Mutations in olfactory signal transduction genes are not a major cause of human congenital general anosmia
Mutations in olfactory signal transduction genes are not a major cause of human congenital general anosmia
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DOI：
10.1093/chemse/bjl032
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发表时间：
2007-01-01
期刊：
影响因子：
3.5
通讯作者：
Lancet, Doron
中科院分区：
文献类型：
--
作者：
Feldmesser, Ester;Bercovich, Dani;Lancet, Doron
嗅觉缺失症影响西方世界的人口，主要是老年人，在45岁以上的受试者中达到5%，严重降低了他们的生活质量。少数人（约0.01%）天生没有嗅觉，患有先天性一般性嗅觉缺失（CGA）。目前还没有发现人类CGA的致病基因，除了一些综合征病例，如Kallman综合征。然而，在小鼠中，3种主要嗅觉转导成分（胍三磷酸结合蛋白、腺苷酸环化酶和环腺苷单磷酸门控通道）中的任何一种缺失都会导致对气味的生理反应大幅降低。为了鉴定人类cga相关突变，我们对受影响的家族进行了全基因组连锁分析，但没有观察到显著的连锁信号，可能是由于分析的家族规模较小。我们进一步对64个无亲缘关系嗅觉缺失个体的3个主要嗅觉转导基因进行了直接突变筛选。没有发现潜在的致病突变，这表明人类CGA的转导基因变异很少，其他基因的突变必须确定。筛选的基因被发现处于纯化选择下，这表明它们不仅在嗅觉中发挥重要的功能作用，而且可能在其他途径中发挥重要作用。
Anosmia affects the western world population, mostly the elderly, reaching to 5% in subjects over the age of 45 years and strongly lowering their quality of life. A smaller minority (about 0.01%) is born without a sense of smell, afflicted with congenital general anosmia (CGA). No causative genes for human CGA have been identified yet, except for some syndromic cases such as Kallman syndrome. In mice, however, deletion of any of the 3 main olfactory transduction components (guanidine triphosphate binding protein, adenylyl cyclase, and the cyclic adenosine monophosphate-gated channel) causes profound reduction of physiological responses to odorants. In an attempt to identify human CGA-related mutations, we performed whole-genome linkage analysis in affected families, but no significant linkage signals were observed, probably due to the small size of families analyzed. We further carried out direct mutation screening in the 3 main olfactory transduction genes in 64 unrelated anosmic individuals. No potentially causative mutations were identified, indicating that transduction gene variations underlie human CGA rarely and that mutations in other genes have to be identified. The screened genes were found to be under purifying selection, suggesting that they play a crucial functional role not only in olfaction but also potentially in additional pathways.