Alternative titles; symbols
HGNC Approved Gene Symbol: ADAM10
SNOMEDCT: 239133004;
Cytogenetic location: 15q21.3 Genomic coordinates (GRCh38): 15:58,588,809-58,749,707 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q21.3 | {Alzheimer disease 18, susceptibility to} | 615590 | 3 | |
| Reticulate acropigmentation of Kitamura | 615537 | Autosomal dominant | 3 |
The ADAM10 gene encodes a member of the ADAM (a disintegrin and metalloprotease) family and possesses alpha-secretase activity (summary by Kim et al., 2009).
Wolfsberg et al. (1995) identified several proteins as members of the ADAM family, including ADAM10. Members of this family are cell surface proteins with a unique structure possessing both potential adhesion and protease function. ADAM proteins contain an N-terminal signal sequence, followed by a prodomain, a metalloprotease-like domain, a disintegrin-like domain, a cysteine-rich region, an EGF (131530)-like repeat, a transmembrane domain, and a C-terminal cytoplasmic tail.
Rosendahl et al. (1997) purified ADAM10 as a TNF (191160)-processing enzyme from membrane extracts of a human monocytic cell line. By peptide sequencing, database analysis, PCR, and screening a human macrophage cDNA library, they cloned ADAM10, which they designated AD10. The deduced 748-amino acid protein shares significant identity with bovine and rat Adam10. The predicted mature processed protein has 535 amino acids and a calculated molecular mass of 59.3 kD. ADAM10 has 4 potential N-glycosylation sites. Northern blot analysis detected a 5.0-kb ADAM10 transcript in all tissues examined. SDS-PAGE detected purified ADAM10 at an apparent molecular mass of 62 kD.
By PCR using primers based on conserved regions in bovine Adam10 and the Drosophila homolog, kuzbanian (kuz), Yavari et al. (1998) cloned 2 variants of human ADAM10, which they called KUZL and KUZS, from a fetal brain cDNA library. The deduced KUZL and KUZS proteins contain 748 and 568 amino acids, respectively. KUZS has only 3 amino acids following the disintegrin domain and lacks the cysteine-rich, transmembrane, and cytoplasmic domains of KUZL. Yavari et al. (1998) suggested that KUZS may be a soluble isoform. Northern blot analysis of human fetal tissues detected variable expression of a 4.9-kb KUZL transcript and a 4.4-kb KUZS transcript. KUZS was highly expressed in testis and ovary and predominated in all other adult tissues examined except thymus and brain, where both KUZS and KUZL were detected. Northern blot analysis of adult and embryonic mouse tissues revealed only a 5.7-kb transcript corresponding to KUZL. In situ hybridization and immunohistochemical analysis of mouse tissues detected Kuz in the developing olfactory system and sympathetic nervous system. It was expressed in developing neuroblasts and in tumors of the adrenal medulla, but not in normal adult adrenals.
Prinzen et al. (2005) determined that the human and mouse ADAM10 genes contain 16 exons and cover about 160 kb. Both lack a TATA box, but have characteristic SP1 (189906) sites and a CAAT box. The human upstream region contains putative binding sites for BRN2 (POU3F2; 600494), SREBP (see 184756), OCT1 (POU2F1; 164175), CREB1 (123810)/JUN (165160), USF (see 191523), MAZ (600999), MZF1 (194550), and NFKB (see 164011).
Using a radiation hybrid mapping method, Yamazaki et al. (1997) mapped the ADAM10 gene to chromosome 15q21.3-q23. By FISH, Yavari et al. (1998) mapped the ADAM10 gene to chromosome 15q22.
Tumor necrosis factor-alpha (TNFA) is synthesized as a proinflammatory cytokine from a 233-amino acid precursor. Conversion of the membrane-bound precursor to a secreted mature protein is mediated by a protease termed TNFA convertase. Lunn et al. (1997) found that ADAM10 possesses TNFA convertase activity.
Rosendahl et al. (1997) found that both ADAM10 purified from a human monocytic cell line and recombinant ADAM10 isolated from a transfected human kidney cell line proteolytically processed the 26-kD TNF proprotein to the 17-kD TNF soluble mature peptide. Both enzymes were sensitive to metal chelators and had pH optima between 9 and 10.
Although ephrins form a high-affinity multivalent complex with their receptors present on axons, axons can be rapidly repelled rather than being bound. Hattori et al. (2000) showed that ephrin-A2 (602756) forms a stable complex with the metalloproteinase Kuzbanian (ADAM10) involving interactions outside the cleavage region and the protease domain. Eph receptor binding triggered ephrin-A2 cleavage in a localized reaction specific to the cognate ligand. The cleavage-inhibiting mutation in ephrin-A2 delayed axon withdrawal. Hattori et al. (2000) concluded that their studies reveal mechanisms for protease recognition and control of cell surface proteins, and, for ephrin-A2, they may provide a means for efficient axon detachment and termination of signaling.
Janes et al. (2005) defined an essential substrate-recognition module for the functional interaction of mammalian Adam10 with the ephrin-A5 (601535)/ephrin receptor EphA3 (179611) complex. While Adam10 constitutively associated with EphA3, the formation of a functional EphA3/ephrin-A5 complex created a new molecular recognition motif for the Adam10 cysteine-rich domain that positioned the protease domain for effective ephrin-A5 cleavage. Janes et al. (2005) also showed that cleavage occurred in trans, with Adam10 and its substrate on the membranes of opposing cells.
Kojro et al. (2001) found that ADAM10 has alpha-secretase activity that mediates the effect of cholesterol on amyloid precursor protein (APP; 104760) metabolism. Treatment of various peripheral and neural human cell lines with either a cholesterol-extracting agent or an HMG-CoA reductase (HMGCR; 142910) inhibitor resulted in a drastic increase of secreted alpha-secretase-cleaved soluble APP peptides. The stimulatory effect was further increased in cells overexpressing ADAM10. In cells overexpressing APP, the increase in alpha-secretase activity resulted in decreased secretion of amyloidogenic beta-secretase-generated APP peptides. Western blot analysis confirmed that HMGCR inhibition increased expression of ADAM10. Kojro et al. (2001) concluded that cholesterol reduction promotes the nonamyloidogenic alpha-secretase pathway and formation of neuroprotective soluble alpha-secretase APP peptides.
By transfecting double-stranded RNA corresponding to several ADAMs, Asai et al. (2003) determined that the alpha-secretase activity displayed by a human glioblastoma cell line toward APP was catalyzed by the combined activity of ADAM9 (602713), ADAM10, and ADAM17 (603639).
Postina et al. (2004) found that moderate neuronal overexpression of human ADAM10 in mice carrying a human APP mutation (V717I; 104760.0002) increased secretion of the neurotrophic soluble alpha-secretase-released N-terminal APP domain, reduced formation of amyloid beta peptides, and prevented their deposition in plaques. Functionally, impaired long-term potentiation and cognitive deficits were alleviated. Expression of mutant catalytically-inactive ADAM10 in mice carrying a human APP mutation led to an enhancement of the number and size of amyloid plaques in the brains of such mice.
Yan et al. (2002) presented evidence that mammalian Adam10 may relay cell signaling between the G protein-coupled receptor and EGF receptor (EGFR; 131550) signaling pathways.
Using specific metalloprotease inhibitors and overexpression studies, Hundhausen et al. (2003) determined that basal shedding of CX3CL1 (601880) from human leukemia and bladder carcinoma cell membranes was mediated by ADAM10, whereas phorbol ester-stimulated CX3CL1 shedding was mediated by TACE (ADAM17). Mouse embryo fibroblasts deficient in Adam10 showed reduced basal Cx3cl1 shedding in comparison with wildtype fibroblasts, but stimulated Cx3cl1 shedding was not affected. Inhibition of CX3CL1 cleavage increased the adhesive properties of an adherent CX3CL1-expressing human bladder carcinoma cell line and prevented deadhesion of attached monocytic leukemia cells. Hundhausen et al. (2003) concluded that constitutive cleavage of CX3CL1 by ADAM10 may regulate recruitment of monocytic cells to CX3CL1-expressing cell layers.
By transfecting human and murine cell lines with CXCL16 (605398) cDNA, followed by treatment with specific ADAM inhibitors, Abel et al. (2004) determined that ADAM10, but not ADAM17, is involved in constitutive cleavage of the transmembrane adhesion molecule CXCL16 to a soluble chemoattractant for activated T cells. Constitutive cleavage was markedly reduced in Adam10-deficient mouse fibroblasts and was restored by retransfection with ADAM10. Abel et al. (2004) concluded that ADAM10 is the most relevant sheddase of CXCL16.
Using EMSA analysis, Prinzen et al. (2005) found that nuclear proteins from a human neuroblastoma cell line bound to 1 of 2 retinoic acid-responsive elements in the ADAM10 promoter. Retinoic acid increased endogenous ADAM10 expression by up to 250%.
Full-length membrane-bound E-cadherin (CDH1; 192090) is cleaved in the extracellular domain by a metalloprotease, generating a 38-kD C-terminal fragment, which can be further processed by a gamma-secretase-like activity into a soluble 33-kD C-terminal fragment. Using a panel of mouse embryonic fibroblasts deficient in various metalloproteases, Maretzky et al. (2005) found that those cells deficient in Adam10 showed reduced generation of the E-cadherin 38-kD C-terminal fragment. They further found that Adam10 was responsible for both constitutive and regulated E-cadherin shedding in mouse fibroblasts and keratinocytes. Adam10-mediated E-cadherin shedding affected epithelial cell-cell adhesion as well as cell migration, and it modulated beta-catenin (CTNNB1; 116806) subcellular localization and downstream signaling.
Following membrane-proximal cleavage, CD23 (FCER2; 151445) is an important mediator of the allergic response. Using loss-of-function and gain-of-function experiments with mouse cells lacking or overexpressing candidate CD23-releasing enzymes, ADAM-knockout mice, and a selective inhibitor, Weskamp et al. (2006) identified ADAM10 as the main CD23-releasing enzyme, or 'sheddase,' in vivo. They proposed that ADAM10 is a likely target for treatment of allergic reactions and that ADAM10 may be involved in other CD23-dependent pathologies.
Chen et al. (2007) found that ADAM10 and ADAM17 mediated shedding of Klotho (KL; 604824) from cell membranes of Klotho-transfected COS-7 cells, a model system they validated by studies in rat kidney slices. Insulin enhanced Klotho shedding, and this effect was abolished by silencing of ADAM10 or ADAM17. Insulin appeared to stimulate ADAM10 and ADAM17 proteolytic activity toward Klotho, but did not increase their mRNA or protein levels.
Using a biochemical approach to purify a putative host receptor for the S. aureus alpha-hemolysin (Hla) cytotoxin followed by immunoblot and flow cytometric analysis, Wilke and Bubeck Wardenburg (2010) identified ADAM10 in rabbit erythrocytes and a human alveolar epithelial cell line. Fluorescence microscopy demonstrated colocalization of Hla with ADAM10 on cell membranes in a complex with CAV1 (601047)-enriched lipid rafts. Knockdown of ADAM10, but not ADAM9 (602713) or ADAM17 (603639), expression with siRNA reduced Hla interaction with cells and prevented cytotoxicity. The Hla-ADAM10 interaction is required for the toxin to be transformed into a cytolytic pore. Wilke and Bubeck Wardenburg (2010) concluded that the Hla-ADAM10 complex initiates intracellular signaling events that culminate in the disruption of focal adhesions.
Using N2a mouse neuroblastoma cells expressing mutant human APP, Lee et al. (2014) found that Sirt1 (604479) increased the secretase activity of Adam10 via activation of retinoic acid receptor-beta (RARB; 180220).
Willem et al. (2015) described a physiologic APP (104760) processing pathway that generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. The authors identified higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-eta, in addition to the long-known CTF-alpha and CTF-beta fragments generated by the alpha- and beta-secretases ADAM10 and BACE1 (604252), respectively. CTF-eta generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP (604871), referred to as eta-secretase activity. Eta-secretase cleavage occurs primarily at amino acids 504-505 of APP(695), releasing a truncated ectodomain. After shedding of this ectodomain, CTF-eta is further processed by ADAM10 and BACE1 to release long and short A-eta peptides (termed A-eta-alpha and A-eta-beta). CTFs produced by eta-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacologic inhibition of BACE1 activity results in robust accumulation of CTF-eta and A-eta-alpha. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic A-eta-alpha was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell 2-photon calcium imaging showed that hippocampal neuronal activity was attenuated by A-eta-alpha.
Atapattu et al. (2016) reported a conformation-specific antibody that recognized an active form of ADAM10 that was preferentially expressed in tumors compared with normal tissue in mouse models and humans. Binding of the antibody depended on disulfide isomerization and oxidative conditions common in tumors. This active form of ADAM10 marked cancer stem-like cells with active Notch signaling. Targeting of Adam10 with the antibody inhibited Notch activity and tumor growth in mouse models, particularly regrowth after chemotherapy. Atapattu et al. (2016) proposed that targeted inhibition of active ADAM10 may serve as a therapy for ADAM10-dependent tumor development and drug resistance.
ADAM10 is regulated by a subgroup of tetraspanins, transmembrane proteins that regulate the intracellular trafficking and membrane localization of the proteins with which they associate. The 6 ADAM10-regulating tetraspanins are known as the TspanC8 subgroup. Reyat et al. (2017) showed that the TspanC8s TSPAN17 (620446) and TSPAN5 (613136) are facilitators of T lymphocyte transmigration through their regulation of ADAM10 and VE-cadherin (601120). Knockdown of ADAM10 in human umbilical vein endothelial cells (HUVECs) resulted in reduced transmigration of peripheral blood T lymphocytes (PBL) by approximately 50%. Flow cytometry showed that VE-cadherin expression levels increased in the absence of ADAM10, and VE-cadherin knockdown to normal levels rescued the PBL transmigration defect in HUVECs. Combination knockdown experiments revealed that expression of either TSPAN17 or TSPAN5 maintained normal PBL transmigration, accompanied by a reduction in surface VE-cadherin levels. Taking into account previous reports of the roles of TspanC8s, ADAM10, and VE-cadherin in leukocyte trafficking, Reyat et al. (2017) proposed a model in which the highly related TSPAN17 and TSPAN5 promote constitutive ADAM10 shedding of VE-cadherin to control surface expression levels.
Keller et al. (2020) demonstrated that ATG16L1 (610767) and other ATG proteins mediate protection against alpha-toxin through the release of ADAM10 on exosomes (extracellular vesicles of endosomal origin). Bacterial DNA and CpG DNA induced the secretion of ADAM10-bearing exosomes from human cells as well as in mice. Transferred exosomes protected host cells in vitro by serving as scavengers that could bind multiple toxins, and improved the survival of mice infected with MRSA in vivo. Keller et al. (2020) concluded that their findings indicated that ATG proteins mediate a previously unknown form of defense in response to infection, facilitating the release of exosomes that serve as decoys for bacterially produced toxins.
Loganathan et al. (2020) focused on 484 genes harboring recurrent but rare mutations ('long tail' genes) in head and neck squamous cell carcinoma (HNSCC; 275355) and used in vivo CRISPR to screen for genes that, upon mutation, trigger tumor development in mice. Of the 15 tumor-suppressor genes identified, ADAM10 and AJUBA (609066) suppressed HNSCC in a haploinsufficient manner by promoting NOTCH (190198) receptor signaling. ADAM10 and AJUBA mutations or monoallelic loss occurred in 28% of human HNSCC cases and were mutually exclusive with NOTCH receptor mutations. Loganathan et al. (2020) concluded that their results showed that oncogenic mutations in 67% of human HNSCC cases converge onto the NOTCH signaling pathway, making NOTCH inactivation a hallmark of this cancer.
Reticulate Acropigmentation of Kitamura
In 5 Japanese families with autosomal dominant reticulate acropigmentation of Kitamura (RAK; 615537), known to be negative for mutation in the KRT5 gene (148040), Kono et al. (2013) identified heterozygous mutations in the ADAM10 gene (602192.0001-602192.0005) that segregated with disease in the respective families and were not found in 102 Japanese controls.
Susceptibility to Alzheimer Disease 18
Kim et al. (2009) presented evidence from SNP analysis for genetic association of ADAM10 with late-onset Alzheimer disease (AD18; 615590) (rs2305421; p = 0.008). Direct sequencing of the gene identified 2 rare, potentially disease-associated nonsynonymous mutations, Q170H (602192.0006) and R181G (602192.0007), in the ADAM10 prodomain. Heterozygosity for these mutations was found in 11 of 16 affected individuals from 7 of 436 AD families (NIMH cohort), as well as in 2 of 5 affected individuals from 2 of 351 additional affected families (NIA cohort). However, there was incomplete segregation with AD; several affected individuals did not carry the mutation, and several unaffected individuals did carry the mutation. These findings suggested either incomplete penetrance or the involvement of additional factors. Combining both mutations to 1 aggregate genotype showed an association with AD across both samples (p = 0.0186), but a nonsignificant p value of 0.212 after exclusion of the probands initially selected for sequencing. In vitro functional studies showed that both mutations significantly attenuated alpha-secretase activity of ADAM10 (greater than 70% decrease) and elevated A-beta levels (1.5- to 3.5-fold). In contrast, Cai et al. (2012) did not find an association between variation in the ADAM10 gene among 305 unrelated AD probands and 271 controls of European ancestry. One identified variant (L9V) was determined to be associated with Ashkenazi ancestry and not with AD. The Q170H and R181G variants found by Kim et al. (2009) were not identified.
Suh et al. (2013) confirmed the pathogenicity of the Q170H and R181G ADAM10 variants in animal studies; see ANIMAL MODEL.
Hartmann et al. (2002) created Adam10-deficient mice. The mice died at day 9.5 of embryogenesis with multiple defects of the developing central nervous system, somites, and cardiovascular system. In situ hybridization revealed a reduced expression of the Notch target gene, hes5 (607348), in the neural tube and an increased expression of the Notch ligand, dll1 (606582), suggesting an important role for Adam10 in Notch signaling. Since the early lethality precluded the establishment of primary neuronal cultures, amyloid precursor protein (APP; 104760) alpha-secretase activity was analyzed in embryonic fibroblasts and found to be preserved in 15 of 17 independently generated Adam10-deficient fibroblast cell lines, albeit at a quantitatively more variable level than in controls. The authors proposed either a regulation between ADAMs on the posttranslational level, or that other, as yet unknown, proteases are able to compensate for Adam10 deficiency. The authors hypothesized the existence of tissue-specific 'teams' of different proteases exerting alpha-secretase activity.
Gibb et al. (2010) generated B cell-specific Adam10-knockout mice and, using flow cytometric and immunohistochemical analyses, found that Adam10 was essential for development of marginal zone B cells (MZB). B cells lacking Adam10 had severely impaired Notch2 (600275) signaling. In addition, B cells lacking Adam10 showed profoundly decreased cleavage of the low-affinity IgE receptor, Cd23. Gibb et al. (2010) concluded that ADAM10 acts as a CD23 sheddase and, by a different mechanism, initiates NOTCH2 signaling that is critical for MZB development and for which there appears to be no compensatory protease.
Inoshima et al. (2011) showed that mice lacking Adam10 in lung epithelium were resistant to lethal pneumonia caused by Staphylococcus aureus. Investigation of the molecular mechanism revealed that S. aureus alpha-hemolysin (Hla) upregulated Adam10 metalloprotease activity in alveolar epithelial cells, resulting in cleavage of e-cadherin, which was associated with disruption of epithelial barrier function. Cleavage was blocked by an Adam10 metalloprotease inhibitor in response to Hla. Toxin-dependent e-cadherin proteolysis and barrier disruption was attenuated in Adam10 -/- mice. Inoshima et al. (2011) concluded that ADAM10 is the cellular receptor for Hla and that Hla usurps the metalloprotease activity of the receptor, suggesting a strategy to attenuate Hla-induced disease.
By generating mice with a conditional knockout that abrogated epidermal Adam10 expression, Inoshima et al. (2012) determined that Adam10 is required for the development of dermatonecrotic lesions following subcutaneous infection with S. aureus. Although abscess size was reduced in Adam10 knockout mice, recovery of bacteria from the lesion was not. Systemic or topical application of an ADAM10 inhibitor also prevented skin breakdown. Inoshima et al. (2012) concluded that ADAM10 is required to mediate epithelial barrier injury.
Suh et al. (2013) generated transgenic mice carrying the late-onset Alzheimer disease (LOAD)-associated ADAM10 prodomain variants Q170H or R181G, as well as an artificial dominant-negative mutant, E384A. All 3 mutant mice showed decreased levels of Adam10 C-terminal fragments compared to wildtype, indicating that these mutations interfere with the normal ectodomain shedding of Adam10 itself. Q170H and R181G mutant mice showed significant attenuation of APP processing compared to wildtype, with a decrease in APP-CTF-alpha levels and an increase in sAPP-beta levels, indicating that the mutations attenuated Adam10 alpha-secretase activity on APP. Crossing these Adam10 mutant mice with the Tg2576 AD mouse model showed that the Adam10 mutations increased amyloidogenic APP processing, as manifest by a shift from the alpha-secretase to the amyloidogenic beta-secretase pathway. This was associated with increased beta-amyloid plaque load and reactive gliosis in the brains of mutant transgenic mice. The changes were not as significant as those observed with the dominant-negative Adam10 mutation, suggesting that the Q170H and R181G mutants diminish, but do not abolish, alpha-secretase activity. The LOAD-associated mutations were shown to decrease hippocampal neurogenesis compared to wildtype Adam10. The LOAD mutations impaired the intramolecular chaperone function of the Adam10 prodomain. Collectively, these findings suggested that diminished alpha-secretase activity of ADAM10 on APP resulting from mutations in the ADAM10 prodomain can cause AD-related pathology.
The article by Donmez et al. (2010) showing that Sirt1 suppressed beta-amyloid production by activating the Adam10 gene in a mouse model of Alzheimer disease was retracted.
In affected members of a 4-generation Japanese family with autosomal dominant reticulate acropigmentation of Kitamura (RAK; 615537), Kono et al. (2013) identified heterozygosity for 2 mutations on the same allele of the ADAM10 gene: a c.415C-T transition in exon 4, resulting in a pro139-to-ser (P139S) substitution, and a 5-bp insertion (c.424insCAGAG) in exon 4, causing a frameshift predicted to result in a premature termination codon (Arg142fsTer43) with loss of the propeptide domain and downstream regions. The mutations segregated with disease in the family and were not found in 102 Japanese controls.
In a 66-year-old Japanese man with reticulate acropigmentation of Kitamura (RAK; 615537) and his affected 36-year-old daughter, Kono et al. (2013) identified heterozygosity for a c.1511G-A transition at the 3-prime end of exon 11 of the ADAM10 gene, predicted to cause a splicing error. The mutation segregated with disease in the family and was not found in 102 Japanese controls. Relative quantification of ADAM10 mRNA in patient cells showed an expression level that was approximately half that of controls.
In a 51-year-old Japanese woman with reticulate acropigmentation of Kitamura (RAK; 615537), Kono et al. (2013) identified heterozygosity for a c.429T-A transversion in exon 4 of the ADAM10 gene, resulting in a tyr143-to-ter (Y143X) substitution predicted to cause loss of the propeptide domain and downstream regions. The mutation segregated with disease in the family and was not found in 102 Japanese controls.
In a 20-year-old Japanese woman with reticulate acropigmentation of Kitamura (RAK; 615537), Kono et al. (2013) identified heterozygosity for a 1-bp deletion (c.1264delA) in exon 10 of the ADAM10 gene, causing a frameshift predicted to result in a premature termination codon (Thr422fsTer19) with loss of the metalloproteinase domain and downstream regions. The mutation segregated with disease in the family and was not found in 102 Japanese controls.
In a 34-year-old Japanese man with reticulate acropigmentation of Kitamura (RAK; 615537), Kono et al. (2013) identified heterozygosity for a c.1571G-A transition in exon 12 of the ADAM10 gene, resulting in a cys524-to-tyr (C524Y) substitution at a highly conserved residue in the disintegrin domain. The mutation segregated with disease in the family and was not found in 102 Japanese controls.
In 7 affected individuals from 4 unrelated families with late-onset Alzheimer disease (AD18; 615590), Kim et al. (2009) identified a heterozygous mutation in the ADAM10 gene, resulting in a gln170-to-his (Q170H) substitution in the prodomain. The mutation was found by direct sequencing of the ADAM10 gene after genetic association was suggested by SNP analysis. The mutation did not segregate perfectly with the disorder: 3 patients with AD did not carry the mutation, and 1 unaffected family member did carry the mutation. These findings suggested either incomplete penetrance or the involvement of additional factors. In vitro functional studies showed that the mutation significantly attenuated alpha-secretase activity of ADAM10 (greater than 70% decrease) and elevated A-beta levels (1.5- to 3.5-fold).
Suh et al. (2013) confirmed the pathogenicity of the Q170H mutation in transgenic mouse studies. The mutation attenuated alpha-secretase activity of ADAM10 and shifted APP processing toward beta-secretase-mediated cleavage, resulting in enhanced beta-amyloid plaque load and reactive gliosis.
In 4 affected individuals from 3 unrelated families with late-onset Alzheimer disease (AD18; 615590), Kim et al. (2009) identified a heterozygous mutation in the ADAM10 gene, resulting in an arg181-to-gly (R181G) substitution in the prodomain. The mutation was found by direct sequencing of the ADAM10 gene after genetic association was suggested by SNP analysis. The mutation did not segregate perfectly with the disorder: 2 patients with AD did not carry the mutation, and 2 unaffected family members did carry the mutation. These findings suggested either incomplete penetrance or the involvement of additional factors. In vitro functional studies showed that the mutation significantly attenuated alpha-secretase activity of ADAM10 (greater than 70% decrease) and elevated A-beta levels (1.5- to 3.5-fold).
Suh et al. (2013) confirmed the pathogenicity of the R181G mutation in transgenic mouse studies. The mutation attenuated alpha-secretase activity of ADAM10 and shifted APP processing toward beta-secretase-mediated cleavage, resulting in enhanced beta-amyloid plaque load and reactive gliosis.
Abel, S., Hundhausen, C., Mentlein, R., Schulte, A., Berkhout, T. A., Broadway, N., Hartmann, D., Sedlacek, R., Dietrich, S., Muetze, B., Schuster, B., Kallen, K.-J., Saftig, P., Rose-John, S., Ludwig, A. The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10. J. Immun. 172: 6362-6372, 2004. [PubMed: 15128827] [Full Text: https://doi.org/10.4049/jimmunol.172.10.6362]
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Chen, C.-D., Podvin, S., Gillespie, E., Leeman, S. E., Abraham, C. R. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc. Nat. Acad. Sci. 104: 19796-19801, 2007. [PubMed: 18056631] [Full Text: https://doi.org/10.1073/pnas.0709805104]
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Hundhausen, C., Misztela, D., Berkhout, T. A., Broadway, N., Saftig, P., Reiss, K., Hartmann, D., Fahrenholz, F., Postina, R., Matthews, V., Kallen, K.-J., Rose-John, S., Ludwig, A. The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion. Blood 102: 1186-1195, 2003. [PubMed: 12714508] [Full Text: https://doi.org/10.1182/blood-2002-12-3775]
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