title: A role for TENM1 mutations 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.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Alkelai
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Olender
authors.affiliation: Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Haffner-Krausz
authors.affiliation: Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: M M
authors.initials: MM
authors.lastname: Tsoory
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: V
authors.initials: V
authors.lastname: Boyko
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: P
authors.initials: P
authors.lastname: Tatarskyy
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Gross-Isseroff
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Milgrom
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.|Department of Otolaryngology-Head and Neck Surgery, Edith Wolfson Medical Center, Holon, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Shushan
authors.affiliation: Department of Otolaryngology, Meir Medical Center, Kfar Saba, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Blau
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Cohn
authors.affiliation: Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Beeri
authors.affiliation: Department of Otolaryngology, Meir Medical Center, Kfar Saba, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Levy-Lahad
authors.affiliation: The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel.|The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Pras
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Lancet
mesh_terms: D000328:Adult; D000818:Animals; D064113:CRISPR-Cas Systems; D004195:Disease Models, Animal; D059472:Exome / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D000857:Olfaction Disorders / Q000151:congenital* / Q000235:genetics / Q000503:physiopathology; D010375:Pedigree; D012903:Smell / Q000235:genetics*; D019063:Tenascin / Q000235:genetics*
chemical_list: D009419:Nerve Tissue Proteins; D019063:Tenascin; C120530:teneurin-1
keywords: CGA; CRISPR-Cas9 system; ODZ1; TENM1; Teneurin; congenital general anosmia; olfaction