ADAM22

ADAM22 (a disintegrin and metalloprotease domain 22) is a human gene located on chromosome 7q21.12 that encodes a single-pass type I transmembrane glycoprotein belonging to the ADAM family of proteins.^[1] The encoded protein, ADAM22, is a non-catalytic member of this family, characterized by its extracellular domain consisting of a metalloprotease-like domain (residues 233–435), a disintegrin domain (residues 445–529), a cysteine-rich domain, and an EGF-like domain, followed by a transmembrane domain and a short cytoplasmic tail.^[2] Lacking the zinc-binding motif essential for proteolytic activity, ADAM22 primarily functions as an adhesion molecule and receptor in cell-cell and cell-matrix interactions, with high expression restricted to the brain and slight detection in tissues like the adrenal gland.^[3][4] ADAM22 plays critical roles in neuronal development and synaptic function, acting as a postsynaptic receptor for leucine-rich glioma-inactivated 1 (LGI1) to regulate the trans-synaptic clustering of ionotropic glutamate receptors, including AMPA and NMDA receptors, which are vital for excitatory synaptic transmission.^[5] It also serves as a ligand for integrins, mediating cell adhesion, spreading, and inhibition of proliferation in brain cells, and is essential for myelination in the peripheral nervous system by facilitating interactions between neurons and Schwann cells.^[1] Through its interaction with LGI1 and postsynaptic scaffolding proteins like PSD-95, ADAM22 contributes to the organization of synaptic complexes, and disruptions in this pathway are implicated in neuronal hyperexcitability.^[6] Mutations in ADAM22 are associated with developmental and epileptic encephalopathy 61 (DEE61), an autosomal recessive disorder characterized by infantile-onset refractory seizures, profound intellectual disability, hypotonia, spasticity, and brain atrophy.^[7] Biallelic loss-of-function variants, such as missense, nonsense, and splice-site mutations, lead to impaired protein function and synaptic organization, resulting in progressive neurodegeneration.^[8] Research highlights ADAM22's therapeutic potential in epilepsy, with studies emphasizing its role in stabilizing synaptic receptor trafficking to mitigate seizure activity.^[5]

Genetics

Gene Structure

The ADAM22 gene is located on the long arm of human chromosome 7 at cytogenetic band 7q21.12 and spans approximately 269 kilobases (kb) of genomic DNA.^[9] The gene structure comprises more than 30 exons, with the canonical transcript (ENST00000265727.11, ADAM22-201) consisting of 31 exons that encode a 2,891-base pair mRNA.^[10][1] Alternative splicing of ADAM22 generates 24 distinct transcript variants, producing mRNA isoforms with varying lengths ranging from 511 bp to 9,508 bp and resulting in proteins of different sizes, such as the full-length 906-amino acid isoform.^[9] These transcripts arise from specific exon-intron boundaries that permit inclusion or exclusion of particular exons, particularly in the 5' untranslated region and cytoplasmic tail-encoding regions.^[11] The gene includes conserved regulatory elements, such as core promoters and enhancers in intronic and flanking regions, which support tissue-specific transcription, notably in neural contexts.^[3] ADAM22 exhibits strong evolutionary conservation across mammals, with the human protein sequence sharing approximately 90% identity with the mouse Adam22 ortholog.^[4]

Genomic Location

The ADAM22 gene is located on the long arm of human chromosome 7 at cytogenetic band q21.12, spanning positions 87,934,251 to 88,202,889 (GRCh38.p14 assembly), which corresponds to approximately 87.93–88.2 Mb.^[1][12] The gene was initially cloned in 1998 from a human brain cDNA library as part of efforts to identify novel metalloprotease-disintegrin family members expressed in neural tissues.^[13] Its chromosomal mapping to 7q21 was confirmed in 1999 using radiation hybrid panel analysis, building on early studies of ADAM family genes in the context of neural development and disorders.^[14][15] The ADAM22 locus spans about 269 kb and consists of 35 exons. Nearby genes in the region include DBF4 (upstream), SLC25A40, RUNDC3B, and RPIP8, as well as downstream genes such as SRI and ABCB1; this genomic neighborhood has been implicated in potential linkage disequilibrium patterns relevant to inheritance of nearby variants associated with neurological traits.^[1][3] Orthologs of ADAM22 are highly conserved across vertebrates, with the mouse Adam22 gene located on chromosome 5 at positions 8,122,352–8,418,160 (GRCm39 assembly, approximately 8.12–8.42 Mb), preserving syntenic relationships with the human locus including flanking genes like Dbf4 and Slc25a40.^[16] Similar orthologous positioning is observed in other mammals such as chimpanzee (chromosome 7) and rat (chromosome 4), supporting evolutionary conservation of the region for neural-related functions.^[1]

Protein Characteristics

Domain Architecture

ADAM22 is a type I transmembrane glycoprotein comprising 906 amino acids in its precursor form.^[4] The protein features a modular domain organization typical of the ADAM family, oriented from N- to C-terminus as follows: an N-terminal signal peptide (residues 1–25) that is cleaved during maturation, a prodomain (residues 26–222) involved in initial folding and inhibition, an inactive metalloproteinase-like domain (residues 233–435) lacking the catalytic glutamate residue essential for proteolytic activity (specifically, the consensus zinc-binding motif HEXGHXXGXXHD is disrupted), a disintegrin domain (residues 445–529) containing an RGD-like adhesion motif, a cysteine-rich domain (residues 530–676) that stabilizes the structure through disulfide bonds, two EGF-like repeats (residues 677–718), a transmembrane helix (residues 737–757), and a short cytoplasmic tail (residues 758–906) ending in a PDZ-binding motif (-ETSI).^[17] The crystal structure of the ADAM22 ectodomain (residues 26–736), determined at 2.36 Å resolution, reveals a compact four-leaf clover topology spanning approximately 80 × 70 × 40 Å, with three calcium ions coordinating key structural elements.^[17] In this arrangement, the inactive metalloproteinase-like domain is nestled against the concave face of a rigid module formed by the disintegrin, cysteine-rich, and EGF-like domains, promoting overall stability without catalytic function.^[17] A 2025 cryo-EM study of the LGI1–ADAM22 complex describes a heterohexameric 3:3 assembly, providing insights into trans-synaptic interactions and the ectodomain's role in synaptic organization.^[18] Unlike catalytic ADAM proteins (e.g., ADAM10 or ADAM17), which possess an active metalloproteinase domain for substrate cleavage and ectodomain shedding, ADAM22's evolutionary divergence—marked by the absence of the catalytic glutamate—shifts its architecture toward adhesion-centric roles, emphasizing the disintegrin and cysteine-rich domains for ligand interactions.^[17]

Expression Patterns

ADAM22 exhibits a predominantly neural-specific expression pattern at the protein level, with high abundance in the central nervous system (CNS), including the brain and spinal cord, while showing low or absent levels in non-neural tissues such as liver and skeletal muscle.^[19][20] In the brain, expression is particularly elevated in the cerebral cortex, hippocampus, and cerebellum, where it localizes to neurons including granule cells in the cerebellum and pyramidal neurons in the hippocampal CA1 region.^[21] Within the spinal cord, ADAM22 protein is primarily detected in the grey matter.^[21] Notably, ADAM22 expression is absent in high-grade gliomas, contrasting with its presence in normal brain tissue and some low-grade gliomas.^[22] Developmentally, ADAM22 protein levels are low during embryogenesis and in newborn stages, with significant upregulation occurring postnatally around day 7 in mice, coinciding with periods of neurogenesis, synaptogenesis, and myelination, and reaching peak expression in the maturing brain.^[21] This temporal pattern underscores its role in CNS maturation. At the subcellular level, ADAM22 is localized to postsynaptic membranes at excitatory synapses, as well as to axons, including juxtaparanodal regions and axon initial segments, as demonstrated through immunohistochemistry and Western blot analyses in neuronal tissues.^[23][24]

Biological Functions

Role in Synaptic Organization

ADAM22 plays an essential role in the maturation of excitatory synapses by facilitating the clustering of AMPA receptors at postsynaptic sites, which is critical for synaptic strengthening and functionality. Studies using cultured hippocampal neurons from ADAM22 knockout mice demonstrate a significant reduction in AMPA receptor-mediated excitatory postsynaptic currents (EPSCs), indicating impaired synaptic transmission due to diminished receptor accumulation. This regulation contributes to the overall organization of postsynaptic densities, where ADAM22 interacts with PDZ domain-containing proteins to stabilize synaptic structures. Although dendritic spine density remains unchanged in ADAM22-deficient neurons, the protein's absence disrupts the functional maturation of spines, leading to altered excitatory synapse efficacy. ADAM22 coordinates transsynaptic nanoalignment, ensuring precise apposition of presynaptic release sites with postsynaptic receptor clusters for efficient neurotransmitter release and reception. Through its organization of pre- and postsynaptic membrane-associated guanylate kinase (MAGUK) networks, ADAM22 promotes the nanodomain condensation of proteins like PSD-95, which aligns AMPA and NMDA receptor nanoclusters opposite presynaptic active zones.^[25] This alignment is vital for high-fidelity synaptic transmission, as evidenced by disrupted nanoorganization and reduced EPSCs in ADAM22 mutant mice lacking key interaction domains. ADAM22 briefly interacts with the secreted protein LGI1 to support this transsynaptic configuration.^[25] In myelinated axons, ADAM22 is involved in the surface expression of Kv1 potassium channels at juxtaparanodes, where it recruits MAGUKs such as PSD-93 and PSD-95 to stabilize channel clusters and maintain axonal excitability. Experimental evidence from ADAM22-null mice shows normal Kv1.2 clustering but a complete loss of juxtaparanodal MAGUKs, highlighting ADAM22's role in anchoring these scaffolds without directly altering channel density.^[26] This positioning modulates action potential repolarization and propagation, preventing aberrant firing. Knockout studies in mice reveal that ADAM22 deficiency leads to impaired synaptic transmission and early-onset seizures, with homozygous mutants dying within three weeks postnatally due to multiple epileptic events originating in the hippocampus. These phenotypes underscore ADAM22's indispensable function in synaptic organization and neuronal stability.^[20]

Cell Adhesion and Signaling

ADAM22 functions as an adhesion receptor primarily through its disintegrin domain, which facilitates binding to integrins such as α9β1, αvβ3, and α6β1, thereby mediating cell-matrix and cell-cell interactions.^[27][28] This non-proteolytic mechanism allows ADAM22 to regulate cellular processes without enzymatic cleavage, positioning it as a key modulator of intercellular adhesion in neural tissues.^[4] In brain development, ADAM22 contributes to neurogenesis and neuronal migration by exerting integrin-dependent growth inhibition, which helps control cellular proliferation and positioning during embryogenesis.^[29] Although ADAM22-deficient mice exhibit no overt defects in neuronal migration, the protein's interaction with integrins supports balanced growth and differentiation in neural progenitors.^[20] Additionally, non-proteolytic signaling emanates from ADAM22's cytoplasmic tail, which binds 14-3-3 proteins in a phosphorylation-dependent manner to influence cell spreading, differentiation, and migration.^[30][21] Additionally, ADAM22 serves as the neuronal receptor for LGI4 secreted by Schwann cells, which is crucial for promoting myelination in the peripheral nervous system.^[31] Regarding cancer, ADAM22 plays a suppressive role in glioma invasion; it is expressed in normal brain tissue but downregulated in high-grade gliomas, where its absence promotes cellular proliferation and tumor progression via loss of disintegrin-mediated inhibition.^[22] In contrast, ADAM22 is upregulated in certain other malignancies, such as pituitary adenomas and head and neck squamous cell carcinomas, where it enhances cell migration and invasion through integrin activation and epithelial-mesenchymal transition.^[32][33] This dual context-dependent function underscores ADAM22's potential as a regulator of invasive behavior in neoplastic cells.

Protein Interactions

Key Binding Partners

ADAM22, a member of the ADAM family of proteins, lacks metalloprotease catalytic activity due to mutations in its zinc-binding motif, functioning primarily through protein-protein interactions rather than enzymatic cleavage.^[4] Its key extracellular binding partner is leucine-rich glioma-inactivated 1 (LGI1), where the disintegrin domain of ADAM22 interacts with the epilepsy-associated repeat (EAR) domain of LGI1; this interaction was first identified through immunoprecipitation of postsynaptic complexes and mass spectrometry, and confirmed by co-immunoprecipitation assays from mouse brain lysates.^[34] Intracellularly, ADAM22 engages postsynaptic density protein 95 (PSD-95, also known as DLG4) via its C-terminal PDZ-binding motif, which docks to the third PDZ domain of PSD-95, as demonstrated through co-immunoprecipitation studies and a 2021 crystal structure of the PSD-95 PDZ3 domain with the ADAM22 C-terminal peptide.^[35][36] ADAM22 also binds other members of the membrane-associated guanylate kinase (MAGUK) family, such as PSD-93 (DLG2), forming scaffolds at synaptic sites, with interactions validated by co-immunoprecipitation in neuronal preparations. While direct binding to SAP97 (DLG1) has been suggested in broader synaptic contexts, confirmatory evidence remains limited compared to PSD-95 and PSD-93.^[37] Additionally, ADAM22 serves as a probable ligand for integrins, particularly integrin β1 (ITGB1), via its disintegrin domain, promoting cell adhesion signaling as shown in co-immunoprecipitation and functional assays in cell lines.^[32] These direct interactions, established through methods like immunoprecipitation, mass spectrometry, and co-immunoprecipitation, underscore ADAM22's role as a non-enzymatic adhesion molecule without extending to higher-order complex assembly.^[34][35]

Complex Formation

ADAM22 forms multi-protein complexes that are critical for synaptic and axonal organization, primarily through its interactions with leucine-rich glioma-inactivated 1 (LGI1). The core assembly is a 2:2 heterotetrameric LGI1-ADAM22 complex at synapses, as revealed by the crystal structure determined in 2018.^[2] This structure demonstrates that two LGI1 molecules bind to two ADAM22 molecules via hydrophobic pocket interactions between the C-terminal region of LGI1 and the disintegrin domain of ADAM22, forming a stable dimer-of-dimers configuration that facilitates transsynaptic bridging.^[2] Building on this, ADAM22 participates in higher-order transsynaptic complexes involving LGI1 and membrane-associated guanylate kinase (MAGUK) proteins, such as PSD-95, to achieve nanoscale alignment of pre- and postsynaptic components. A 2021 study identified the LGI1-ADAM22-MAGUK complex as essential for organizing synaptic nanodomains, where ADAM22's intracellular C-terminal tail recruits PSD-95 to align AMPA receptors postsynaptically with presynaptic release sites.^[37] Recent cryo-EM structural analysis in 2025 has advanced this model, resolving a heterohexameric 3:3 LGI1-ADAM22 assembly that supports dynamic nanoalignment and precise synaptic transmission.^[38] In axonal regions, ADAM22 contributes to complexes with voltage-gated Kv1 potassium channels, mediated by LGI1, to promote channel clustering at the axon initial segment and juxtaparanodes. This LGI1-ADAM22-Kv1 assembly regulates potassium conductance and action potential firing, with ADAM22 acting as a scaffold to recruit channel-associated proteins like CASPR2.^[39] The 2025 structural insights further indicate that the 3:3 heterohexameric form may enhance the efficiency of Kv1 clustering by controlling channel density along axons.^[38] Complex stability is modulated by post-translational modifications, notably phosphorylation of ADAM22 by protein kinase A (PKA). A 2021 investigation showed that PKA phosphorylates ADAM22 at serine residues S832 and S855, which recruits 14-3-3 proteins to stabilize surface levels of the LGI1-ADAM22 complex and prevent degradation, thereby maintaining physiological seizure thresholds.^[40]

Pathophysiology

Associated Diseases

Mutations in the ADAM22 gene are primarily associated with developmental and epileptic encephalopathy 61 (DEE61), an autosomal recessive disorder characterized by refractory seizures beginning in the first year of life, profound developmental delay, and progressive brain atrophy.^[7] Affected individuals often exhibit hypotonia, poor head control, and feeding difficulties, with neuroimaging revealing cerebral and cerebellar atrophy.^[7] The prevalence of DEE61 remains rare, with approximately 30-40 cases reported worldwide as of 2024, predominantly in consanguineous families.^[7][8] Specific ADAM22 variants have been linked to focal epilepsy and behavioral disorders, as demonstrated in a 2023 study of an ethnic-specific homozygous variant (p.S905F) prevalent in the Roma population.^[41] This variant impairs ADAM22 binding to membrane-associated guanylate kinases, resulting in pharmacoresistant focal seizures and neurodevelopmental issues including intellectual disability and autism spectrum-like behaviors.^[41] Such cases highlight a narrower phenotypic spectrum compared to DEE61, with onset in early childhood and potential for partial seizure control.^[42] ADAM22 dysregulation plays a potential role in glioma progression, where its expression is notably reduced in high-grade gliomas compared to normal brain tissue. This loss of expression correlates with increased cellular proliferation, as ADAM22 normally inhibits glioma cell growth through its disintegrin domain. While direct survival correlations in glioma cohorts are limited, the absence of ADAM22 in aggressive tumors suggests it may act as a suppressor, with low levels contributing to poorer outcomes.^[43] Overexpression of ADAM22 is associated with adverse outcomes in estrogen receptor-positive breast cancer, where high levels in primary tumors predict poor disease-free survival.^[44] Furthermore, ADAM22 upregulation contributes to tamoxifen resistance in these cancers, mediated by reduced miR-449a expression, leading to enhanced cell proliferation and survival despite endocrine therapy.^[45] Recent analyses as of 2025 confirm this mechanism, positioning ADAM22 as a key factor in endocrine-resistant progression.^[46]

Pathogenic Variants

Pathogenic variants in the ADAM22 gene have been identified as causative of developmental and epileptic encephalopathy 61 (DEE61), an autosomal recessive disorder characterized by severe infantile-onset epilepsy and progressive neurological decline. The initial discovery in 2016 involved compound heterozygous mutations consisting of a missense variant c.1202G>A (p.Cys401Tyr) and a frameshift variant c.2396delG (p.Ser799Ilefs*96) in a patient with progressive encephalopathy, cortical atrophy, and epilepsy; these variants disrupt the disintegrin domain and abolish binding to the secreted protein LGI1, thereby preventing formation of the LGI1-ADAM22 ligand-receptor complex essential for synaptic function.^[47] Subsequent studies have reported biallelic loss-of-function mutations, including nonsense (e.g., p.Arg860*) and frameshift variants, which lead to premature termination codons, nonsense-mediated decay, and significantly reduced ADAM22 protein levels in patient-derived fibroblasts and brain tissue. These alterations, identified in multiple unrelated families with DEE61, impair postsynaptic localization and transsynaptic signaling, contributing to refractory seizures and encephalopathy.^[48] Additional missense variants affecting the extracellular domain have been shown to variably impair LGI1 binding in functional assays, with reduced co-immunoprecipitation and impaired clustering at synapses, directly linking these changes to epileptic phenotypes in affected individuals. A rare homozygous missense variant, c.2714C>T (p.Ser905Phe), prevalent in cohorts of Roma ancestry, reduces binding to membrane-associated guanylate kinases (MAGUKs) like PSD-95, as demonstrated by co-immunoprecipitation and surface plasmon resonance assays, and is associated with focal epilepsy and behavioral disorders in homozygous carriers.^[41]