ADAM22

Summary

ADAM22 (ADAM metallopeptidase domain 22, HGNC:201) is a protein-coding gene on chromosome 7q21.12, encoding Disintegrin and metalloproteinase domain-containing protein 22 (Q9P0K1). Probable ligand for integrin in the brain.

This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. Unlike other members of the ADAM protein family, the protein encoded by this gene lacks metalloprotease activity since it has no zinc-binding motif. This gene is highly expressed in the brain and may function as an integrin ligand in the brain. In mice, it has been shown to be essential for correct myelination in the peripheral nervous system. Alternative splicing results in several transcript variants.

Source: NCBI Gene 53616 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 201 total — 6 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 19
• MANE Select transcript: NM_001324418

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:201
Approved symbol	ADAM22
Name	ADAM metallopeptidase domain 22
Location	7q21.12
Locus type	gene with protein product
Status	Approved
Aliases	MDC2
Ensembl gene	ENSG00000008277
Ensembl biotype	protein_coding
OMIM	603709
Entrez	53616

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 20 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000265727, ENST00000398201, ENST00000398203, ENST00000398204, ENST00000398209, ENST00000412441, ENST00000413139, ENST00000426930, ENST00000439864, ENST00000476330, ENST00000478920, ENST00000682337, ENST00000683525, ENST00000684002, ENST00000898401, ENST00000898402, ENST00000898403, ENST00000898404, ENST00000898405, ENST00000915158, ENST00000915159, ENST00000915160, ENST00000915161, ENST00000966491

RefSeq mRNA: 18 — MANE Select: NM_001324418 NM_001324417, NM_001324418, NM_001324419, NM_001324420, NM_001324421, NM_001391975, NM_001391976, NM_001391977, NM_001391978, NM_001391979, NM_001391980, NM_001391981, NM_001391982, NM_004194, NM_016351, NM_021721, NM_021722, NM_021723

CCDS: CCDS43608, CCDS43609, CCDS43610, CCDS47637, CCDS94137, CCDS94138

Canonical transcript exons

ENST00000413139 — 32 exons

Exon	Start	End
ENSE00001532154	88178935	88179129
ENSE00001598655	88153221	88153326
ENSE00001600252	88168137	88168227
ENSE00001604889	88193116	88193239
ENSE00001616533	88150981	88151031
ENSE00001619287	88186615	88186701
ENSE00001624623	88145125	88145196
ENSE00001643258	88075626	88075692
ENSE00001651331	88148977	88149057
ENSE00001657928	88165832	88165946
ENSE00001664560	87935026	87935186
ENSE00001688570	88181505	88181605
ENSE00001702530	87978336	87978412
ENSE00001727075	88134329	88134419
ENSE00001728426	88145415	88145507
ENSE00001732410	88163012	88163180
ENSE00001749617	88155887	88156006
ENSE00001755054	88151257	88151320
ENSE00001758452	88143026	88143125
ENSE00001767844	88181958	88182024
ENSE00001767948	88131269	88131435
ENSE00001788240	88132867	88132951
ENSE00001792629	88130388	88130459
ENSE00001796545	88135980	88136031
ENSE00001945378	88196471	88202889
ENSE00002521367	88171544	88171561
ENSE00003525900	88125589	88125659
ENSE00003552588	88128602	88128676
ENSE00003590586	88116745	88116814
ENSE00003690694	88108176	88108258
ENSE00003694739	88114584	88114647
ENSE00003916738	87934251	87934550

Expression profiles

Bgee: expression breadth ubiquitous, 221 present calls, max score 97.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.2154 / max 533.1286, expressed in 1039 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
79412	10.5015	1027
79411	0.5856	206
79410	0.1283	67

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	97.85	gold quality
middle temporal gyrus	UBERON:0002771	97.34	gold quality
pons	UBERON:0000988	96.59	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.44	gold quality
postcentral gyrus	UBERON:0002581	95.54	gold quality
parietal lobe	UBERON:0001872	95.28	gold quality
orbitofrontal cortex	UBERON:0004167	95.12	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.93	gold quality
cerebellum	UBERON:0002037	94.41	gold quality
cerebellar hemisphere	UBERON:0002245	94.18	gold quality
cerebellar cortex	UBERON:0002129	94.16	gold quality
superior frontal gyrus	UBERON:0002661	93.83	gold quality
paraflocculus	UBERON:0005351	93.76	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.60	gold quality
occipital lobe	UBERON:0002021	93.21	gold quality
superior vestibular nucleus	UBERON:0007227	93.05	gold quality
primary visual cortex	UBERON:0002436	92.79	gold quality
substantia nigra pars compacta	UBERON:0001965	91.76	gold quality
medulla oblongata	UBERON:0001896	91.48	gold quality
lateral globus pallidus	UBERON:0002476	91.47	gold quality
CA1 field of hippocampus	UBERON:0003881	90.99	gold quality
entorhinal cortex	UBERON:0002728	90.94	gold quality
prefrontal cortex	UBERON:0000451	90.43	gold quality
dorsal root ganglion	UBERON:0000044	90.40	gold quality
frontal pole	UBERON:0002795	89.82	gold quality
Brodmann (1909) area 10	UBERON:0013541	89.74	gold quality
substantia nigra pars reticulata	UBERON:0001966	89.43	gold quality
frontal cortex	UBERON:0001870	89.22	gold quality
globus pallidus	UBERON:0001875	89.04	gold quality
dorsal plus ventral thalamus	UBERON:0001897	88.94	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-GEOD-99795	no	58.61
E-ANND-3	no	7.46

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

298 targeting ADAM22, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-LET-7A-3P	100.00	74.03	3932
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684

Literature-anchored findings (GeneRIF, showing 19)

• role for the 14-3-3zeta/ADAM 22 association in the regulation of cell adhesion and related signaling events (PMID:12589811)
• demonstrated a functional role for ADAM22/14-3-3 in cell adhesion and spreading (PMID:15882968)
• ADAM22, a brain-specific cell surface protein, mediates growth inhibition using an integrin dependent pathway. It is expressed in normal brain but not in high-grade gliomas. (PMID:16385342)
• This study indicated ADAM22 gene is probably not a major gene for this epilepsy syndrome. (PMID:17681454)
• Differential coding potential of ADAM22 mRNAs. (PMID:17884303)
• our results suggest that neither ADAM22 nor any of the three Kv1 channel genes are major causative genes for ADLTE. (PMID:18440780)
• The pro domains of ADAMs are expressed as two subdomains. The most N-terminal subdomain (ADAM22-P(N)) was found to be susceptible to proteolysis and was required for folding stability of the second subdomain (ADAM22-P(C)). (PMID:18593599)
• Mutations in disintegrin domain sequence in ADAM22 gene is associted with reduced LGI4-binding abilities resulting in epilepsy. (PMID:20156119)
• Transgenic leucine-rich glioma-inactivated 4 (Lgi4) and transgenic Adam22 proteins are both expressed in Schwann cells as well as in sensory neurons; binding of Lgi4 to axonal Adam22 is required on axons to drive myelin formation. (PMID:20220021)
• findings suggest that SRC-1 switches steroid-responsive tumors to a steroid-resistant state in which the SRC-1 target gene ADAM22 has a critical role (PMID:22072566)
• Data suggest that ADAM22 plays roles in cell differentiation, cell migration, and resistance to endocrine therapy in breast cancer; ADAM22 may serve as biomarker for poor disease-free survival in breast cancer patients. [REVIEW] (PMID:23810013)
• Disruption of LGI1-ADAM22 interaction reduces synaptic AMPA receptors in hippocampal neurons. (PMID:24227725)
• these results support the existence of a second mechanism, alternative to inhibition of protein secretion, by which ADLTE-causing LGI1 mutations exert their loss-of-function effect extracellularly, and suggest that interactions of LGI1 with both ADAM22 and ADAM23 play an important role in the molecular mechanisms leading to utosomal dominant lateral temporal epilepsy (PMID:27760137)
• the LGI1-ADAM22 complex functions as the trans-synaptic machinery for precise synaptic transmission (PMID:29670100)
• ADAM22 is critically involved in miR-449a-reduced tamoxifen resistance of estrogen receptor-positive breast cancer cells as a direct target of miR-449a. (PMID:30278449)
• LGI3 is secreted and binds to ADAM22 via TRIF-dependent NF-kappaB pathway in response to LPS in human keratinocytes. (PMID:31627033)
• ADAM22/LGI1 complex as a new actionable target for breast cancer brain metastasis. (PMID:33208158)
• Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy. (PMID:35373813)
• ADAM22 acts as a novel predictive biomarker for unfavorable prognosis and facilitates metastasis via PI3K/AKT signaling pathway in nasopharyngeal carcinoma. (PMID:38518731)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	adam22	ENSDARG00000060532
mus_musculus	Adam22	ENSMUSG00000040537
rattus_norvegicus	Adam22	ENSRNOG00000042478

Paralogs (20): ADAM28 (ENSG00000042980), ADAM7 (ENSG00000069206), ADAM11 (ENSG00000073670), ADAM2 (ENSG00000104755), ADAM23 (ENSG00000114948), ADAM20 (ENSG00000134007), ADAMDEC1 (ENSG00000134028), ADAM30 (ENSG00000134249), ADAM19 (ENSG00000135074), ADAM10 (ENSG00000137845), ADAM21 (ENSG00000139985), ADAM15 (ENSG00000143537), ADAM12 (ENSG00000148848), ADAM33 (ENSG00000149451), ADAM8 (ENSG00000151651), ADAM17 (ENSG00000151694), ADAM29 (ENSG00000168594), ADAM9 (ENSG00000168615), ADAM18 (ENSG00000168619), ADAM32 (ENSG00000197140)

Protein

Protein identifiers

Disintegrin and metalloproteinase domain-containing protein 22 — Q9P0K1 (reviewed: Q9P0K1)

Alternative names: Metalloproteinase-disintegrin ADAM22-3, Metalloproteinase-like, disintegrin-like, and cysteine-rich protein 2

All UniProt accessions (7): Q9P0K1, A0A804HHS1, A0A804HIW1, E9PF78, F8WAD8, H7C0Q9, H7C3I4

UniProt curated annotations — full annotation on UniProt →

Function. Probable ligand for integrin in the brain. This is a non catalytic metalloprotease-like protein. Involved in regulation of cell adhesion and spreading and in inhibition of cell proliferation. Neuronal receptor for LGI1.

Subunit / interactions. Interacts with LGI1. Interacts with DLG4/PSD95. Also binds LGI4. Interacts with KCNA2 and DLG2. Interacts with ADAM11. Interacts (via C-terminus) with YWHAB/14-3-3 beta. Interacts (via C-terminus) with YWHAZ/14-3-3 zeta.

Subcellular location. Cell membrane. Cell projection. Axon.

Tissue specificity. Highly expressed in the brain and in some high-grade but not low-grade gliomas. Detected slightly or not at all in other tissues.

Post-translational modifications. The precursor is cleaved by a furin endopeptidase.

Disease relevance. Developmental and epileptic encephalopathy 61 (DEE61) [MIM:617933] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE61 is an autosomal recessive condition characterized by onset of seizures in infancy. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9P0K1-1	1, Epsilon	yes
Q9P0K1-2	2, Delta
Q9P0K1-3	3, Alpha
Q9P0K1-4	4, Beta
Q9P0K1-5	5

RefSeq proteins (18): NP_001311346, NP_001311347, NP_001311348, NP_001311349, NP_001311350, NP_001378904, NP_001378905, NP_001378906, NP_001378907, NP_001378908, NP_001378909, NP_001378910, NP_001378911, NP_004185, NP_057435, NP_068367, NP_068368, NP_068369 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR001590	Peptidase_M12B	Domain
IPR001762	Disintegrin_dom	Domain
IPR002870	Peptidase_M12B_N	Domain
IPR006586	ADAM_Cys-rich	Domain
IPR013111	EGF_extracell	Domain
IPR018358	Disintegrin_CS	Conserved_site
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR034027	Reprolysin_adamalysin	Domain
IPR036436	Disintegrin_dom_sf	Homologous_superfamily

Pfam: PF00200, PF01421, PF01562, PF07974, PF08516

UniProt features (105 total): strand 33, disulfide bond 20, helix 13, modified residue 6, turn 5, compositionally biased region 4, glycosylation site 4, sequence variant 4, splice variant 3, domain 3, topological domain 2, mutagenesis site 2, signal peptide 1, propeptide 1, sequence conflict 1, chain 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
7CQF	X-RAY DIFFRACTION	1.8
3G5C	X-RAY DIFFRACTION	2.36
5Y2Z	X-RAY DIFFRACTION	2.67
9KZC	ELECTRON MICROSCOPY	2.78
8HQ2	X-RAY DIFFRACTION	2.93
8Y6B	X-RAY DIFFRACTION	3.49
9KZT	ELECTRON MICROSCOPY	3.79
8HQ1	X-RAY DIFFRACTION	4.17
8HPY	X-RAY DIFFRACTION	5.87
5Y31	X-RAY DIFFRACTION	7.12

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P0K1-F1	73.17	0.43

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (6): 810, 834, 857, 862, 866, 870

Disulfide bonds (20): 349–433, 392–417, 394–401, 447–477, 458–474, 460–466, 473–494, 485–491, 490–516, 503–523, 510–542, 535–547, 554–605, 569–635, 583–593, 600–663, 657–668, 679–694, 688–700, 702–711

Glycosylation sites (4): 175, 519, 634, 675

Mutagenesis-validated functional residues (2):

Position	Phenotype
834	abolishes interactions with ywhab and ywhaz; when associated with a-857.
857	abolishes interactions with ywhab and ywhaz; when associated with a-834.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5682910	LGI-ADAM interactions
R-HSA-1266738	Developmental Biology

MSigDB gene sets: 285 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, BENPORATH_ES_WITH_H3K27ME3, GOMF_METALLOPEPTIDASE_ACTIVITY, AACYNNNNTTCCS_UNKNOWN, MORF_RAD51L3, GOBP_CELL_CELL_SIGNALING, GOBP_SYNAPTIC_SIGNALING, DODD_NASOPHARYNGEAL_CARCINOMA_UP, ZHAN_MULTIPLE_MYELOMA_LB_UP, GOCC_NEURON_PROJECTION, GOBP_POSITIVE_REGULATION_OF_SYNAPTIC_TRANSMISSION, GOMF_SIGNALING_RECEPTOR_BINDING, MORF_ATF2, DANG_BOUND_BY_MYC, IVANOVA_HEMATOPOIESIS_STEM_CELL_LONG_TERM

GO Biological Process (11): proteolysis (GO:0006508), cell adhesion (GO:0007155), negative regulation of cell adhesion (GO:0007162), central nervous system development (GO:0007417), positive regulation of synaptic transmission (GO:0050806), adult locomotory behavior (GO:0008344), Schwann cell differentiation (GO:0014037), myelination in peripheral nervous system (GO:0022011), gliogenesis (GO:0042063), neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0099645), positive regulation of protein localization (GO:1903829)

GO Molecular Function (5): metalloendopeptidase activity (GO:0004222), integrin binding (GO:0005178), signaling receptor activity (GO:0038023), protein binding (GO:0005515), metallopeptidase activity (GO:0008237)

GO Cellular Component (8): plasma membrane (GO:0005886), membrane (GO:0016020), axon (GO:0030424), postsynaptic density membrane (GO:0098839), endomembrane system (GO:0012505), cell projection (GO:0042995), axon initial segment (GO:0043194), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein metabolic process	1
cellular process	1
cell adhesion	1
regulation of cell adhesion	1
negative regulation of cellular process	1
nervous system development	1
system development	1
chemical synaptic transmission	1
positive regulation of cell communication	1
positive regulation of signaling	1
modulation of chemical synaptic transmission	1
locomotory behavior	1
adult behavior	1
peripheral nervous system development	1
glial cell differentiation	1
Schwann cell development	1
peripheral nervous system axon ensheathment	1
myelination	1
neurogenesis	1
protein-containing complex localization	1
receptor localization to synapse	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
protein localization to postsynaptic specialization membrane	1
intracellular protein localization	1
regulation of protein localization	1
positive regulation of biological process	1
endopeptidase activity	1
metallopeptidase activity	1
signaling receptor binding	1
protein-containing complex binding	1
cell adhesion molecule binding	1
molecular transducer activity	1
binding	1
peptidase activity	1
membrane	1
cell periphery	1
neuron projection	1
postsynaptic density	1
postsynaptic membrane	1

Protein interactions and networks

STRING

966 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAM22	LGI1	O95970	999
ADAM22	DLG4	P78352	981
ADAM22	DLG2	Q15700	899
ADAM22	ADAM23	O75077	896
ADAM22	ADAM28	Q9UKQ2	888
ADAM22	LGI4	Q8N135	886
ADAM22	CACNG2	Q9Y698	874
ADAM22	CNTNAP2	Q9UHC6	852
ADAM22	LGI3	Q8N145	842
ADAM22	KCNA1	Q09470	823
ADAM22	MDC1	Q14676	817
ADAM22	CNTN2	P78432	730
ADAM22	LGI2	Q8N0V4	695
ADAM22	KCNA2	P16389	633
ADAM22	THBD	P07204	581

IntAct

136 interactions, top by confidence:

A	B	Type	Score
SCRIB	ADAM22	psi-mi:“MI:0915”(physical association)	0.720
SCRIB	ADAM22	psi-mi:“MI:0407”(direct interaction)	0.720
ADAM22	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.720
YWHAZ	ADAM22	psi-mi:“MI:0915”(physical association)	0.630
YWHAZ	ADAM22	psi-mi:“MI:0407”(direct interaction)	0.630
DLG1	ADAM22	psi-mi:“MI:0407”(direct interaction)	0.620
ADAM22	DLG1	psi-mi:“MI:0407”(direct interaction)	0.620
CSNK1E	ZSWIM8	psi-mi:“MI:0914”(association)	0.530
ADAM22	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM22	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM22	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM22	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM22	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM22	PDZRN4	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM22	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM22	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM22	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM22	PDZRN3	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM22	SNTG2	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM22	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM22	SNTG1	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM22	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (35): ADAM22 (Affinity Capture-RNA), ADAM22 (Reconstituted Complex), ADAM22 (Synthetic Lethality), ADAM22 (Affinity Capture-MS), ADAM22 (Affinity Capture-RNA), ADAM22 (Affinity Capture-MS), ADAM22 (Affinity Capture-Western), DLG4 (Affinity Capture-Western), LGI1 (Affinity Capture-Western), DLG4 (Affinity Capture-MS), LGI1 (Affinity Capture-MS), ADAM22 (Proximity Label-MS), ADAM22 (Proximity Label-MS), ADAM22 (Affinity Capture-MS), ADAM22 (Affinity Capture-MS)

ESM2 similar proteins: A1XQX1, A1XQX3, A1XQY0, A8WGA3, C6K2K4, D0PRN2, D0PRN4, D4A1J9, E9PUN2, O13097, O42596, O73612, O73874, P0DI97, P52795, P52796, P58400, P58401, P98172, Q01974, Q0PMD2, Q17QD6, Q28142, Q28143, Q460M5, Q63373, Q63376, Q6NW40, Q6PCX7, Q6PFE7, Q7TQ33, Q80TG9, Q8BNJ6, Q8BXA0, Q8C985, Q8IYR6, Q8NC67, Q91590, Q96B86, Q96NI6

Diamond homologs: A2CJE2, A2CJE3, A2CJE4, A8QL59, C0LZJ5, C5FUK3, D4B1G0, D4DCV9, E9NW26, F8VQ03, G5EFD5, J3S830, O13766, O35227, O42596, O73795, O75077, O75078, O77780, O93515, O93517, O93518, P0C6B6, P0C6E3, P0C6R9, P0C7B0, P0DJ87, P0DM87, P17497, P23323, P31989, P83912, Q05910, Q0NZX6, Q0NZX7, Q0NZX8, Q0NZX9, Q0NZY0, Q13443, Q13444

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 98 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	43.9×	7e-06
Assembly and cell surface presentation of NMDA receptors	11	43.0×	3e-13
Unblocking of NMDA receptors, glutamate binding and activation	5	41.8×	7e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	41.8×	7e-06
Long-term potentiation	5	36.6×	1e-05
Neurexins and neuroligins	9	27.3×	5e-09
Protein-protein interactions at synapses	5	20.4×	2e-04
Activation of NMDA receptors and postsynaptic events	5	14.2×	7e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	56.9×	2e-11
regulation of postsynaptic membrane neurotransmitter receptor levels	8	43.1×	3e-09
protein localization to synapse	5	41.6×	9e-06
receptor clustering	6	40.7×	1e-06
cell-cell adhesion	10	11.0×	3e-06
protein-containing complex assembly	6	7.4×	6e-03
chemical synaptic transmission	7	5.9×	6e-03
nervous system development	10	5.0×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

201 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	4
Uncertain significance	121
Likely benign	32
Benign	15

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1713132	NM_001324418.2(ADAM22):c.2888C>T (p.Ser963Phe)	Pathogenic
242972	NC_000007.13:g.(20954043_21001537)_(114528369_114556605)inv	Pathogenic
3775562	NM_001324418.2(ADAM22):c.1617+1G>A	Pathogenic
518457	NM_001324418.2(ADAM22):c.1202G>A (p.Cys401Tyr)	Pathogenic
518458	NM_001324418.2(ADAM22):c.2396del (p.Ser799fs)	Pathogenic
997684	NM_001324418.2(ADAM22):c.2860C>T (p.Arg954Ter)	Pathogenic
3032420	NM_001324418.2(ADAM22):c.2255_2259del (p.Ile752fs)	Likely pathogenic
3065798	NM_001324418.2(ADAM22):c.2283-2del	Likely pathogenic
3337784	NM_001324418.2(ADAM22):c.1193G>C (p.Trp398Ser)	Likely pathogenic
992726	NM_001324418.2(ADAM22):c.1981dup (p.Met661fs)	Likely pathogenic

SpliceAI

6526 predictions. Top by Δscore:

Variant	Effect	Δscore
7:87934547:GCAG:G	donor_gain	1.0000
7:87934548:CAGGT:C	donor_loss	1.0000
7:87934550:GGTA:G	donor_loss	1.0000
7:87934551:G:GG	donor_gain	1.0000
7:87934551:GTAA:G	donor_loss	1.0000
7:87934996:A:AG	acceptor_gain	1.0000
7:87934997:C:G	acceptor_gain	1.0000
7:87935010:C:CA	acceptor_gain	1.0000
7:87935011:G:A	acceptor_gain	1.0000
7:87935021:T:A	acceptor_gain	1.0000
7:87978325:T:TA	acceptor_gain	1.0000
7:87978331:TGTA:T	acceptor_loss	1.0000
7:87978332:GTAG:G	acceptor_loss	1.0000
7:87978333:TAGTT:T	acceptor_loss	1.0000
7:87978334:A:AG	acceptor_gain	1.0000
7:87978334:AGT:A	acceptor_loss	1.0000
7:87978334:AGTT:A	acceptor_gain	1.0000
7:87978335:G:GA	acceptor_gain	1.0000
7:87978335:GT:G	acceptor_gain	1.0000
7:87978335:GTT:G	acceptor_gain	1.0000
7:87978335:GTTG:G	acceptor_gain	1.0000
7:87978335:GTTGA:G	acceptor_gain	1.0000
7:87978408:AATCA:A	donor_gain	1.0000
7:87978409:ATCA:A	donor_gain	1.0000
7:87978409:ATCAG:A	donor_loss	1.0000
7:87978410:TCA:T	donor_gain	1.0000
7:87978411:CA:C	donor_gain	1.0000
7:87978411:CAG:C	donor_loss	1.0000
7:87978412:AGTAA:A	donor_loss	1.0000
7:87978413:G:GG	donor_gain	1.0000

AlphaMissense

6365 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:88128651:T:C	L243P	1.000
7:88131320:T:A	W293R	1.000
7:88131320:T:C	W293R	1.000
7:88145176:T:A	C458S	1.000
7:88145177:G:C	C458S	1.000
7:88145475:T:A	C485S	1.000
7:88145475:T:C	C485R	1.000
7:88145476:G:C	C485S	1.000
7:88145477:C:G	C485W	1.000
7:88149002:G:C	R504P	1.000
7:88149019:T:C	C510R	1.000
7:88149020:G:A	C510Y	1.000
7:88150981:T:A	C523S	1.000
7:88150982:G:C	C523S	1.000
7:88151265:C:G	C542W	1.000
7:88151313:G:C	W558C	1.000
7:88151313:G:T	W558C	1.000
7:88153261:T:A	N574K	1.000
7:88153261:T:G	N574K	1.000
7:88153316:T:A	C593S	1.000
7:88153317:G:C	C593S	1.000
7:88155912:T:C	C605R	1.000
7:88155914:T:G	C605W	1.000
7:88163166:T:A	C688S	1.000
7:88163167:G:C	C688S	1.000
7:88165886:T:A	C711S	1.000
7:88165887:G:C	C711S	1.000
7:88165888:C:G	C711W	1.000
7:88131308:G:C	A289P	0.999
7:88131322:G:C	W293C	0.999

dbSNP variants (sampled 300 via entrez): RS1000002312 (7:87984108 A>G,T), RS1000008544 (7:88150227 C>G,T), RS1000036344 (7:88098123 C>A), RS1000039261 (7:88197777 G>A,C), RS1000042981 (7:88196157 A>G), RS1000049091 (7:88065146 C>T), RS1000060702 (7:88051674 C>T), RS1000073433 (7:88124225 A>G), RS1000086553 (7:87963376 A>G), RS1000087433 (7:88104963 C>T), RS1000121575 (7:88105392 T>G), RS1000124982 (7:88010573 G>C), RS1000133776 (7:88049534 G>A,C), RS1000150339 (7:88096381 T>G), RS1000164624 (7:88191747 A>C)

Disease associations

OMIM: gene MIM:603709 | disease phenotypes: MIM:617933, MIM:602081

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 61	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
developmental and epileptic encephalopathy	Definitive	AR

Mondo (2): developmental and epileptic encephalopathy, 61 (MONDO:0033370), childhood apraxia of speech (MONDO:0011184)

Orphanet (1): Isolated childhood apraxia of speech (Orphanet:209908)

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000341	Narrow forehead
HP:0000648	Optic atrophy
HP:0000817	Reduced eye contact
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001290	Generalized hypotonia
HP:0002059	Cerebral atrophy
HP:0002104	Apnea
HP:0002187	Profound intellectual disability
HP:0002266	Focal clonic seizure
HP:0002505	Loss of ambulation
HP:0003593	Infantile onset
HP:0005484	Secondary microcephaly
HP:0007334	Bilateral tonic-clonic seizure with focal onset
HP:0012471	Thick vermilion border
HP:0200134	Epileptic encephalopathy

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000942_4	Drug-induced Stevens-Johnson syndrome or toxic epidermal necrolysis (SJS/TEN)	7.000000e-06
GCST006585_1860	Blood protein levels	1.000000e-11

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — M12: Astacin/Adamalysin

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects methylation	2
Panobinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Valproic Acid	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
methylselenic acid	increases expression	1
trichostatin A	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sulforaphane	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Calcitriol	decreases expression, affects cotreatment	1
Diazinon	decreases methylation	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	decreases expression	1
Methapyrilene	increases methylation	1
Methotrexate	increases expression	1
Nickel	decreases expression	1
Tamoxifen	decreases expression	1
Testosterone	decreases expression, affects cotreatment	1

Clinical trials (associated diseases)

16 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05185583	PHASE2	COMPLETED	Methylphenidate in Childhood Apraxia of Speech
NCT07216001	PHASE2	NOT_YET_RECRUITING	Role of Omega-DEK in Childhood Apraxia of Speech
NCT03903120	PHASE1	COMPLETED	ASSIST: Treatment for Childhood Apraxia of Speech
NCT01097161	Not specified	COMPLETED	Stuttering and Apraxia of Speech: the Efficacy of an Intervention Program
NCT02022410	Not specified	COMPLETED	CAS and Length of Hospital Stay After TKA
NCT03238677	Not specified	COMPLETED	Treating Childhood Apraxia of Speech
NCT03700151	Not specified	UNKNOWN	Efficacy of an Intervention for the Children With Severe Speech Sounds Disorders
NCT04642053	Not specified	RECRUITING	A Randomized Control Trial of Motor-based Intervention for CAS
NCT04825145	Not specified	COMPLETED	Preeclampsia and Contact Activation
NCT04832503	Not specified	COMPLETED	Childhood Apraxia of Speech: Experience Dependent Changes Induced by Treatment
NCT05066178	Not specified	RECRUITING	Speech Treatment for Minimally Verbal Children With ASD and CAS
NCT05675306	Not specified	ACTIVE_NOT_RECRUITING	Dose Frequency RCT on DTTC in Children With CAS
NCT05916222	Not specified	RECRUITING	The Effects of Caregiver Training on DTTC Treatment Outcomes in CAS
NCT06385470	Not specified	UNKNOWN	Treatment of Cantonese Speakers With Childhood Apraxia of Speech
NCT07087249	Not specified	NOT_YET_RECRUITING	Efficacy of Ultrasound Biofeedback in Brazilian Childhood Apraxia of Speech
NCT07526246	Not specified	NOT_YET_RECRUITING	Motor-based Intervention for Childhood Apraxia of Speech: DTTC-Connect