A role forTENM1mutations in congenital general anosmia

Abstract

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.

Isolated Congenital Anosmia and CNGA2 Mutation

“…Rarely, however, it can occur as a congenital condition (prevalence 1 in 10,000) 21 (Isolated Congenital Anosmia) (Online Mendelian Inheritance in Man [OMIM] % 107200). Few candidate genes have been identified as potential causal genes for ICA in humans 3, 6, 11–13, 22 . For instance, Karstensen et al .…”

“…Also, Alkelai et al . 6 reported a family with congenital general anosmia segregating an X-linked missense mutation in the TENM1 gene 6 . In the present study, we employed whole-exome sequencing to identify the underlying genetic variants associated with ICA in a large Iranian family (five affected and five un-affected family members).…”

“…Unlike syndromic forms of anosmia, ICA patients have no additional symptoms, and no other underlying disease-causing condition can be identified 1 . ICA usually occurs sporadically, although some familial cases have previously been reported 1–6 . While several causal genes have been identified for syndromic cases of anosmia (such as Kallmann syndrome and Bardet-Biedl syndrome) 7–9 , the underlying genetic architecture of ICA is barely known.…”

“…first reported ICA as a potentially hereditary trait nearly 100 years ago 10 , there have been few candidate genes identified as the potential genetic cause for ICA 3, 6, 11–13 . Moreover, most reported anosmia cases are inherited through autosomal dominant patterns 2, 14 , however, in some instances, it is an X-linked trait 3, 6, 10 . For instance, In 2015, Karstensen et al .…”

“…Also, Alkelai et al . 6 reported a family with congenital general anosmia segregating an X-linked missense mutation in the TENM1 gene 6 . Together, these studies indicate that ICA is very heterogeneous and that rare pathogenic variants in multiple genes may contribute to the phenotype.…”