Alternative titles; symbols
HGNC Approved Gene Symbol: ADAM22
Cytogenetic location: 7q21.12 Genomic coordinates (GRCh38): 7:87,934,251-88,202,889 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q21.12 | Developmental and epileptic encephalopathy 61 | 617933 | Autosomal recessive | 3 |
The cellular disintegrins, also known as ADAM (a disintegrin and metalloproteinase) and MDC (metalloproteinase-like, disintegrin-like, and cysteine-rich) proteins, are potential regulators of cell-cell and cell-matrix interactions. They contain multiple regions, including pro-, metalloproteinase-like, disintegrin-like, cysteine-rich, epidermal growth factor-like, transmembrane, and cytoplasmic domains.
The ADAM22 gene encodes a protein that interacts with LGI1 (604619) and forms a complex on the neuronal surface. The complex localizes to the postsynaptic membrane and regulates synaptic maturation and function (summary by Muona et al., 2016).
Sagane et al. (1998) screened a human brain cDNA library and searched an EST database to identify sequences related to MDC3 (ADAM23; 603710). They isolated mouse and human MDC2 cDNAs. Three-prime RACE yielded products corresponding to 2 MDC2 mRNAs, MDC2-alpha and -beta, in both mouse and human. MDC2-alpha encodes a predicted 859-amino acid protein. The shorter transcript, MDC2-beta, results from exon skipping and encodes an 823-amino acid protein. The MDC2-alpha protein shares 56% and 51% sequence similarity with MDC (155120) and MDC3, respectively. The zinc-binding motif, which is critical for proteinase activity, is disrupted in the metalloproteinase-like domain of all 3 MDC proteins. Northern blot analysis revealed that the 9.5-kb MDC2 mRNA was expressed predominantly in brain.
Fukata et al. (2006) showed that ADAM22 serves as a receptor for LGI1 (604619). LGI1 enhances AMPA receptor-mediated synaptic transmission in hippocampal slices. The mutated form of LGI1 failed to bind to ADAM22. ADAM22 is anchored in the postsynaptic density by cytoskeletal scaffolds containing stargazin (602911). Fukata et al. (2006) found that the interaction of ADAM22 and LGI1 with PSD95 (602887) was specific, as PSD95 and LGI1 quantitatively coimmunoprecipitated with ADAM22. Because PSD95 controls synaptic AMPA receptor number, Fukata et al. (2006) asked whether application of LGI1 to hippocampal slices would influence glutaminergic transmission. Incubation of hippocampal slices in LGI1-AP media significantly increased the synaptic AMPA/NMDA ratio; nontagged LGI1 showed a similar effect. Fukata et al. (2006) concluded that their study established a neuronal ligand-receptor interaction between LGI1 and ADAM22, both of which are genetically related to epilepsy. This study also identified LGI1 as an extracellular factor that controls synaptic strength at the excitatory synapses. Stargazin controls the trafficking and gating of AMPA receptors,0j and PSD95 anchors the AMPA receptor/stargazin complex at postsynaptic sites. Because the ADAM22 and stargazin binding sites on PSD95 do not overlap, the LGI1/ADAM22 complex may stabilize the AMPA receptor/stargazin complex on the PSD95 scaffolding platform.
Using immunostaining analysis, Hivert et al. (2019) showed that the voltage-gated Kv1 K+ channel (see 176260)-associated protein Lgi1 was targeted to the axon initial segment (AIS) of cultured rat hippocampal neurons. Lgi1 colocalized with Adam22, but not with Adam23. However, both ADAM proteins appeared to modulate Lgi1 targeting to the AIS. Coexpression analysis in HEK cells revealed that human ADAM22 and ADAM23 were involved in intracellular trafficking of LGI1 and promoted endoplasmic reticulum exit and N-glycan maturation of LGI1. Missense mutations in the EPTP6 domain of LGI1 reduced its interaction with ADAM22 and impaired its recruitment to the AIS. Moreover, Lgi1 and Adam23 colocalized in transport vesicles of rat hippocampal neurons, and Lgi1 likely required coexpression with Adam22 or Adam23 for proper trafficking and axonal transport. ADAM22 and ADAM23 also selectively associated with several cell adhesion molecules, including TAG1 (CNTN1; 190197) and CASPR2 (CNTNAP2; 604569), that associated with Kv1 channels at discrete regions of the axon. Axonal targeting of ADAM23 was modulated by its coexpression with TAG1 and CASPR2 in hippocampal neurons.
By radiation hybrid analysis, Poindexter et al. (1999) mapped the ADAM22 gene to chromosome 7q21.
In a 26-year-old woman, born of unrelated Finnish parents, with developmental and epileptic encephalopathy-61 (DEE61; 617933), Muona et al. (2016) identified compound heterozygous mutations in the ADAM22 gene (603709.0001 and 603709.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression assays indicated that both variants result in a loss of function. Muona et al. (2016) suggested that loss of function of the LGI1-ADAM22 complex may leave synapses immature and could possibly promote seizure activity.
In an 18-year-old man (patient 15DG1266), born of consanguineous parents, with DEE61, Maddirevula et al. (2019) identified a homozygous nonsense mutation in the ADAM22 gene (R860X; 603709.0003). The mutation, which was found by exome sequencing of a cohort of over 2,500 patients with various mendelian phenotypes, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
Sagane et al. (2005) employed gene targeting to generate Adam22 knockout mice. Adam22-deficient mice were produced in good accordance with mendelian ratio and appeared normal at birth. After one week, severe ataxia was observed, and all homozygotes died before weaning, probably due to convulsions. No major histologic abnormalities were detected in the cerebral cortex or cerebellum of the homozygous mutants; however, marked hypomyelination of the peripheral nerves was observed.
In a 26-year-old Finnish woman with developmental and epileptic encephalopathy-61 (DEE61; 617933), Muona et al. (2016) identified compound heterozygous mutations in the ADAM22 gene: a c.1202G-A transition (c.1202G-A, NM_021723) in exon 14, resulting in a cys401-to-tyr (C401Y) substitution at a highly conserved residue in the metalloproteinase-like domain, and a 1-bp deletion (c.2396delG; 603709.0002) in exon 27, predicted to result in a frameshift and premature termination (Ser799IlefsTer96) in the cytoplasmic domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The C401Y variant was found at a low frequency in heterozygous state in the ExAC database (1.7 x 10(-5)). The c.2396delG mutation occurs in exon 27 of the longest isoform of ADAM22, which encodes residues in the cytoplasmic tail, and is subjected to alternative splicing. The authors suggested that the frameshift mutation may result in a hypomorphic allele. In vitro functional expression studies showed that neither variant bound to LGI1 (604619) on the cell surface or in immunoprecipitation studies. The C401Y variant was able to bind to PSD95 (602887), but the frameshift variant did not. The studies indicated that both variants result in a loss of function. The patient developed intractable seizures between 2 and 3 months of age. She had profoundly delayed development and was nonambulatory as an adult.
For discussion of the 1-bp deletion (c.2396delG, NM_021723) in exon 27 of the ADAM22 gene, predicted to result in a frameshift and premature termination (Ser799IlefsTer96), that was found in compound heterozygous state in a patient with developmental and epileptic encephalopathy-61 (DEE61; 617933) by Muona et al. (2016), see 603709.0001.
In an 18-year-old man (patient 15DG1266), born of consanguineous parents, with developmental and epileptic encephalopathy-61 (DEE61; 617933), Maddirevula et al. (2019) identified a homozygous c.2578C-T transition in the ADAM22 gene, resulting in an arg860-to-ter (R860X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. The patient had onset of focal seizures at 5 months of age, followed by refractory generalized tonic-clonic seizures in the first 2 years of life.
Fukata, Y., Adesnik, H., Iwanaga, T., Bredt, D. S., Nicoll, R. A., Fukata, M. Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission. Science 313: 1792-1795, 2006. [PubMed: 16990550] [Full Text: https://doi.org/10.1126/science.1129947]
Hivert, B., Marien, L., Agbam, K. N., Faivre-Sarralh, C. ADAM22 and ADAM23 modulate the targeting of the Kv1 channel-associated protein LGI1 to the axon initial segment. J. Cell Sci. 132: jcs219774, 2019. [PubMed: 30598502] [Full Text: https://doi.org/10.1242/jcs.219774]
Maddirevula, S., Alzahrani, F., Al-Owain, M., Al Muhaizea, M. A., Kayyali, H. R., AlHashem, A., Rahbeeni, Z., Al-Otaibi, M., Alzaidan, H. I., Balobaid, A., El Khashab, H. Y., Bubshait, D. K., and 36 others. Autozygome and high throughput confirmation of disease genes candidacy. Genet. Med. 21: 736-742, 2019. [PubMed: 30237576] [Full Text: https://doi.org/10.1038/s41436-018-0138-x]
Muona, M., Fukata, Y., Anttonen, A.-K., Laari, A., Palotie, A., Pihko, H., Lonnqvist, T., Valanne, L., Somer, M., Fukata, M., Lehesjoki, A.-E. Dysfunctional ADAM22 implicated in progressive encephalopathy with cortical atrophy and epilepsy. Neurol. Genet. 2: e46, 2016. Note: Electronic Article. [PubMed: 27066583] [Full Text: https://doi.org/10.1212/NXG.0000000000000046]
Poindexter, K., Nelson, N., DuBose, R. F., Black, R. A., Cerretti, D. P. The identification of seven metalloproteinase-disintegrin (ADAM) genes from genomic libraries. Gene 237: 61-70, 1999. [PubMed: 10524237] [Full Text: https://doi.org/10.1016/s0378-1119(99)00302-9]
Sagane, K., Hayakawa, K., Kai, J., Hirohashi, T., Takahashi, E., Miyamoto, N., Ino, M., Oki, T., Yamazaki, K., Nagasu, T. Ataxia and peripheral nerve hypomyelination in ADAM22-deficient mice. BMC Neurosci. 6: 33, 2005. Note: Electronic Article. [PubMed: 15876356] [Full Text: https://doi.org/10.1186/1471-2202-6-33]
Sagane, K., Ohya, Y., Hasegawa, Y., Tanaka, I. Metalloproteinase-like, disintegrin-like, cysteine-rich proteins MDC2 and MDC3: novel human cellular disintegrins highly expressed in the brain. Biochem. J. 334: 93-98, 1998. [PubMed: 9693107] [Full Text: https://doi.org/10.1042/bj3340093]