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): 241 total — 4 pathogenic, 4 likely-pathogenic
• GTEx eGene: eQTL in 25 tissues, sQTL in 0 (q < 0.05)
• Phenotypes (HPO): 19
• Constraint (gnomAD): pLI 0.55 (intermediate), LOEUF 0.52 (moderately constrained)
• 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: 25 — 21 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

MANE Select: ENST00000413139

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 5, TSL 4: 1, TSL 5: 5

ENST00000413139, ENST00000265727, ENST00000398201, ENST00000398203, ENST00000398204, ENST00000398209, ENST00000412441, ENST00000426930, ENST00000439864, ENST00000476330, ENST00000478920, ENST00000682337, ENST00000683525, ENST00000684002, ENST00000898401, ENST00000898402, ENST00000898403, ENST00000898404, ENST00000898405, ENST00000915158, ENST00000915159, ENST00000915160, ENST00000915161, ENST00000966491, ENST00001112153

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.

Highest expression (Bgee): lateral nuclear group of thalamus, middle temporal gyrus, pons, Brodmann (1909) area 23, postcentral gyrus.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ADAM22 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 25 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 25 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	eqtl	2.7e-34	-0.34	7:88099652:A:C
Skin Sun Exposed Lower leg	eqtl	6.1e-14	+0.19	7:87973403:AG:A
Skin Not Sun Exposed Suprapubic	eqtl	2.4e-10	-0.21	7:88009607:A:AGT
Uterus	eqtl	6.6e-10	-0.62	7:88008891:TATAATA:T
Cells Cultured fibroblasts	eqtl	8.3e-10	-0.26	7:87924014:C:T
Ovary	eqtl	6.3e-08	-0.50	7:88042020:G:T
Thyroid	eqtl	1.3e-06	-0.18	7:88041426:A:G
Brain Cerebellum	eqtl	2.7e-06	-0.34	7:87998412:A:G
Nerve Tibial	eqtl	7.6e-06	-0.17	7:88006367:C:T
Artery Tibial	eqtl	1.0e-04	-0.18	7:87924014:C:T
Colon Transverse	eqtl	1.4e-04	+0.60	7:88199122:G:A
Brain Cerebellar Hemisphere	eqtl	1.7e-04	-0.22	7:87998412:A:G
Pancreas	eqtl	1.4e-03	-0.22	7:88113327:G:A
Adrenal Gland	eqtl	1.8e-03	+0.26	7:87924014:C:T
Artery Aorta	eqtl	2.0e-03	-0.19	7:87938726:G:T
Heart Atrial Appendage	eqtl	3.7e-03	+0.22	7:87627286:T:C
Brain Hypothalamus	eqtl	6.3e-03	-0.38	7:87748057:G:A
Minor Salivary Gland	eqtl	1.1e-02	-0.28	7:88041426:A:G
Brain Caudate basal ganglia	eqtl	1.3e-02	-0.30	7:87069568:T:C
Vagina	eqtl	1.4e-02	+0.23	7:87976931:C:T

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

showing 100 of 292 tissues 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
medial globus pallidus	UBERON:0002477	88.66	gold quality
corpus callosum	UBERON:0002336	88.15	gold quality
ventral tegmental area	UBERON:0002691	88.09	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	88.08	gold quality
cerebral cortex	UBERON:0000956	87.95	gold quality
neocortex	UBERON:0001950	87.95	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.46	gold quality
trigeminal ganglion	UBERON:0001675	87.42	gold quality
cerebellar vermis	UBERON:0004720	86.64	gold quality
inferior vagus X ganglion	UBERON:0005363	86.50	gold quality
telencephalon	UBERON:0001893	86.38	gold quality
Ammon’s horn	UBERON:0001954	86.16	gold quality
brain	UBERON:0000955	86.14	gold quality
central nervous system	UBERON:0001017	86.00	gold quality
inferior olivary complex	UBERON:0002127	85.95	gold quality
temporal lobe	UBERON:0001871	85.56	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	85.50	gold quality
forebrain	UBERON:0001890	84.97	gold quality
right frontal lobe	UBERON:0002810	84.82	gold quality
subthalamic nucleus	UBERON:0001906	84.78	gold quality
hypothalamus	UBERON:0001898	84.18	gold quality
midbrain	UBERON:0001891	84.02	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.36	gold quality
cingulate cortex	UBERON:0003027	83.36	gold quality
tibia	UBERON:0000979	83.33	gold quality
substantia nigra	UBERON:0002038	83.31	gold quality
anterior cingulate cortex	UBERON:0009835	83.22	gold quality
middle frontal gyrus	UBERON:0002702	82.81	gold quality
nucleus accumbens	UBERON:0001882	82.71	gold quality
cortical plate	UBERON:0005343	81.96	gold quality
spinal cord	UBERON:0002240	81.78	gold quality
putamen	UBERON:0001874	81.71	gold quality
caudate nucleus	UBERON:0001873	81.67	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	81.39	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.37	gold quality
calcaneal tendon	UBERON:0003701	81.37	gold quality
amygdala	UBERON:0001876	81.36	gold quality
endothelial cell	CL:0000115	81.07	gold quality
cranial nerve II	UBERON:0000941	78.87	gold quality
caput epididymis	UBERON:0004358	78.74	gold quality
adrenal tissue	UBERON:0018303	78.65	gold quality
corpus epididymis	UBERON:0004359	78.54	gold quality
right adrenal gland cortex	UBERON:0035827	77.97	gold quality
adrenal gland	UBERON:0002369	77.65	gold quality
left adrenal gland	UBERON:0001234	77.34	gold quality
left adrenal gland cortex	UBERON:0035825	77.26	gold quality
right adrenal gland	UBERON:0001233	77.23	gold quality
adrenal cortex	UBERON:0001235	77.21	gold quality
ganglionic eminence	UBERON:0004023	76.87	gold quality
adult organism	UBERON:0007023	76.37	gold quality
ventricular zone	UBERON:0003053	75.41	gold quality
tendon	UBERON:0000043	73.42	gold quality
metanephros cortex	UBERON:0010533	73.15	gold quality
prostate gland	UBERON:0002367	72.89	gold quality
islet of Langerhans	UBERON:0000006	72.10	gold quality
body of uterus	UBERON:0009853	70.39	gold quality
sural nerve	UBERON:0015488	70.26	gold quality
renal medulla	UBERON:0000362	70.20	gold quality
endocervix	UBERON:0000458	69.92	gold quality
gall bladder	UBERON:0002110	69.91	gold quality
pituitary gland	UBERON:0000007	69.69	gold quality
ectocervix	UBERON:0012249	69.61	gold quality
right ovary	UBERON:0002118	69.21	gold quality
adenohypophysis	UBERON:0002196	69.10	gold quality
thyroid gland	UBERON:0002046	69.03	gold quality
smooth muscle tissue	UBERON:0001135	68.86	gold quality
left lobe of thyroid gland	UBERON:0001120	68.82	gold quality
lymph node	UBERON:0000029	68.65	gold quality
ovary	UBERON:0000992	68.57	gold quality
vagina	UBERON:0000996	68.48	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

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Cerebellum	tissue	127.0
Postcentral gyrus	tissue	90.8
Cerebral cortex	tissue	85.6
Somatosensory cortex	tissue	85.6
Occipital cortex	tissue	79.6
Motor cortex	tissue	65.4
Hippocampal formation	tissue	65.3
Entorhinal cortex	tissue	65.3
Retrosplenial and cingulate cortex	tissue	63.9
Temporal cortex	tissue	62.6
Putamen	tissue	60.6
Prefrontal cortex	tissue	60.5
Retrosplenial cortex	tissue	57.3
Basal ganglia	tissue	53.7
Locus coeruleus	tissue	52.9
Insular cortex	tissue	52.5
Olfactory bulb	tissue	51.6
Septum	tissue	50.8
Hippocampus	tissue	49.0
Pons	tissue	48.5
Caudate putamen	tissue	48.3
Ventral forebrain	tissue	47.1
Hypothalamus	tissue	46.2
Frontal cortex	tissue	43.3
Nucleus accumbens	tissue	42.9
Midbrain	tissue	42.4
Thalamus	tissue	42.1
Superior colliculi	tissue	40.2
Medulla oblongata	tissue	34.4
Periaqueductal gray	tissue	33.4
Amygdala	tissue	31.8
Substantia nigra	tissue	27.8
Spinal cord	tissue	20.4
Prostate	tissue	9.9
Corpus callosum	tissue	9.4
Retina	tissue	8.5
Adrenal gland	tissue	8.0
Epididymis	tissue	7.7
Choroid plexus	tissue	7.7
Cervix	tissue	5.3
Seminal vesicle	tissue	4.8
Endometrium 1	tissue	4.1
Kidney	tissue	3.2
Pituitary gland	tissue	3.1
Smooth muscle	tissue	3.1
Thyroid gland	tissue	2.9
Ovary	tissue	2.7
Vagina	tissue	2.3
Thymus	tissue	2.2
Fallopian tube	tissue	2.2
Gallbladder	tissue	2.1
Lymph node	tissue	2.0
Parathyroid gland	tissue	1.8
Skeletal muscle	tissue	1.8
Spleen	tissue	1.8
Adipose tissue	tissue	1.7
Heart muscle	tissue	1.6
Testis	tissue	1.4
Breast	tissue	1.2
Colon	tissue	1.2

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Cerebellar cortex (167.7), Vermis (156.8), Flocculonodular lobe (140.8), Precentral gyrus, middle (79.0), Postcentral gyrus, middle (76.2).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting ADAM22 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 298 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 0.553, LOEUF 0.518, missense Z 2.29 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000413139 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
7:87,934,466–88,114,647	240 / 234.3	1.02	no
7:88,116,745–88,196,488	734 / 950.6	0.77	no

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1340046) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 11 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal myelination	2
demyelination	2
decreased body weight	2
convulsive seizures	1
abnormal Schwann cell morphology	1
decreased body size	1
ataxia	1
abnormal neuron morphology	1
abnormal glial cell morphology	1
postnatal lethality, complete penetrance	1
neonatal lethality, incomplete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Trichophyton benhamiae CBS 112371	D4B1G0	97.9%	Diamond
Bothrops jararaca	P22028	96.0%	Diamond
Microsporum canis CBS 113480	C5FUK3	81.2%	Diamond
Xenopus laevis	Q9PSZ3	77.8%	Diamond
Aspergillus fumigatus Af293	Q4WQ08	57.3%	Diamond
Caenorhabditis elegans	Q94316	38.7%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
SRI	protein-coding	6717
STEAP4	protein-coding	79689
SRI-AS1	ncRNA	102723885
DBF4	protein-coding	10926
RUNDC3B	protein-coding	154661
ABCB1	protein-coding	5243
SLC25A40	protein-coding	55972

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 (110 total): strand 34, disulfide bond 20, helix 17, 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 by resolution:

PDB	Title	Method	Resolution (Å)
7CQF	Crystal structure of PSD-95 PDZ3 fused with ADAM22 C-terminal peptide	X-RAY DIFFRACTION	1.8
3G5C	Structural and biochemical studies on the ectodomain of human ADAM22	X-RAY DIFFRACTION	2.36
5Y2Z	Crystal structure of human LGI1 EPTP-ADAM22 complex	X-RAY DIFFRACTION	2.67
9KZC	Cryo-EM structure of the LGI1 LRR-LGI1 EPTP-ADAM22 ECD complex	ELECTRON MICROSCOPY	2.78
8HQ2	Crystal structure of human ADAM22 in complex with human LGI1 mutant	X-RAY DIFFRACTION	2.93
8Y6B	Structure of human LGI1-ADAM22 complex in space group P212121	X-RAY DIFFRACTION	3.49
9KZT	Cryo-EM structure of the 3:3 LGI1-ADAM22 complex	ELECTRON MICROSCOPY	3.79
8HQ1	Crystal Structure Of Human Lgi1-Adam22 Complex In Space Group C2	X-RAY DIFFRACTION	4.17
8HPY	Crystal structure of human LGI1-ADAM22 complex	X-RAY DIFFRACTION	5.87
5Y31	Crystal structure of human LGI1-ADAM22 complex	X-RAY DIFFRACTION	7.12

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Predicted membrane proteins, Predicted intracellular proteins, Disease related genes, Human disease related genes, Epilepsy

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cell junctions

Antibody reliability (HPA): IF approved

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)

Type	Positions
Phosphoserine	810, 834, 857, 862, 866, 870

Disulfide bonds (20)

Type	Positions
Disulfide bond	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)

Type	Positions
N-linked (glcnac…) asparagine	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

1 curated (TAS) of 2; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

2 pathways:

ID	Pathway	Evidence
R-HSA-5682910	LGI-ADAM interactions	curated
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 (9): 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), regulation of synapse assembly (GO:0051963), positive regulation of protein localization (GO:1903829), regulation of AMPA glutamate receptor clustering (GO:1904717), regulation of AMPA receptor activity (GO:2000311)

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 (6): plasma membrane (GO:0005886), membrane (GO:0016020), axon (GO:0030424), postsynaptic density membrane (GO:0098839), endomembrane system (GO:0012505), axon initial segment (GO:0043194)

Reactome top-level categories

1 top-level categories:

Category	Pathways
Developmental Biology	1

GO top-level categories

41 GO namespaces:

Category	Terms
cellular anatomical structure	3
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
animal gross anatomical part developmental process	1
chemical synaptic transmission	1
positive regulation of cell communication	1
positive regulation of signaling	1
modulation of chemical synaptic transmission	1
synapse assembly	1
regulation of synapse organization	1
regulation of cell junction assembly	1
intracellular protein localization	1
regulation of protein localization	1
positive regulation of biological process	1
AMPA glutamate receptor clustering	1
regulation of glutamate receptor clustering	1
AMPA glutamate receptor activity	1
regulation of transmembrane transporter activity	1
regulation of neurotransmitter receptor activity	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
postsynaptic specialization membrane	1
vacuole	1
plasma membrane	1
main axon	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 1 of 20 annotations. The rest are phylogenetic / computational / electronic (IEA).

1 experimentally-supported GO terms:

GO term	NS	Evidence
plasma membrane	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 916 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAM22	LGI1	O95970	943
ADAM22	CACNG2	Q9Y698	794
ADAM22	DLG4	P78352	733
ADAM22	LGI4	Q8N135	722
ADAM22	MDC1	Q14676	701
ADAM22	LGI3	Q8N145	670
ADAM22	LGI2	Q8N0V4	648
ADAM22	ADAM23	O75077	610
ADAM22	KCNA1	Q09470	606
ADAM22	CNTNAP2	Q9UHC6	606
ADAM22	NFASC	O94856	597
ADAM22	ADAM28	Q9UKQ2	588
ADAM22	CNTN2	P78432	566
ADAM22	TEX47	Q8TBZ9	535
ADAM22	THBD	P07204	500

IntAct

Human interaction partners of ADAM22 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 80 partners by confidence:

Partner	Interaction type	MIscore	Records
SCRIB	physical association	0.720	6
YWHAZ	physical association	0.630	5
DLG1	direct interaction	0.620	4
PATJ	direct interaction	0.440	6
GRIP1	direct interaction	0.440	5
GRIP2	direct interaction	0.440	4
DLG3	direct interaction	0.440	3
DLG4	direct interaction	0.440	3
FRMPD2	direct interaction	0.440	3
LNX1	direct interaction	0.440	3
MAGI2	direct interaction	0.440	3
MPDZ	direct interaction	0.440	3
PDZK1	direct interaction	0.440	3
APBA1	direct interaction	0.440	2
APBA2	direct interaction	0.440	2
GRID2IP	direct interaction	0.440	2
LNX2	direct interaction	0.440	2
MAGI1	direct interaction	0.440	2
NHERF4	direct interaction	0.440	2
TJP1	direct interaction	0.440	2
WHRN	direct interaction	0.440	2
AHNAK	direct interaction	0.440	1
APBA3	direct interaction	0.440	1
ARHGAP21	direct interaction	0.440	1
ARHGEF12	direct interaction	0.440	1
CARD11	direct interaction	0.440	1
CASK	direct interaction	0.440	1
DLG2	direct interaction	0.440	1
DLG5	direct interaction	0.440	1
DVL3	direct interaction	0.440	1

BioGRID (35 interactions; top human partners by supporting records): DLG4 (Affinity Capture-MS; 4 records), LGI1 (Affinity Capture-Western; 3 records), KRAS (Synthetic Lethality; 2 records), ADAM9 (Co-fractionation), APP (Reconstituted Complex), CANX (Affinity Capture-MS), CSNK1E (Affinity Capture-MS), DYRK1A (Two-hybrid), DYRK3 (Two-hybrid), EPS8 (Two-hybrid), GPIHBP1 (Affinity Capture-MS), HFE (Affinity Capture-MS), KIAA1429 (Affinity Capture-RNA), LCOR (Two-hybrid), LSMEM2 (Affinity Capture-MS)

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
ADAM22-LGI1 complex	2	ADAM22, LGI1

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 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	52.9×	2e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	50.4×	2e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	50.4×	2e-06
Long-term potentiation	5	44.1×	3e-06
Assembly and cell surface presentation of NMDA receptors	9	42.3×	1e-10
Neurexins and neuroligins	9	32.8×	7e-10
Protein-protein interactions at synapses	5	24.6×	6e-05
RHOA GTPase cycle	5	6.9×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	67.9×	3e-12
regulation of postsynaptic membrane neurotransmitter receptor levels	8	51.5×	6e-10
protein localization to synapse	5	49.7×	3e-06
receptor clustering	6	48.6×	3e-07
cell-cell adhesion	10	13.2×	5e-07
chemical synaptic transmission	7	7.0×	2e-03
nervous system development	8	4.8×	7e-03

Disease & clinical

Genetic variants

Variant evidence for ADAM22: 241 ClinVar records (8 pathogenic / likely pathogenic); 2 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	4
Uncertain significance	133
Likely benign	58
Benign	15

Top pathogenic / likely-pathogenic (8)

Showing all 8 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
997684	NM_001324418.2(ADAM22):c.2860C>T (p.Arg954Ter)	Pathogenic	criteria provided, single submitter	2
3775562	NM_001324418.2(ADAM22):c.1617+1G>A	Pathogenic	criteria provided, single submitter	1
992726	NM_001324418.2(ADAM22):c.1981dup (p.Met661fs)	Likely pathogenic	criteria provided, single submitter	1
3065798	NM_001324418.2(ADAM22):c.2283-2del	Likely pathogenic	criteria provided, single submitter	1
3337784	NM_001324418.2(ADAM22):c.1193G>C (p.Trp398Ser)	Likely pathogenic	criteria provided, single submitter	1
518457	NM_001324418.2(ADAM22):c.1202G>A (p.Cys401Tyr)	Pathogenic	no assertion criteria provided	1
518458	NM_001324418.2(ADAM22):c.2396del (p.Ser799fs)	Pathogenic	no assertion criteria provided	1
3032420	NM_001324418.2(ADAM22):c.2255_2259del (p.Ile752fs)	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ADAM22’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 27 predictions of 3,946):

Position(s)	Effect	Δscore	Sites
7:87934551	donor_loss	1.0000
7:87934997	acceptor_gain	1.0000
7:87935010–87935011	acceptor_gain	1.0000	2
7:87935021	acceptor_gain	1.0000
7:87978334	acceptor_loss	1.0000
7:87978413–87978414	donor_loss	1.0000	5
7:88074640	donor_gain	1.0000
7:88075624–88075625	acceptor_loss	1.0000	6
7:88075693–88075694	donor_loss	1.0000	4
7:88108174–88108175	acceptor_loss	1.0000	5

AlphaMissense

2,285 missense substitutions predicted likely pathogenic (of 6,365 scored), across 541 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M403	9	0.893	0.983
D511	8	0.996	0.999
D459	8	0.995	0.998
D248	8	0.989	0.998
N574	8	0.983	1.000
D325	8	0.982	0.993
N449	8	0.969	0.998
D274	8	0.955	0.993
F414	8	0.954	0.999
F335	8	0.952	0.996
D531	8	0.940	0.995
F91	8	0.923	0.997
F312	8	0.918	0.996
N107	8	0.905	0.984
D597	8	0.900	0.991
F161	8	0.894	0.997
H85	8	0.878	0.957
H185	8	0.853	0.967
H809	8	0.846	0.919
F330	8	0.841	0.995

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Glioblastoma Multiforme)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

5 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	7.75e-08
Glioblastoma Multiforme (validation)	favorable	6.83e-05
Thyroid Carcinoma (TCGA)	unfavorable	0.000304
Colon Adenocarcinoma (validation)	unfavorable	0.000356
Bladder Urothelial Carcinoma (TCGA)	favorable	0.000991

Disease associations

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

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
developmental and epileptic encephalopathy, 61	Strong	Autosomal recessive	4

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
developmental and epileptic encephalopathy	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (7 panels, 4 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

7 panels:

Panel	Rating
DDG2P	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Early onset or syndromic epilepsy	amber
Paediatric disorders	amber
Unexplained death in infancy and sudden unexplained death in childhood	amber

Mondo (1): developmental and epileptic encephalopathy, 61 (MONDO:0033370)

HPO phenotypes

19 phenotypes (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:

Study	Trait	p-value
GCST006585_727	Blood protein levels	1e-11
GCST000942_4	Drug-induced Stevens-Johnson syndrome or toxic epidermal necrolysis (SJS/TEN)	7e-6

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

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	affects methylation, decreases expression	2
Panobinostat	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	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	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.