Tenm3, also known as ODZ3, is a gene encoding the teneurin transmembrane protein 3. Teneurins are cell adhesion receptors involved in brain development, neuronal wiring, and the formation of trans-synaptic complexes with latrophilins [6,8]. They play a crucial role in processes such as hippocampal circuit assembly and cortical neuron migration [6,8].

In neuroblastoma, a translocation between chromosome 2p and 4q can form an in-frame fusion gene of TENM3 and ALK. The TENM3-ALK fusion protein has constitutive tyrosine kinase activity, activates downstream targets like ERK, AKT, and STAT3, causes oncogenic transformation in mice, and is sensitive to ALK inhibitors. This discovery provides new insights into ALK activation mechanism and is a potential therapeutic target and diagnostic marker for neuroblastoma [1]. Mutations in TENM3 are also associated with various eye anomalies. A novel homozygous c.5069-1G>C variation was found in an Iranian patient with colobomatous microphthalmia [2]. Siblings with motor developmental delay, ocular coloboma, and oval cornea had a novel truncating mutation in TENM3 [3]. Patients with eye anomalies and intellectual disability had pathogenic variations in TENM3, expanding the phenotypic spectrum associated with this gene [4]. Two new cases with biallelic variants in TENM3 further widened the molecular and clinical spectrum, with one patient presenting with microcephaly potentially expanding the neurologic phenotype [5]. A Chinese patient with microcornea, iris and choroidal coloboma, and global developmental delay had compound mutations in TENM3 [7].

In conclusion, Tenm3 is essential for brain development, neuronal wiring, and eye development. Studies on TENM3-related fusion genes in neuroblastoma and TENM3 mutations in eye-related disorders have enhanced our understanding of the role of Tenm3 in disease. These findings from various patient-based studies contribute to the knowledge of Tenm3's function in specific disease conditions, highlighting its importance as a potential target for disease diagnosis and treatment in these areas.

References:

1. Hiwatari, Mitsuteru, Seki, Masafumi, Matsuno, Ryosuke, Ogawa, Seishi, Takita, Junko. 2022. Novel TENM3-ALK fusion is an alternate mechanism for ALK activation in neuroblastoma. In Oncogene, 41, 2789-2797. doi:10.1038/s41388-022-02301-1. https://pubmed.ncbi.nlm.nih.gov/35411036/

2. Gholami Yarahmadi, Sepideh, Sarlaki, Fatemeh, Morovvati, Saeid. 2022. Novel mutation in TENM3 gene in an Iranian patient with colobomatous microphthalmia. In Clinical case reports, 10, e05532. doi:10.1002/ccr3.5532. https://pubmed.ncbi.nlm.nih.gov/35280100/

3. Stephen, Joshi, Nampoothiri, Sheela, Kuppa, Srikar, Gahl, William A, Malicdan, May Christine V. 2018. Novel truncating mutation in TENM3 in siblings with motor developmental delay, ocular coloboma, oval cornea, without microphthalmia. In American journal of medical genetics. Part A, 176, 2930-2933. doi:10.1002/ajmg.a.40658. https://pubmed.ncbi.nlm.nih.gov/30513139/

4. Singh, Bharti, Srivastava, Priyanka, Phadke, Shubha R. 2018. Sequence variations in TENM3 gene causing eye anomalies with intellectual disability: Expanding the phenotypic spectrum. In European journal of medical genetics, 62, 61-64. doi:10.1016/j.ejmg.2018.05.004. https://pubmed.ncbi.nlm.nih.gov/29753094/

5. Lu, Fen, Xu, Xin, Zheng, Bixia, Tang, Jian, Zhao, Xiaoke. 2023. Case report: Expansion of phenotypic and genotypic data in TENM3-related syndrome: Report of two cases. In Frontiers in pediatrics, 11, 1111771. doi:10.3389/fped.2023.1111771. https://pubmed.ncbi.nlm.nih.gov/36911040/

6. Liakath-Ali, Kif, Refaee, Rebecca, Südhof, Thomas C. 2024. Cartography of teneurin and latrophilin expression reveals spatiotemporal axis heterogeneity in the mouse hippocampus during development. In PLoS biology, 22, e3002599. doi:10.1371/journal.pbio.3002599. https://pubmed.ncbi.nlm.nih.gov/38713721/

7. Zhou, Youfeng, Xu, Ke, Gu, Weiyue, Huang, Yan. 2022. Microcornea, iris and choroidal coloboma, and global developmental delay caused by TENM3 pathogenic variants in a Chinese patient. In Molecular genetics & genomic medicine, 10, e1948. doi:10.1002/mgg3.1948. https://pubmed.ncbi.nlm.nih.gov/35397152/

8. Del Toro, Daniel, Carrasquero-Ordaz, Maria A, Chu, Amy, Klein, Rüdiger, Seiradake, Elena. 2020. Structural Basis of Teneurin-Latrophilin Interaction in Repulsive Guidance of Migrating Neurons. In Cell, 180, 323-339.e19. doi:10.1016/j.cell.2019.12.014. https://pubmed.ncbi.nlm.nih.gov/31928845/