Alkelai A, Olender T, Haffner-Krausz R, Tsoory M M, Boyko V, Tatarskyy P, Gross-Isseroff R, Milgrom R, Shushan S, Blau I, Cohn E, Beeri R, Levy-Lahad E, Pras E, Lancet D
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel.
Clin Genet. 2016 Sep;90(3):211-9. doi: 10.1111/cge.12782. Epub 2016 May 31.
Congenital general anosmia (CGA) is a neurological disorder entailing a complete innate inability to sense odors. While the mechanisms underlying vertebrate olfaction have been studied in detail, there are still gaps in our understanding of the molecular genetic basis of innate olfactory disorders. Applying whole-exome sequencing to a family multiply affected with CGA, we identified three members with a rare X-linked missense mutation in the TENM1 (teneurin 1) gene (ENST00000422452:c.C4829T). In Drosophila melanogaster, TENM1 functions in synaptic-partner-matching between axons of olfactory sensory neurons and target projection neurons and is involved in synapse organization in the olfactory system. We used CRISPR-Cas9 system to generate a Tenm1 disrupted mouse model. Tenm1(-/-) and point-mutated Tenm1(A) (/A) adult mice were shown to have an altered ability to locate a buried food pellet. Tenm1(A) (/A) mice also displayed an altered ability to sense aversive odors. Results of our study, that describes a new Tenm1 mouse, agree with the hypothesis that TENM1 has a role in olfaction. However, additional studies should be done in larger CGA cohorts, to provide statistical evidence that loss-of-function mutations in TENM1 can solely cause the disease in our and other CGA cases.
先天性全嗅觉缺失（CGA）是一种神经障碍，表现为完全先天性无法感知气味。虽然脊椎动物嗅觉的潜在机制已得到详细研究，但我们对先天性嗅觉障碍的分子遗传基础的理解仍存在差距。对一个多名成员患CGA的家族应用全外显子组测序，我们在TENM1（腱蛋白1）基因（ENST00000422452:c.C4829T）中鉴定出三名成员存在罕见的X连锁错义突变。在果蝇中，TENM1在嗅觉感觉神经元轴突与靶投射神经元之间的突触伙伴匹配中发挥作用，并参与嗅觉系统中的突触组织。我们使用CRISPR-Cas9系统构建了一个Tenm1基因敲除小鼠模型。Tenm1（-/-）和点突变的Tenm1（A）/（A）成年小鼠在定位埋藏食物颗粒的能力上表现出改变。Tenm1（A）/（A）小鼠在感知厌恶气味的能力上也表现出改变。我们描述新的Tenm1小鼠的研究结果与TENM1在嗅觉中起作用的假设一致。然而，应在更大的CGA队列中进行进一步研究，以提供统计证据证明TENM1功能丧失突变在我们的和其他CGA病例中可单独导致该疾病。
