed for several other odours(4-6). The mechanistic basis of variation in odour perception between individuals is unknown. We investigated whether genetic variation in human odorant receptor genes accounts in part for variation in odour perception between individuals(7,8). Here we show that a human odorant receptor, OR7D4, is selectively activated in vitro by androstenone and the related odorous steroid androstadienone (androsta-4,16-dien-3-one) and does not respond to a panel of 64 other odours and two solvents. A common variant of this receptor (OR7D4 WM) contains two non-synonymous single nucleotide polymorphisms (SNPs), resulting in two amino acid substitutions (R88W, T133M; hence 'RT') that severely impair function in vitro. Human subjects with RT/WM or WM/WM genotypes as a group were less sensitive to androstenone and androstadienone and found both odours less unpleasant than the RT/RT group. Genotypic variation in OR7D4 accounts for a significant proportion of the valence (pleasantness or unpleasantness) and intensity variance in perception of these steroidal odours. Our results demonstrate the first link between the function of a human odorant receptor in vitro and odour perception.