MADD

Summary

MADD (MAP kinase activating death domain, HGNC:6766) is a protein-coding gene on chromosome 11p11.2, encoding MAP kinase-activating death domain protein (Q8WXG6). Guanyl-nucleotide exchange factor that regulates small GTPases of the Rab family.

Tumor necrosis factor alpha (TNF-alpha) is a signaling molecule that interacts with one of two receptors on cells targeted for apoptosis. The apoptotic signal is transduced inside these cells by cytoplasmic adaptor proteins. The protein encoded by this gene is a death domain-containing adaptor protein that interacts with the death domain of TNF-alpha receptor 1 to activate mitogen-activated protein kinase (MAPK) and propagate the apoptotic signal. It is membrane-bound and expressed at a higher level in neoplastic cells than in normal cells. Several transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 8567 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (Strong, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 419 total — 16 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 2
• MANE Select transcript: NM_001376571

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6766
Approved symbol	MADD
Name	MAP kinase activating death domain
Location	11p11.2
Locus type	gene with protein product
Status	Approved
Aliases	DENN, KIAA0358, RAB3GEP, IG20
Ensembl gene	ENSG00000110514
Ensembl biotype	protein_coding
OMIM	603584
Entrez	8567

Gene structure

Transcript identifiers

Ensembl transcripts: 105 — 96 protein_coding, 5 protein_coding_CDS_not_defined, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000311027, ENST00000342922, ENST00000349238, ENST00000395336, ENST00000395344, ENST00000402192, ENST00000402799, ENST00000405573, ENST00000406482, ENST00000407859, ENST00000422579, ENST00000428807, ENST00000444117, ENST00000453571, ENST00000460452, ENST00000469699, ENST00000489415, ENST00000494403, ENST00000524530, ENST00000524686, ENST00000526603, ENST00000534808, ENST00000634938, ENST00000706886, ENST00000706887, ENST00000706888, ENST00000706889, ENST00000706890, ENST00000706891, ENST00000908683, ENST00000908684, ENST00000908685, ENST00000908686, ENST00000908687, ENST00000908688, ENST00000908689, ENST00000908690, ENST00000908691, ENST00000908692, ENST00000908693, ENST00000908694, ENST00000908695, ENST00000908696, ENST00000908697, ENST00000908698, ENST00000908699, ENST00000908700, ENST00000908701, ENST00000908702, ENST00000908703, ENST00000908704, ENST00000908705, ENST00000908706, ENST00000908707, ENST00000908708, ENST00000908709, ENST00000908710, ENST00000908711, ENST00000908712, ENST00000908713, ENST00000908714, ENST00000922716, ENST00000922717, ENST00000922718, ENST00000922719, ENST00000922720, ENST00000922721, ENST00000922722, ENST00000922723, ENST00000922724, ENST00000922725, ENST00000922726, ENST00000922727, ENST00000922728, ENST00000922729, ENST00000922730, ENST00000922731, ENST00000922732, ENST00000922733, ENST00000945113, ENST00000945114, ENST00000945115, ENST00000945116, ENST00000945117, ENST00000945118, ENST00000945119, ENST00000945120, ENST00000945121, ENST00000945122, ENST00000945123, ENST00000945124, ENST00000945125, ENST00000945126, ENST00000945127, ENST00000945128, ENST00000945129, ENST00000945130, ENST00000945131, ENST00000945132, ENST00000945133, ENST00000945134, ENST00000945135, ENST00000945136, ENST00000945137, ENST00000945138

RefSeq mRNA: 97 — MANE Select: NM_001376571 NM_001135943, NM_001135944, NM_001376571, NM_001376572, NM_001376573, NM_001376574, NM_001376575, NM_001376576, NM_001376577, NM_001376578, NM_001376579, NM_001376580, NM_001376581, NM_001376582, NM_001376583, NM_001376584, NM_001376585, NM_001376586, NM_001376593, NM_001376594, NM_001376595, NM_001376596, NM_001376597, NM_001376598, NM_001376599, NM_001376600, NM_001376601, NM_001376602, NM_001376603, NM_001376604, NM_001376605, NM_001376606, NM_001376607, NM_001376608, NM_001376609, NM_001376610, NM_001376611, NM_001376612, NM_001376613, NM_001376614, NM_001376615, NM_001376616, NM_001376617, NM_001376618, NM_001376619, NM_001376620, NM_001376621, NM_001376622, NM_001376623, NM_001376624, NM_001376625, NM_001376626, NM_001376627, NM_001376628, NM_001376629, NM_001376630, NM_001376631, NM_001376632, NM_001376633, NM_001376634, NM_001376635, NM_001376636, NM_001376637, NM_001376638, NM_001376639, NM_001376640, NM_001376641, NM_001376642, NM_001376643, NM_001376644, NM_001376645, NM_001376646, NM_001376647, NM_001376648, NM_001376649, NM_001376650, NM_001376651, NM_001376652, NM_001376653, NM_001376654, NM_001376655, NM_001376656, NM_001376657, NM_001376658, NM_001376659, NM_001376660, NM_001376661, NM_001376662, NM_001376663, NM_003682, NM_130470, NM_130471, NM_130472, NM_130473, NM_130474, NM_130475, NM_130476

CCDS: CCDS41642, CCDS44586, CCDS44587, CCDS44588, CCDS44589, CCDS44590, CCDS7930, CCDS7931, CCDS7932

Canonical transcript exons

ENST00000706887 — 37 exons

Exon	Start	End
ENSE00000839266	47274563	47275159
ENSE00000921216	47282381	47282616
ENSE00000921218	47282813	47282969
ENSE00000921221	47284178	47284281
ENSE00000921222	47284375	47284565
ENSE00000921224	47284941	47285194
ENSE00000921230	47288968	47289027
ENSE00000921233	47289867	47290053
ENSE00000921236	47290149	47290299
ENSE00000921238	47290610	47290816
ENSE00000921239	47292543	47292596
ENSE00000921242	47295496	47295579
ENSE00000921245	47295897	47296055
ENSE00000921247	47308591	47308699
ENSE00000921248	47308980	47309042
ENSE00000921250	47309281	47309401
ENSE00000921251	47309507	47309612
ENSE00000921253	47311732	47311842
ENSE00000921256	47315220	47315327
ENSE00001316877	47276732	47276863
ENSE00001326771	47326738	47326807
ENSE00001387749	47273827	47273976
ENSE00001563646	47270133	47270246
ENSE00003516201	47275899	47276202
ENSE00003522632	47289391	47289493
ENSE00003544708	47278999	47279079
ENSE00003556201	47324265	47324337
ENSE00003556575	47329046	47330031
ENSE00003567773	47293883	47293983
ENSE00003597442	47286433	47286534
ENSE00003624641	47328658	47328704
ENSE00003625089	47278165	47278278
ENSE00003627459	47324471	47324577
ENSE00003636999	47323671	47323835
ENSE00003642745	47285451	47285590
ENSE00003675750	47281575	47281753
ENSE00003997324	47326544	47326552

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 99.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.8396 / max 247.5100, expressed in 1800 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114182	14.7996	1776
114181	7.1176	1689
114180	2.5339	980
114183	0.3212	147
114186	0.0454	15
114184	0.0219	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.41	gold quality
cerebellar hemisphere	UBERON:0002245	99.35	gold quality
cerebellar cortex	UBERON:0002129	99.27	gold quality
cerebellum	UBERON:0002037	98.69	gold quality
right frontal lobe	UBERON:0002810	98.07	gold quality
adenohypophysis	UBERON:0002196	97.75	gold quality
pituitary gland	UBERON:0000007	97.72	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.10	gold quality
prefrontal cortex	UBERON:0000451	96.40	gold quality
cortical plate	UBERON:0005343	96.37	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.97	gold quality
frontal cortex	UBERON:0001870	95.81	gold quality
neocortex	UBERON:0001950	95.50	gold quality
apex of heart	UBERON:0002098	95.44	gold quality
cingulate cortex	UBERON:0003027	95.40	gold quality
left testis	UBERON:0004533	95.40	gold quality
right testis	UBERON:0004534	95.30	gold quality
anterior cingulate cortex	UBERON:0009835	95.30	gold quality
granulocyte	CL:0000094	95.16	gold quality
brain	UBERON:0000955	94.82	gold quality
cerebral cortex	UBERON:0000956	94.81	gold quality
central nervous system	UBERON:0001017	94.76	gold quality
ganglionic eminence	UBERON:0004023	94.60	gold quality
forebrain	UBERON:0001890	94.53	gold quality
nucleus accumbens	UBERON:0001882	94.47	gold quality
metanephros cortex	UBERON:0010533	94.39	gold quality
telencephalon	UBERON:0001893	94.36	gold quality
amygdala	UBERON:0001876	94.25	gold quality
right adrenal gland cortex	UBERON:0035827	94.24	gold quality
right adrenal gland	UBERON:0001233	94.21	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.62

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

30 targeting MADD, 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-6127	100.00	66.76	2188
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6760-5P	98.87	66.73	1515
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-6780A-3P	98.42	67.49	1518
HSA-MIR-4704-3P	98.28	69.33	1300
HSA-MIR-1225-3P	97.29	64.60	876
HSA-MIR-3192-5P	96.98	65.76	1926
HSA-MIR-3126-5P	96.87	65.83	912
HSA-MIR-6875-5P	96.87	65.49	958
HSA-MIR-1233-3P	96.81	65.44	573

Literature-anchored findings (GeneRIF, showing 31)

• Denn is intimately involved in anti-apoptotic and cell survival processes in cancer cells (PMID:12410563)
• IG20 overexpression enhanced the combined apoptotic effects of TRAIL and gamma-irradiation on HeLa cells. (PMID:14695193)
• IG20 suppresses tumor cell survival and enhances susceptibility to apoptosis and cancer therapy. (PMID:14716293)
• DENN has anti-apoptotic and cell survival roles in tumor cells (PMID:14735464)
• IG20 (MADD splice variant-5) enhances TRAIL-induced apoptosis by increasing recruitment of FADD and caspase-8 to the death-inducing signaling complex. (PMID:15208670)
• Knockdown of MADD can render cells susceptible to spontaneous apoptosis but had no discernible effect on cell proliferation, colony size or cell cycle progression. MADD alone is sufficient and necessary for cancer cell survival. (PMID:16682944)
• MADD has a role in the control of cancer cell survival/death as a negative regulator of caspase-8 and confers significant resistance to TRAIL-induced apoptosis (PMID:17314102)
• data strongly indicate that germline mutations in SPI1 and MADD genes do not confer a high risk of chronic lymphocytic leukaemia and do not make a major contribution to the familial risk of the disease (PMID:17410194)
• we have identified an essential role for splice variants of the IG20 gene in TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)resistance. (PMID:18223207)
• Expression of KIAA0358 exerted a potent antiapoptotic effect in both the SK-N-SH and SH-SY5Y neuroblastoma cell lines, whereas expression of IG20-SV4 had proapoptotic effects directly related to the activation of caspase-8 in these cells. (PMID:18794122)
• KIF1Bbeta- and KIF1A-mediated axonal transport of presynaptic regulator Rab3 occurs in a GTP-dependent manner through MADD. (PMID:18849981)
• Loss of MADD expression resulted in reduced Grb2 and Sos1/2 recruitment to the TNFR1 complex and decreased Ras and MEKK1/2 activation (PMID:19289468)
• Endogenous MADD is phosphorylated at three highly conserved sites by Akt, and only the phosphorylated MADD can directly interact with the TRAIL receptor DR4 thereby preventing Fas-associated death domain recruitment. (PMID:20484047)
• Data show that SNPs from MADD, PROX1, and SLC30A8 were associated with type 2 diabetes. (PMID:21103350)
• The SNP in ADCY5 is implicated in defective proinsulin-to-insulin conversion and previous findings on the role of a genetic variant in MADD on proinsulin-to-insulin conversion, were confirmed. (PMID:21887289)
• Data show that ehe expression of MAPK-activating death domain protein (MADD) increases obviously in lung adenocarcinoma, and MADD can promote survival of lung adenocarcinoma cells by inhibiting apoptosis. (PMID:22482404)
• SNP rs2290149, located in a genetic cluster of MYBPC3 and MADD gene, was found to be associated with diastolic heart failure. (PMID:22529996)
• We analyzed DENN/MADD/IG20 (DMI), the complex of four splice variants in Alzheimer’s disease. (PMID:22678883)
• These results suggest that MADD may be a potential therapeutic target for lung adenocarcinoma therapy involving the TRAIL-induced apoptosis pathway (PMID:23443411)
• MADD knockdown resulted in enhanced spontaneous apoptosis in human breast cancer cell lines (PMID:23457619)
• Taken together, our data reveal that PTEN can convey the death signal by preventing MADD phosphorylation by Akt. (PMID:24038283)
• miR-3151 silencing by DNA methylation protected chronic lymphocytic leukemia cells from apoptosis by over-expression of its direct targets MADD and PIK3R2, constitutive activation of MEK/ERK and PI3K/AKT signaling , and over-expression of MCL1. (PMID:26517243)
• The risk of coronary disease and ischemic stroke associated with multiple polymorphisms and haplotypes of MADD and FOLH1 in Han Chinese patients are reported in association with alcohol consumption. (PMID:27070640)
• Authors show the crucial role of MADD in ATC tumorigenesis and metastasis. (PMID:30760700)
• MADD Expression in Lung Adenocarcinoma and its Impact on Proliferation and Apoptosis of Lung Adenocarcinoma Cells (PMID:30947659)
• Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder. (PMID:32761064)
• Homozygous variant in MADD, encoding a Rab guanine nucleotide exchange factor, results in pleiotropic effects and a multisystemic disorder. (PMID:33723354)
• GDP/GTP exchange factor MADD drives activation and recruitment of secretory Rab GTPases to Weibel-Palade bodies. (PMID:34551092)
• Calloso-adreno-scrotal agenesis associated with biallelic MAPK-activating death domain protein (MADD) variant: Further phenotypic delineation of MADD deficiency. (PMID:37932938)
• New insights into the clinical and molecular spectrum of the MADD-related neurodevelopmental disorder. (PMID:38459224)
• MADD regulates natural killer cell degranulation through Rab27a activation. (PMID:38506245)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	madd	ENSDARG00000003495
mus_musculus	Madd	ENSMUSG00000040687
rattus_norvegicus	Madd	ENSRNOG00000012568
drosophila_melanogaster	Rab3-GEF	FBGN0030613
caenorhabditis_elegans		WBGENE00000086

Protein

Protein identifiers

MAP kinase-activating death domain protein — Q8WXG6 (reviewed: Q8WXG6)

Alternative names: Differentially expressed in normal and neoplastic cells, Insulinoma glucagonoma clone 20, Rab3 GDP/GTP exchange factor, Rab3 GDP/GTP exchange protein

All UniProt accessions (14): Q8WXG6, A0A0A0MRB5, A0A0U1RR25, A0A9L9PXF1, A0A9L9PXN0, A0A9L9PXZ0, A0A9L9PXZ3, A0A9L9PY18, A0A9L9PY22, A0A9L9PYF5, C9J6B0, C9JLZ9, C9JM97, C9K0L0

UniProt curated annotations — full annotation on UniProt →

Function. Guanyl-nucleotide exchange factor that regulates small GTPases of the Rab family. Converts GDP-bound inactive form of RAB27A and RAB27B to the GTP-bound active forms. Converts GDP-bound inactive form of RAB3A, RAB3C and RAB3D to the GTP-bound active forms, GTPases involved in synaptic vesicle exocytosis and vesicle secretion. Plays a role in synaptic vesicle formation and in vesicle trafficking at the neuromuscular junction. Involved in up-regulating a post-docking step of synaptic exocytosis in central synapses. Probably by binding to the motor proteins KIF1B and KIF1A, mediates motor-dependent transport of GTP-RAB3A-positive vesicles to the presynaptic nerve terminals. Plays a role in TNFA-mediated activation of the MAPK pathway, including ERK1/2. May link TNFRSF1A with MAP kinase activation. May be involved in the regulation of TNFA-induced apoptosis.

Subunit / interactions. Interacts (via death domain) with TNFRSF1A (via death domain). Interacts with PIDD1. Interacts with YWHAZ. Interacts (via death domain) with KIF1B; links the motor KIF1B to Rab3-carrying vesicles in anterograde synaptic vesicle transport. Interacts with KIF1A. Interacts (via uDENN domain) with RAB3A, RAB3B, RAB3C and RAB3D; the GTP-bound form of the Rab proteins is preferred for interaction.

Subcellular location. Cell membrane. Cytoplasm. Cell projection. Axon.

Tissue specificity. Expressed in testis, ovary, brain and heart. Expressed in spleen, thymus, prostate, testis, ovary, small instestine and colon. Expressed in liver. Not detected in the brain, breast, kidney, lung, ovary, pancreas, testis, uterus, stomach and thyroid. Expressed in the brain, breast, kidney, lung, ovary, pancreas, testis, uterus, stomach and thyroid. Expressed in the brain, breast, kidney, lung, ovary, pancreas, testis, uterus, stomach and thyroid. Expressed in the brain, breast, kidney, lung, ovary, pancreas, testis, uterus, stomach and thyroid. Expressed in the brain, breast, kidney, lung, ovary, pancreas, testis, uterus, stomach and thyroid. Not detected in the brain, breast, kidney, lung, ovary, pancreas, testis, uterus, stomach and thyroid. Not detected in the brain, breast, kidney, lung, ovary, pancreas, testis, uterus, stomach and thyroid.

Disease relevance. DEEAH syndrome (DEEAH) [MIM:619004] An autosomal recessive disorder characterized by moderate to severe global developmental delay, impaired intellectual development, poor or absent speech, and endocrine, pancreatic exocrine and autonomic dysfunction, as well as hematologic abnormalities. Additional features include facial dysmorphism, seizures, undescended testes, and distal skeletal anomalies. Death in early childhood may occur. The disease is caused by variants affecting the gene represented in this entry. Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (NEDDISH) [MIM:619005] An autosomal recessive disorder characterized by global developmental delay, mildly to severely impaired intellectual development, poor speech and language acquisition. Some patients may have early normal development with onset of the disorder in the first years of life. More variable neurologic abnormalities include hypotonia, seizures, apnea, mild signs of autonomic or peripheral neuropathy, and autism. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Overexpression of MADD activates the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (ERK). Expression of the MADD death domain stimulates both the ERK and c-JUN N-terminal kinase MAP kinases and induces the phosphorylation of cytosolic phospholipase A2.

Similarity. Belongs to the MADD family.

Isoforms (8)

UniProt ID	Names	Canonical?
Q8WXG6-1	1, IG20, IG20-FL	yes
Q8WXG6-2	2, IG20, IG20-PA, IG20-PASV
Q8WXG6-3	3, DENN, IG20-SV1, MADD
Q8WXG6-4	4, IG20-SV2
Q8WXG6-5	5, DENN-SV, IG20-SV3
Q8WXG6-6	6, IG20-SV4
Q8WXG6-7	7, KIAA0358
Q8WXG6-8	8

RefSeq proteins (97): NP_001129415, NP_001129416, NP_001363500, NP_001363501, NP_001363502, NP_001363503, NP_001363504, NP_001363505, NP_001363506, NP_001363507, NP_001363508, NP_001363509, NP_001363510, NP_001363511, NP_001363512, NP_001363513, NP_001363514, NP_001363515, NP_001363522, NP_001363523, NP_001363524, NP_001363525, NP_001363526, NP_001363527, NP_001363528, NP_001363529, NP_001363530, NP_001363531, NP_001363532, NP_001363533, NP_001363534, NP_001363535, NP_001363536, NP_001363537, NP_001363538, NP_001363539, NP_001363540, NP_001363541, NP_001363542, NP_001363543, NP_001363544, NP_001363545, NP_001363546, NP_001363547, NP_001363548, NP_001363549, NP_001363550, NP_001363551, NP_001363552, NP_001363553, NP_001363554, NP_001363555, NP_001363556, NP_001363557, NP_001363558, NP_001363559, NP_001363560, NP_001363561, NP_001363562, NP_001363563, NP_001363564, NP_001363565, NP_001363566, NP_001363567, NP_001363568, NP_001363569, NP_001363570, NP_001363571, NP_001363572, NP_001363573, NP_001363574, NP_001363575, NP_001363576, NP_001363577, NP_001363578, NP_001363579, NP_001363580, NP_001363581, NP_001363582, NP_001363583, NP_001363584, NP_001363585, NP_001363586, NP_001363587, NP_001363588, NP_001363589, NP_001363590, NP_001363591, NP_001363592, NP_003673, NP_569826, NP_569827, NP_569828, NP_569829, NP_569830, NP_569831, NP_569832 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001194	cDENN_dom	Domain
IPR005112	dDENN_dom	Domain
IPR005113	uDENN_dom	Domain
IPR037516	Tripartite_DENN	Domain
IPR039980	MADD	Family
IPR043153	DENN_C	Homologous_superfamily
IPR056574	Death_MADD	Domain
IPR057469	PH_MADD	Domain

Pfam: PF02141, PF03456, PF23629, PF25328

UniProt features (81 total): sequence variant 21, modified residue 18, compositionally biased region 14, sequence conflict 9, splice variant 8, region of interest 6, domain 4, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WXG6-F1	64.59	0.27

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 (18): 156, 689, 692, 813, 818, 820, 858, 862, 916, 921, 930, 1059, 1061, 1066, 1110, 1237, 1239, 1270

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-8876198	RAB GEFs exchange GTP for GDP on RABs

MSigDB gene sets: 399 (showing top): ROVERSI_GLIOMA_COPY_NUMBER_UP, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, RACCACAR_AML_Q6, TGACCTY_ERR1_Q2, REACTOME_MEMBRANE_TRAFFICKING, GGAMTNNNNNTCCY_UNKNOWN, GCM_PRKCG, GOMF_KINASE_ACTIVATOR_ACTIVITY, GOBP_REGULATION_OF_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_VIA_DEATH_DOMAIN_RECEPTORS, GCM_RING1, GOBP_APOPTOTIC_SIGNALING_PATHWAY, PID_TNF_PATHWAY

GO Biological Process (9): cell surface receptor signaling pathway (GO:0007166), regulation of Rab protein signal transduction (GO:0032483), regulation of apoptotic process (GO:0042981), positive regulation of MAPK cascade (GO:0043410), regulation of cell cycle (GO:0051726), execution phase of apoptosis (GO:0097194), regulation of extrinsic apoptotic signaling pathway via death domain receptors (GO:1902041), regulation of extrinsic apoptotic signaling pathway (GO:2001236), apoptotic process (GO:0006915)

GO Molecular Function (4): guanyl-nucleotide exchange factor activity (GO:0005085), death receptor binding (GO:0005123), protein kinase activator activity (GO:0030295), protein binding (GO:0005515)

GO Cellular Component (6): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), axon (GO:0030424), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
TNF signaling	1
Rab regulation of trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
apoptotic process	2
signal transduction	1
Rab protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
regulation of programmed cell death	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
cell cycle	1
regulation of cellular process	1
cellular process	1
bleb assembly	1
extrinsic apoptotic signaling pathway via death domain receptors	1
regulation of extrinsic apoptotic signaling pathway	1
extrinsic apoptotic signaling pathway	1
regulation of apoptotic signaling pathway	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
tumor necrosis factor receptor superfamily binding	1
protein kinase activity	1
kinase activator activity	1
protein kinase regulator activity	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1
neuron projection	1

Protein interactions and networks

STRING

838 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MADD	RAB35	Q15286	954
MADD	DENND1A	Q8TEH3	939
MADD	DMXL2	Q8TDJ6	937
MADD	RAB3GAP2	Q9H2M9	853
MADD	RAB3GAP1	Q15042	838
MADD	WDR7	Q9Y4E6	808
MADD	KIF1A	Q12756	742
MADD	SMCR8	Q8TEV9	728
MADD	RAB3A	P20336	723
MADD	WDR41	Q9HAD4	715
MADD	RAB27A	P51159	712
MADD	RAB1A	P11476	702
MADD	C9orf72	Q96LT7	692
MADD	CLTC	Q00610	678
MADD	DENND1B	Q6P3S1	656

IntAct

70 interactions, top by confidence:

A	B	Type	Score
BBS7	BBS9	psi-mi:“MI:0914”(association)	0.860
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
SYT12	B4GALT5	psi-mi:“MI:0914”(association)	0.530
ALOX5	DDHD2	psi-mi:“MI:0914”(association)	0.530
SYT3	PGK2	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
TUBA4A	PLD2	psi-mi:“MI:0914”(association)	0.530
SPCS3	ENTPD6	psi-mi:“MI:0914”(association)	0.530
SYT12	PDK2	psi-mi:“MI:0914”(association)	0.530
POT1	MADD	psi-mi:“MI:0915”(physical association)	0.510
PTPRN	MADD	psi-mi:“MI:0915”(physical association)	0.510
MADD	PTPRN	psi-mi:“MI:0915”(physical association)	0.510
PTPRB	MADD	psi-mi:“MI:0915”(physical association)	0.400
MADD	THRAP3	psi-mi:“MI:0915”(physical association)	0.400
NUP37	MADD	psi-mi:“MI:0915”(physical association)	0.400
ZNF625	MADD	psi-mi:“MI:0915”(physical association)	0.400
YWHAZ	MADD	psi-mi:“MI:0915”(physical association)	0.400
MADD	VPS13D	psi-mi:“MI:0915”(physical association)	0.370
RB1CC1	MADD	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
RIPK4	VWA8	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
MTMR8	MADD	psi-mi:“MI:0914”(association)	0.350
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
CSNK2B	OSBPL8	psi-mi:“MI:0914”(association)	0.350
SYT2	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
BBS7	TARS3	psi-mi:“MI:0914”(association)	0.350
SOCS1	ZSWIM8	psi-mi:“MI:0914”(association)	0.350

BioGRID (113): MADD (Affinity Capture-RNA), MADD (Affinity Capture-MS), MADD (Affinity Capture-MS), MADD (Affinity Capture-MS), MADD (Affinity Capture-MS), MADD (Affinity Capture-MS), MADD (Affinity Capture-MS), MADD (Affinity Capture-MS), MADD (Two-hybrid), MADD (Affinity Capture-MS), MADD (Affinity Capture-MS), MADD (Affinity Capture-MS), MADD (Affinity Capture-MS), MADD (Affinity Capture-MS), MADD (Affinity Capture-MS)

ESM2 similar proteins: A0A5F9C6I2, A0JPN6, A4IIZ9, A5WUL3, D3ZUQ0, D3ZXK7, F1R7R1, O43513, O57595, O75916, P51593, P53349, P68943, P85299, Q08DY8, Q13233, Q15528, Q17QG3, Q2F7Z4, Q2TBN4, Q2YDF2, Q3B8I4, Q3T123, Q5BJ48, Q5E9K2, Q5EBL4, Q5FVG6, Q5RKN3, Q5XIX8, Q5XPI3, Q5XPI4, Q62276, Q62739, Q6GQ95, Q6QB00, Q6ZUS6, Q7TMY8, Q7ZV35, Q800L3, Q80U62

Diamond homologs: A2RSQ0, C8YR32, G3V7Q0, Q5FVJ0, Q6IQ26, Q6NXD8, Q6P3S1, Q6PAL8, Q6ZUT9, Q8BIJ7, Q8C4S8, Q8CFK6, Q8IV53, Q8IVV2, Q8RXA7, Q8WXG6, Q96T51, Q9TXP3, O02626, O08873, P78524, Q3U1T9, Q80U28, Q924W7, Q9VXY2, Q9W3D3, G2WWH6, I1RQE2, Q68D51, Q6P9P8, Q91VV4, Q9H6A0, Q9ULE3, Q9Y7Q7, X0JZ91, A6H8H2, O75064, Q3U1Y4, Q5VZ89, Q7Z401

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
MADD	“up-regulates activity”	RAB3A	“guanine nucleotide exchange factor”
DMXL2	“up-regulates quantity”	MADD	binding

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
Translocation of SLC2A4 (GLUT4) to the plasma membrane	5	11.5×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of calcium ion-dependent exocytosis	6	63.1×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	20
Uncertain significance	274
Likely benign	37
Benign	13

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1326727	NM_001376571.1(MADD):c.710C>G (p.Ser237Ter)	Pathogenic
1699228	NM_001376571.1(MADD):c.4109T>A (p.Leu1370Ter)	Pathogenic
2048411	NM_001376571.1(MADD):c.4594C>T (p.Arg1532Ter)	Pathogenic
2307248	NM_001376571.1(MADD):c.4392_4395del (p.Cys1464fs)	Pathogenic
2665104	NC_000011.10:g.(47329894_47331627)_(47335115_47335951)del	Pathogenic
4050443	NM_001376571.1(MADD):c.4286_4287del (p.Ser1429fs)	Pathogenic
635764	arr[hg19]11p11.2(47339995x2,47343435_47375684x1,47387184x2)	Pathogenic
973492	NM_001376571.1(MADD):c.2816+1G>A	Pathogenic
978041	NM_001376571.1(MADD):c.4080del (p.Lys1361fs)	Pathogenic
978081	NM_001376571.1(MADD):c.3559del (p.Val1186_Met1187insTer)	Pathogenic
978082	NM_001376571.1(MADD):c.1061C>T (p.Pro354Leu)	Pathogenic
978083	NM_001376571.1(MADD):c.914G>T (p.Gly305Val)	Pathogenic
978084	NM_003682.4:c.(1862+1_1863-1)_(3759+1_3760-1)del	Pathogenic
978085	NM_001376571.1(MADD):c.963+1G>A	Pathogenic
978086	NM_001376571.1(MADD):c.770C>T (p.Ser257Phe)	Pathogenic
978087	NM_001376571.1(MADD):c.3637_3638del (p.Asp1212_Ser1213insTer)	Pathogenic
1199417	NM_001376571.1(MADD):c.3070C>T (p.Gln1024Ter)	Likely pathogenic
1334389	NM_001376571.1(MADD):c.2383C>T (p.Arg795Ter)	Likely pathogenic
1334664	NM_001376571.1(MADD):c.1291-2A>G	Likely pathogenic
1334762	NM_001376571.1(MADD):c.310C>T (p.Arg104Ter)	Likely pathogenic
2500335	NM_001376571.1(MADD):c.3458_3459del (p.Glu1153fs)	Likely pathogenic
2507161	NM_001376571.1(MADD):c.268C>T (p.Arg90Ter)	Likely pathogenic
2630124	NM_001376571.1(MADD):c.568C>T (p.Arg190Ter)	Likely pathogenic
3065452	NM_001376571.1(MADD):c.63-2A>G	Likely pathogenic
3065471	NM_001376571.1(MADD):c.1967A>G (p.Asn656Ser)	Likely pathogenic
3348287	NM_001376571.1(MADD):c.2591C>A (p.Ser864Ter)	Likely pathogenic
3381873	NM_001376571.1(MADD):c.1045_1046del (p.Met349fs)	Likely pathogenic
3600518	NM_001376571.1(MADD):c.62_62+3del	Likely pathogenic
3773863	NM_001376571.1(MADD):c.1603dup (p.Gln535fs)	Likely pathogenic
3779826	NM_001376571.1(MADD):c.4821G>A (p.Val1607=)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000000184 (11:47322780 G>A), RS1000008260 (11:47298485 TGA>T), RS1000057628 (11:47316132 G>A), RS1000065232 (11:47299838 A>G), RS1000110179 (11:47304758 C>A), RS1000280138 (11:47291684 G>A), RS1000332059 (11:47291448 C>G,T), RS1000349990 (11:47322541 G>A), RS1000381161 (11:47318174 G>A), RS1000412577 (11:47318504 A>G), RS1000517462 (11:47323475 C>T), RS1000526972 (11:47296294 A>T), RS1000534776 (11:47274093 A>C,T), RS1000535168 (11:47281012 T>C), RS1000596697 (11:47298011 A>G)

Disease associations

OMIM: gene MIM:603584 | disease phenotypes: MIM:619004, MIM:619005, MIM:115197, MIM:209850, MIM:615396

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia	Strong	Autosomal recessive
deeah syndrome	Strong	Autosomal recessive
syndromic intellectual disability	Supportive	Autosomal dominant

Mondo (8): deeah syndrome (MONDO:0033561), neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (MONDO:0033562), hypertrophic cardiomyopathy (MONDO:0005045), multiple acyl-CoA dehydrogenase deficiency, severe neonatal type (MONDO:0018332), hypertrophic cardiomyopathy 4 (MONDO:0007268), autism (MONDO:0005260), left ventricular noncompaction 10 (MONDO:0014163), syndromic intellectual disability (MONDO:0000508)

Orphanet (5): MADD-related developmental delay-endocrine dysfunction-hypohemoglobinemia syndrome (Orphanet:686495), Rare hypertrophic cardiomyopathy (Orphanet:217569), Multiple acyl-CoA dehydrogenase deficiency, severe neonatal type (Orphanet:394529), Familial isolated dilated cardiomyopathy (Orphanet:154), Left ventricular noncompaction (Orphanet:54260)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0001639	Hypertrophic cardiomyopathy
HP:0000717	Autism

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
C566169	Cardiomyopathy, Familial Hypertrophic, 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Estradiol	increases expression, decreases expression	2
Ozone	increases abundance, affects cotreatment, increases oxidation	2
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	decreases methylation	1
coumarin	decreases phosphorylation	1
cardanol	decreases expression	1
pinostrobin	increases expression	1
10’(Z),13’(E),15’(E)-heptadecatrienylhydroquinone	increases expression	1
beta-hydroxy simvastatin acid	decreases expression	1
Resveratrol	decreases expression	1
Sunitinib	increases expression	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Aspirin	decreases expression	1
Atrazine	decreases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Dexamethasone	decreases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Fluorouracil	affects expression	1
Indomethacin	affects cotreatment, decreases expression	1
Menthol	increases expression	1
Nicotine	decreases expression	1
Tretinoin	increases expression	1
Urethane	increases expression	1
Valproic Acid	decreases methylation	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SW21	HAP1 MADD (-) 1	Cancer cell line	Male
CVCL_SW22	HAP1 MADD (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart
NCT00698074	PHASE3	UNKNOWN	Diastolic Ventricular Interaction and the Effects of Biventricular Pacing in Hypertrophic Cardiomyopathy
NCT00821353	PHASE3	COMPLETED	Antiarrhythmic Therapy Versus Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy