Alternative titles; symbols
HGNC Approved Gene Symbol: CADM3
Cytogenetic location: 1q23.2 Genomic coordinates (GRCh38): 1:159,171,615-159,203,313 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q23.2 | Charcot-Marie-Tooth disease, axonal, type 2FF | 619519 | Autosomal dominant | 3 |
The CADM3 gene encodes a member of the CADM family of cell-cell adhesion molecules. CADM3 is expressed in axons, where it interacts primarily with CADM4 (609744) and plays an important role in axon guidance, myelination, and maintenance of the axonal architecture (summary by Rebelo et al., 2021).
IGSF4B is a brain-specific protein related to the calcium-independent cell-cell adhesion molecules known as nectins (see PVRL3; 607147) (Kakunaga et al., 2005).
By searching databases for genes encoding proteins homologous to the TSLC1 (IGSF4; 605686) tumor suppressor, followed by screening an adult brain cDNA library, Fukuhara et al. (2001) cloned IGSF4B and IGSF4C (CADM4; 609744), which they called TSLL1 and TSLL2, respectively. The predicted 398-amino acid TSLL1 protein has an extracellular domain, a transmembrane domain, and a short cytoplasmic domain. The extracellular domain contains 3 Ig-like, C2-type loops with several potential N-glycosylation sites. Northern blot analysis detected expression of 2.6- and 3.8-kb transcripts restricted to adult and fetal brain. Expression was reduced or absent in glioma cell lines, suggesting that TSLL1 may be a tumor suppressor.
Fukami et al. (2003) cloned and characterized mouse Tsll1. The mouse Tsll1 protein is 95% identical to the human protein.
By database analysis, Biederer (2006) identified a SYNCAM3 splice variant in which skipping of exon 2 leads to a protein lacking sequence immediately following the signal peptide.
Using immunofluorescence and electron microscopy, Kakunaga et al. (2005) found that IGSF4B, which they termed NECL1, localized at contact sites among axons, their terminals, and glia cell processes that cooperatively formed synapses, axon bundles, and myelinated axons. NECL1 showed calcium-independent homophilic cell-cell adhesion activity. Furthermore, it showed calcium-independent heterophilic cell-cell adhesion activity with NECL2 (IGSF4), nectin-1 (PVRL1; 600644), or nectin-3 (PVRL3), but not with NECL5 (PVR; 173850) or nectin-2 (PVRL2; 600798). Yeast 2-hybrid analysis indicated that the PDZ domain-binding motif of NECL1 bound to the L27 domain-containing proteins DLG3 (300189), PALS2 (MPP6; 606959), and CASK (300172), but unlike most other nectins, it did not bind to afadin (MLLT4; 159559). Kakunaga et al. (2005) concluded that NECL1 is a neural tissue-specific, calcium-independent, Ig-like cell-cell adhesion molecule that may have membrane-associated guanylate kinase (MAGUK) subfamily member-binding activity and localizes at nonjunctional cell-cell contact sites.
Fukuhara et al. (2001) determined that the IGSF4B gene contains 9 exons and spans 30 kb. The upstream region meets the criteria of a CpG island.
Biederer (2006) determined that the SYNCAM3 gene contains 10 exons and spans 29 kb.
Using FISH, Fukuhara et al. (2001) mapped the IGSF4B gene to chromosome 1q21.2-q22. Fukami et al. (2003) mapped the mouse Igsf4b gene to chromosome 1H2-H4, which shows homology of synteny to human chromosome 1q.
In 3 unrelated probands with Charcot-Marie-Tooth disease type 2FF (CMT2FF; 619519), Rebelo et al. (2021) identified the same heterozygous missense variant in the CADM3 gene (Y172C; 609743.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in 1 family and occurred de novo in another. In vitro cellular expression studies suggested that the mutation resulted in abnormal axon-glia interactions.
Rebelo et al. (2021) found that knock-in mice carrying a heterozygous Y170C mutation in the Cadm3 gene (corresponding to the human Y172C mutation; 609743.0001) did not show an overt neurologic phenotype, although there was decreased expression of mutant Cadm3 in the sciatic nerve compared to controls. Nerve conduction velocities were similar to wildtype. Detailed studies of mutant mouse sciatic nerved showed no major differences from wildtype, although there were some fibers with thickened myelin. There was also abnormal accumulation and distribution of K(v)1.2 (KCNA2; 176262) channels around the juxtaparanodes and in patches along the internodes. These findings were consistent with abnormal axon-glia interactions.
In 3 unrelated probands with Charcot-Marie-Tooth disease type 2FF (CMT2FF; 619519), Rebelo et al. (2021) identified a heterozygous c.515A-G transition (c.515A-G, NM_021189.4) in exon 5 of the CADM3 gene, resulting in a tyr172-to-cys (Y172C) substitution at a highly conserved residue in the extracellular domain adjacent to the second Ig loop, which is essential for cell adhesion. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from an affected mother in family 3 and occurred de novo in the proband from family 1. Parental DNA from the proband in family 2 was not available for segregation studies. The mutation was not present in the gnomAD database. Expression of the mutation into HEK293 cells showed that it created an abnormal disulfide bond, indicating structural protein rearrangement predicted to impact folding of the molecule. In Schwann cells, the mutant protein was retained in the endoplasmic reticulum and triggered the unfolded protein response (UPR). Further detailed studies of transfected cells showed that although a small amount of the protein reached the cell membrane where it colocalized with its glial ligand CADM4, the interaction was not as robust as observed with wildtype CADM3. Rebelo et al. (2021) suggested disturbance of the axon-glia interface as the pathologic mechanism of the disease.
Biederer, T. Bioinformatic characterization of the SynCAM family of immunoglobulin-like domain-containing adhesion molecules. Genomics 87: 139-150, 2006. [PubMed: 16311015] [Full Text: https://doi.org/10.1016/j.ygeno.2005.08.017]
Fukami, T., Satoh, H., Williams, Y. N., Masuda, M., Fukuhara, H., Maruyama, T., Yageta, M., Kuramochi, M., Takamoto, S., Murakami, Y. Isolation of the mouse Tsll1 and Tsll2 genes, orthologues of the human TSLC1-like genes 1 and 2 (TSLL1 and TSLL2). Gene 323: 11-18, 2003. [PubMed: 14659875] [Full Text: https://doi.org/10.1016/j.gene.2003.09.018]
Fukuhara, H., Kuramochi, M., Nokukuni, T., Fukami, T., Saino, M., Maruyama, T., Nomura, S., Sekiya, T., Murakami, Y. Isolation of the TSLL1 and TSLL2 genes, members of the tumor suppressor TSLC1 gene family encoding transmembrane proteins. Oncogene 20: 5401-5407, 2001. [PubMed: 11536053] [Full Text: https://doi.org/10.1038/sj.onc.1204696]
Kakunaga, S., Ikeda, W., Itoh, S., Deguchi-Tawarada, M., Ohtsuka, T., Mizoguchi, A., Takai, Y. Nectin-like molecule-1/TSLL1/SynCAM3: a neural tissue-specific immunoglobulin-like cell-cell adhesion molecule localizing at non-junctional contact sites of presynaptic nerve terminals, axons and glia cell processes. J. Cell Sci. 118: 1267-1277, 2005. [PubMed: 15741237] [Full Text: https://doi.org/10.1242/jcs.01656]
Rebelo, A. P., Cortese, A., Abraham, A., Eshed-Eisenbach, Y., Shner, G., Vainshtein, A., Buglo, E., Camarena, V., Gaidosh, G., Shiekhattar, R., Abreu, L., Courel, S., and 9 others. A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement. Brain 144: 1197-1213, 2021. Note: Erratum: Brain 144: e64, 2021. [PubMed: 33889941] [Full Text: https://doi.org/10.1093/brain/awab019]