Alternative titles; symbols
HGNC Approved Gene Symbol: CDH15
Cytogenetic location: 16q24.3 Genomic coordinates (GRCh38): 16:89,171,748-89,195,492 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q24.3 | Intellectual developmental disorder, autosomal dominant 3 | 612580 | Autosomal dominant | 3 |
CDH15, or M-cadherin, belongs to the cadherin family of Ca(2+)-dependent cell adhesion molecules. Cadherins are transmembrane glycoproteins consisting of an extracellular domain, a transmembrane region, and a cytoplasmic domain. The extracellular domains mediate Ca(2+)-dependent intercellular adhesion by homophilic interactions. The binding properties and specificities of the adhesive function are located in the N-terminal part of the molecules. In addition to M-cadherin, neural (114020), placental (114021), and epithelial (also called uvomorulin; 192090) forms of cadherin have been characterized (Donalies et al., 1991).
Donalies et al. (1991) identified M-cadherin in myogenic mouse cells. M-cadherin was not found in fibroblasts and was expressed at low levels in myoblasts.
In whole human brain and cerebellum, Bhalla et al. (2008) detected predominant expression of a 2.9-kb CDH15 transcript and faint expression of 3 larger transcripts of 3.8-, 6.9-, and 8.0-kb. Other brain sections including occipital lobe, thalamus, and hippocampus showed very faint or no detectable expression.
Donalies et al. (1991) found that M-cadherin was upregulated after induction of myotube formation, indicating a specific function in skeletal muscle cell differentiation.
Kaupmann et al. (1992) used a mouse myotube-derived cDNA encoding M-cadherin to demonstrate linkage of the gene (symbolized Cdh3 by them) to the gene for E-cadherin (uvomorulin; Um) in a mouse interspecific backcross. The linkage group is located on chromosome 8 in a region of conserved synteny with human chromosome 16q. The gene order was cen--Junb--Um--Tat--(Cdh3/Aprt). The human homolog, symbolized CDH3 by them, was mapped to 16q24.1-qter by analyzing human/mouse somatic cell hybrids. Kremmidiotis et al. (1998) mapped the human CDH15 gene to 16q24.3 using somatic cell hybrid panels.
In 4 of 647 unrelated patients with autosomal dominant intellectual development disorder-3 (MRD3; 612580), Bhalla et al. (2008) identified 4 different heterozygous mutations in the CDH15 gene (see, e.g., 114019.0001-114019.0003). In vitro functional expression studies in mouse cells showed that 3 of the mutant proteins resulted in decreased cell adhesion. Bhalla et al. (2008) concluded that alterations in the CDH15 gene, either alone or in combination with other factors, likely play a role in mental retardation.
Hollnagel et al. (2002) developed M-cadherin-null mice. Homozygous mutant mice were viable and fertile and showed no gross developmental defects. Skeletal musculature appeared normal, and satellite cells were able to form new myofibers following muscle damage. In the cerebellum of M-cadherin-null mice, typical adherens junctions were present and appeared normal; however, expression of N-cadherin was increased compared with wildtype animals. Hollnagel et al. (2002) concluded that M-cadherin is not absolutely required for muscle and cerebellar development, and that N-cadherin or other cadherins largely compensate for lack of M-cadherin.
The human cadherin gene represented by this entry, CDH15, is symbolized Cdh14 in mouse. CDH15 has also been referred to as CDH3; however, CDH3 is the official gene symbol for P-cadherin (114021).
In a woman with autosomal dominant intellectual developmental disorder (MRD3; 612580), Bhalla et al. (2008) identified a heterozygous 178C-T transition in the CDH15 gene, resulting in an arg60-to-cys (R60C) substitution in a highly conserved residue within the first extracellular cadherin ectodomain repeat. In vitro functional expression studies in mouse cells that lack cadherins showed that the R60C-mutant protein decreased cell-to-cell adhesion by greater than 80% compared to normal.
In a woman with autosomal dominant intellectual developmental disorder (MRD3; 612580), Bhalla et al. (2008) identified a heterozygous 274C-T transition in the CDH15 gene, resulting in an arg92-to-trp (R92W) substitution in a highly conserved residue within the first extracellular cadherin ectodomain repeat. The mutant allele was transmitted to her son, who had learning and memory difficulties. In vitro functional expression studies in mouse cells that lack cadherins showed that the R92W-mutant protein decreased cell-to-cell adhesion by greater than 80% compared to normal.
In a woman with autosomal dominant intellectual developmental disorder (MRD3; 612580), Bhalla et al. (2008) identified a heterozygous 365C-T transition in the CDH15 gene, resulting in an ala122-to-val (A122V) substitution in a highly conserved residue within the first extracellular cadherin ectodomain repeat. She inherited the mutant allele from her father, who was reported as having normal cognitive function but had no formal clinical evaluation. The authors postulated either incomplete penetrance or that this variant may only produce symptoms upon interaction with other factors. In vitro functional expression studies in mouse cells that lack cadherins showed that the A122V-mutant protein decreased cell-to-cell adhesion by greater than 80% compared to normal.
Bhalla, K., Luo, Y., Buchan, T., Beachem, M. A., Guzauskas, G. F., Ladd, S., Bratcher, S. J., Schroer, R. J., Balsamo, J., DuPont, B. R., Lilien, J., Srivastava, A. K. Alterations in CDH15 and KIRREL3 in patients with mild to severe intellectual disability. Am. J. Hum. Genet. 83: 703-713, 2008. [PubMed: 19012874] [Full Text: https://doi.org/10.1016/j.ajhg.2008.10.020]
Donalies, M., Cramer, M., Ringwald, M., Starzinski-Powitz, A. Expression of M-cadherin, a member of the cadherin multigene family, correlates with differentiation of skeletal muscle cells. Proc. Nat. Acad. Sci. 88: 8024-8028, 1991. [PubMed: 1840697] [Full Text: https://doi.org/10.1073/pnas.88.18.8024]
Hollnagel, A., Grund, C., Franke, W. W., Arnold, H.-H. The cell adhesion molecule M-cadherin is not essential for muscle development and regeneration. Molec. Cell. Biol. 22: 4760-4770, 2002. [PubMed: 12052883] [Full Text: https://doi.org/10.1128/MCB.22.13.4760-4770.2002]
Kaupmann, K., Becker-Follmann, J., Scherer, G., Jockusch, H., Starzinski-Powitz, A. The gene for the cell adhesion molecule M-cadherin maps to mouse chromosome 8 and human chromosome 16q24.1-qter and is near the E-cadherin (uvomorulin) locus in both species. Genomics 14: 488-490, 1992. [PubMed: 1427864] [Full Text: https://doi.org/10.1016/s0888-7543(05)80247-2]
Kremmidiotis, G., Baker, E., Crawford, J., Eyre, H. J., Nahmias, J., Callen, D. F. Localization of human cadherin genes to chromosome regions exhibiting cancer-related loss of heterozygosity. Genomics 49: 467-471, 1998. [PubMed: 9615235] [Full Text: https://doi.org/10.1006/geno.1998.5281]