GSDME

Summary

GSDME (gasdermin E, HGNC:2810) is a protein-coding gene on chromosome 7p15.3, encoding Gasdermin-E (O60443). Precursor of a pore-forming protein that converts non-inflammatory apoptosis to pyroptosis.

Hearing impairment is a heterogeneous condition with over 40 loci described. The protein encoded by this gene is expressed in fetal cochlea, however, its function is not known. Nonsyndromic hearing impairment is associated with a mutation in this gene. Three transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 1687 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 451 total — 6 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 2
• MANE Select transcript: NM_001127453

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2810
Approved symbol	GSDME
Name	gasdermin E
Location	7p15.3
Locus type	gene with protein product
Status	Approved
Aliases	ICERE-1
Ensembl gene	ENSG00000105928
Ensembl biotype	protein_coding
OMIM	608798
Entrez	1687

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 13 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000342947, ENST00000409970, ENST00000411476, ENST00000414428, ENST00000415480, ENST00000419307, ENST00000430096, ENST00000446822, ENST00000469133, ENST00000473990, ENST00000479636, ENST00000493723, ENST00000559637, ENST00000645220, ENST00000896379, ENST00000896380, ENST00000924586, ENST00000949624, ENST00000949625

RefSeq mRNA: 3 — MANE Select: NM_001127453 NM_001127453, NM_001127454, NM_004403

CCDS: CCDS47563, CCDS5389

Canonical transcript exons

ENST00000645220 — 10 exons

Exon	Start	End
ENSE00000673961	24702760	24702833
ENSE00000673962	24706184	24706376
ENSE00000673963	24708127	24708254
ENSE00001380440	24698355	24699259
ENSE00003459622	24749564	24749793
ENSE00003515929	24719047	24719218
ENSE00003530407	24744562	24744754
ENSE00003618350	24710224	24710388
ENSE00003675802	24717254	24717374
ENSE00003820735	24757396	24757464

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 97.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.7578 / max 104.5413, expressed in 1393 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83135	6.1212	1363
83138	1.4383	651
83137	0.1227	51
83136	0.0757	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	97.95	gold quality
jejunal mucosa	UBERON:0000399	95.57	gold quality
stromal cell of endometrium	CL:0002255	95.15	gold quality
endothelial cell	CL:0000115	95.14	gold quality
cranial nerve II	UBERON:0000941	94.94	gold quality
placenta	UBERON:0001987	94.88	gold quality
oocyte	CL:0000023	94.79	gold quality
secondary oocyte	CL:0000655	94.75	gold quality
adrenal tissue	UBERON:0018303	93.40	gold quality
middle temporal gyrus	UBERON:0002771	93.36	gold quality
decidua	UBERON:0002450	93.07	gold quality
spinal cord	UBERON:0002240	92.92	gold quality
parietal pleura	UBERON:0002400	92.86	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	92.84	gold quality
saphenous vein	UBERON:0007318	91.58	gold quality
lateral nuclear group of thalamus	UBERON:0002736	91.27	gold quality
Brodmann (1909) area 23	UBERON:0013554	90.84	gold quality
body of uterus	UBERON:0009853	90.57	gold quality
cortical plate	UBERON:0005343	90.15	gold quality
pigmented layer of retina	UBERON:0001782	90.13	gold quality
myometrium	UBERON:0001296	90.04	gold quality
pleura	UBERON:0000977	89.65	gold quality
subthalamic nucleus	UBERON:0001906	89.38	gold quality
urethra	UBERON:0000057	88.43	gold quality
left uterine tube	UBERON:0001303	88.41	gold quality
smooth muscle tissue	UBERON:0001135	88.40	gold quality
adult organism	UBERON:0007023	88.22	gold quality
medulla oblongata	UBERON:0001896	88.17	gold quality
primary visual cortex	UBERON:0002436	88.03	gold quality
CA1 field of hippocampus	UBERON:0003881	87.93	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	114.11
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

39 targeting GSDME, 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-4455	100.00	65.48	1587
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-370-5P	99.78	66.81	706
HSA-MIR-379-3P	99.69	69.60	1524
HSA-MIR-411-3P	99.69	69.63	1524
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-5004-3P	99.54	68.27	1371
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-1912-3P	99.32	67.40	936
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-499A-3P	99.18	69.20	1392
HSA-MIR-499B-3P	99.18	69.27	1391
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-1295B-5P	99.03	67.50	810
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-6877-3P	98.98	65.83	560

Literature-anchored findings (GeneRIF, showing 40)

• no significant linkage between age-related hearing impairment (ARHI) and microsatellite markers from the DFNA5 region; there exists no strong association between DFNA5 and ARHI (PMID:12461698)
• Here, we report another mutation in DFNA5, a CTT deletion in the polypyrimidine tract of intron 7. (PMID:14559215)
• A novel DFNA5 mutation was found in a Dutch family, of which 37 members were examined. (PMID:14676472)
• These results suggest that DFNA5 plays a role in the p53-regulated cellular response to genotoxic stress probably by cooperating with p53. (PMID:16897187)
• description of a DFNA5 mutation: the insertion of a cytosine at nucleotide position 640 (AF073308.1:_c.640insC, AAC69324.1:_p. Thr215HisfsX8) which does not lead to hearing impairment (PMID:17427029)
• GCs induce dfna5 mRNA and its expression appears to be repressed in the basal state. Induction of dfna5 mRNA correlates with GC-dependent apoptosis of CEM cells, though dfna5 expression alone is not sufficient for apoptosis. (PMID:17616391)
• DFNA5-associated hearing loss is caused by a very specific gain-of-function mutation. (PMID:17868390)
• DFNA5 is a novel tumor suppressor gene in CRC and a valuable molecular marker for human cancer (PMID:18223688)
• These data implicate DFNA5 promoter methylation as a novel molecular biomarker in human breast cancer. (PMID:18346456)
• A founder effect was demonstrated for the mutation of the DFNA5 gene casusing hearing loss in East Asians. (PMID:19911014)
• DFNA5 is composed of two domains, separated by a hinge region. The first region induces apoptosis when transfected in HEK293T cells, the second region masks and probably regulates this apoptosis inducing capability (PMID:21522185)
• A mutation in DFNA5 leads to a type of hearing loss that closely resembles the frequently observed age-related hearing impairment. (PMID:21805831)
• DFNA5 protein expression in hepatocellular carcinoma cells was significantly lower than that in normal cells. (PMID:24154762)
• DFNA5 deletion mutation is associated with autosomal dominant hereditary hearing loss in Japanese families. (PMID:24506266)
• We identified a novel c.991-2A>G mutation in DFNA5 which again may lead to exon 8 skipping at the mRNA level. (PMID:24933359)
• Study identified a novel DFNA5 mutation IVS8+1 delG in a Chinese family which led to skipping of exon 8. This is the sixth DFNA5 mutation relates to hearing loss and the second one in DFNA5 intron 8. (PMID:26365971)
• Genetic variations in the EYA4, GRHL2 and DFNA5 genes and their interactions with occupational noise exposure may play an important role in the incidence of noise-induced hearing loss (NIHL). (PMID:26400775)
• DFNA5 methylation shows strong potential as a biomarker for detection of breast cancer. Slightly increased methylation in histologically normal breast tissue surrounding the tumor suggests that it may be a good early detection marker. (PMID:28404884)
• findings suggest that caspase-3 activation can trigger necrosis by cleaving GSDME and offer new insights into cancer chemotherapy (PMID:28459430)
• In conclusion, our findings firstly revealed that GSDME switches chemotherapy drug-induced caspase-3 dependent apoptosis into pyroptosis in gastric cancer cells. (PMID:29183726)
• the first exonic mutations in DFNA5 to cause deafness, are reported. (PMID:29266521)
• DFNA5 methylation and expression were significantly different between breast cancer and normal breast samples. DFNA5 methylation, in 10 out of 22 CpGs, and expression were significantly higher in lobular compared to ductal breast cancers. (PMID:29682089)
• specific gain-of-function mechanism of DFNA5 related hearing loss (PMID:29849037)
• These results pinpoint GSDME-dependent pyroptosis as a previously unrecognized mechanism of action for molecular targeted agents to eradicate oncogene-addicted neoplastic cells, which may have important implications for the clinical development and optimal application of anticancer therapeutics. (PMID:30061362)
• DFNA5 variant is associated with tobacco- and HPV-mediated oral oncogenesis. (PMID:30091681)
• The function of GSDME in regulating membrane permeabilization and cell disassembly during apoptosis may be more limited. (PMID:30564238)
• The levels of secondary necrosis/pyroptosis correlated with the levels of active caspase-3 and GSDME-NT. (PMID:30710195)
• Study demonstrated that in addition to its pyroptotic activity, GSDME augments caspase-3/7 activation and apoptotic cell death by targeting the mitochondria and releasing cytochrome c. Like Bid, cleavage of GSDME by death receptor signaling bridges the extrinsic to the intrinsic apoptotic pathway. (PMID:30976076)
• Results found differential methylation in all 22 GSDME CpGs between colorectal cancer (GC) tumor and normal tissues, and in 18 CpGs between the left- and right-sided groups. Although the methylation of 5 distinct probes was a good predictor of gene expression, no association was found between GSDME methylation and its expression. However, a combination of 2 CpGs was found to discriminate between cancer and normal tumor. (PMID:30993897)
• Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome. (PMID:31953257)
• tumor GSDME acts as a tumor suppressor by activating pyroptosis, enhancing anti-tumor immunity (PMID:32188940)
• Gasdermine E-Dependent Mitochondrial Pyroptotic Pathway in Dermatomyositis: A Possible Mechanism of Perifascicular Atrophy. (PMID:32296846)
• DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot? (PMID:32486382)
• GSDME enhances Cisplatin sensitivity to regress non-small cell lung carcinoma by mediating pyroptosis to trigger antitumor immunocyte infiltration. (PMID:32839451)
• Ultraviolet B induces proteolytic cleavage of the pyroptosis inducer gasdermin E in keratinocytes. (PMID:33004249)
• GSDME and its role in cancer: From behind the scenes to the front of the stage. (PMID:33186472)
• GSDME: A Potential Ally in Cancer Detection and Treatment. (PMID:33422423)
• Gasdermin E deficiency attenuates acute kidney injury by inhibiting pyroptosis and inflammation. (PMID:33542198)
• Dihydroartemisinin induces pyroptosis by promoting the AIM2/caspase-3/DFNA5 axis in breast cancer cells. (PMID:33689708)
• Virus-mediated inactivation of anti-apoptotic Bcl-2 family members promotes Gasdermin-E-dependent pyroptosis in barrier epithelial cells. (PMID:33979579)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gsdmeb	ENSDARG00000040485
danio_rerio	gsdmea	ENSDARG00000086762
mus_musculus	Gsdme	ENSMUSG00000029821
rattus_norvegicus	Gsdme	ENSRNOG00000009970

Protein

Protein identifiers

Gasdermin-E — O60443 (reviewed: O60443)

Alternative names: Inversely correlated with estrogen receptor expression 1, Non-syndromic hearing impairment protein 5

All UniProt accessions (5): O60443, C9JSR4, H7BZJ0, H7C0L2, H7C147

UniProt curated annotations — full annotation on UniProt →

Function. Precursor of a pore-forming protein that converts non-inflammatory apoptosis to pyroptosis. This form constitutes the precursor of the pore-forming protein: upon cleavage, the released N-terminal moiety (Gasdermin-E, N-terminal) binds to membranes and forms pores, triggering pyroptosis. Pore-forming protein produced by cleavage by CASP3 or granzyme B (GZMB), which converts non-inflammatory apoptosis to pyroptosis or promotes granzyme-mediated pyroptosis, respectively. After cleavage, moves to the plasma membrane, homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, allowing the release of mature interleukins (IL1B and IL16) and triggering pyroptosis. Binds to inner leaflet lipids, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate. Cleavage by CASP3 switches CASP3-mediated apoptosis induced by TNF or danger signals, such as chemotherapy drugs, to pyroptosis. Mediates secondary necrosis downstream of the mitochondrial apoptotic pathway and CASP3 activation as well as in response to viral agents. Exhibits bactericidal activity. Cleavage by GZMB promotes tumor suppressor activity by triggering robust anti-tumor immunity. Suppresses tumors by mediating granzyme-mediated pyroptosis in target cells of natural killer (NK) cells: cleavage by granzyme B (GZMB), delivered to target cells from NK-cells, triggers pyroptosis of tumor cells and tumor suppression. May play a role in the p53/TP53-regulated cellular response to DNA damage. (Microbial infection) Pore-forming protein, which promotes maternal placental pyroptosis in response to Zika virus infection, contributing to adverse fetal outcomes.

Subunit / interactions. Homooligomer; homooligomeric ring-shaped pore complex containing 27-28 subunits when inserted in the membrane.

Subcellular location. Cell membrane Cytoplasm. Cytosol.

Tissue specificity. Expressed in cochlea. Low level of expression in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas, with highest expression in placenta.

Post-translational modifications. Cleavage at Asp-270 by CASP3 (mature and uncleaved precursor forms) or granzyme B (GZMB) relieves autoinhibition and is sufficient to initiate pyroptosis. Succination by the Krebs cycle intermediate fumarate, which leads to S-(2-succinyl)cysteine residues, inhibits processing by caspases, and ability to initiate pyroptosis. Succination modification is catalyzed by a non-enzymatic reaction caused by an accumulation of fumarate. Ubiquitinated at Lys-120 and Lys-189 via ‘Lys-48’-linked polyubiquitin chains, leading to proteasomal degradation. Deubiquitinated by USP48, leading to increased stability. Palmitoylated.

Disease relevance. Deafness, autosomal dominant, 5 (DFNA5) [MIM:600994] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry. Is a tumor suppressor gene with an important role in colorectal cancer (CRC).

Activity regulation. The full-length protein before cleavage is inactive: intramolecular interactions between N- and C-terminal domains mediate autoinhibition in the absence of activation signal. The intrinsic pyroptosis-inducing activity is carried by the released N-terminal moiety (Gasdermin-E, N-terminal) following cleavage by CASP3 or granzyme B (GZMB). Activated by NLRP1 in the absence of GSDMD expression: NLRP1 cleaves and activates CASP8, promoting downstream activation of CASP3 and subsequent activation of GSDME. (Microbial infection) Activated upon human coronavirus SARS-CoV-2 infection, leading to lung epithelial cell death. Activation takes place in response to (1) activation of NLRP1 and (2) inactivation of GSDMD following NLRP1 and GSDMD cleavage by the SARS-CoV-2 3C-like proteinase nsp5.

Domain organisation. Intramolecular interactions between N- and C-terminal domains may be important for autoinhibition in the absence of activation signal. The intrinsic pyroptosis-inducing activity is carried by the N-terminal domain, that is released upon cleavage by CASP3 or granzyme B (GZMB).

Similarity. Belongs to the gasdermin family.

Isoforms (3)

UniProt ID	Names	Canonical?
O60443-1	1, Long	yes
O60443-2	2, Short
O60443-3	3

RefSeq proteins (3): NP_001120925, NP_001120926, NP_004394 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR040460	Gasdermin_pore	Domain
IPR041263	Gasdermin_PUB	Domain
IPR042377	GSDME	Family

Pfam: PF04598, PF17708

UniProt features (39 total): sequence variant 12, modified residue 9, mutagenesis site 9, chain 3, cross-link 2, splice variant 2, region of interest 1, site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9UXV	X-RAY DIFFRACTION	2.95
9H5M	ELECTRON MICROSCOPY	3.6
9PE0	ELECTRON MICROSCOPY	3.64

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60443-F1	77.89	0.29

Functional residue map

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

Catalytic / active sites (1): 270–271 (cleavage; by casp3 or granzyme b)

Post-translational modifications (11): 371, 408, 417, 489, 120, 189, 45, 156, 168, 180, 235

Mutagenesis-validated functional residues (9):

Position	Phenotype
2	no effect on plasma membrane targeting. decreases induction of necrotic activity. disrupts plasma membrane targeting and
39	disrupts plasma membrane targeting and induction of necrotic activity; when associated with a-40 and/or a-41.
40	no effect on plasma membrane targeting. no effect on induction of cytotoxivity. disrupts plasma membrane targeting and i
41	disrupts plasma membrane targeting and induction of necrotic activity; when associated with a-39 and/or a-41.
267	abolishes cleavage by casp3. abolishes pyroptosis induction.
270	abolishes cleavage by casp3 or granzyme b. abolishes pyroptosis induction.
313	no spontaneous pyroptosis-inducing activity.
388	low spontaneous pyroptosis-inducing activity.
392	low spontaneous pyroptosis-inducing activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-111457	Release of apoptotic factors from the mitochondria
R-HSA-5620971	Pyroptosis
R-HSA-5686938	Regulation of TLR by endogenous ligand
R-HSA-9710421	Defective pyroptosis

MSigDB gene sets: 240 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, GOBP_CELLULAR_RESPONSE_TO_VIRUS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, PAL_PRMT5_TARGETS_UP, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_NEUROGENESIS, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, BRUECKNER_TARGETS_OF_MIRLET7A3_DN

GO Biological Process (12): positive regulation of immune response to tumor cell (GO:0002839), sensory perception of sound (GO:0007605), negative regulation of cell population proliferation (GO:0008285), programmed cell death (GO:0012501), inner ear auditory receptor cell differentiation (GO:0042491), positive regulation of MAPK cascade (GO:0043410), pyroptotic inflammatory response (GO:0070269), cellular response to tumor necrosis factor (GO:0071356), cellular response to virus (GO:0098586), pyroptotic cell death (GO:0141201), positive regulation of intrinsic apoptotic signaling pathway (GO:2001244), transmembrane transport (GO:0055085)

GO Molecular Function (4): phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), wide pore channel activity (GO:0022829), cardiolipin binding (GO:1901612), protein binding (GO:0005515)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Apoptotic factor-mediated response	1
Regulated Necrosis	1
Toll-like Receptor Cascades	1
Diseases of programmed cell death	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
positive regulation of intracellular signal transduction	2
immune response to tumor cell	1
positive regulation of response to tumor cell	1
regulation of immune response to tumor cell	1
positive regulation of immune response	1
sensory perception of mechanical stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
signal transduction	1
cell death	1
hair cell differentiation	1
inner ear receptor cell differentiation	1
MAPK cascade	1
regulation of MAPK cascade	1
inflammatory response	1
response to tumor necrosis factor	1
cellular response to cytokine stimulus	1
response to virus	1
programmed cell death	1
pyroptotic inflammatory response	1
intrinsic apoptotic signaling pathway	1
positive regulation of apoptotic signaling pathway	1
regulation of intrinsic apoptotic signaling pathway	1
transport	1
cellular process	1
phosphatidylinositol phosphate binding	1
phosphatidylinositol bisphosphate binding	1
channel activity	1
phosphatidylglycerol binding	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

662 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GSDME	GSDMA	Q96QA5	979
GSDME	GSDMC	Q9BYG8	901
GSDME	GSDMB	Q8TAX9	888
GSDME	CASP1	P29466	747
GSDME	CASP3	P42574	668
GSDME	CASP5	P51878	647
GSDME	CASP4	P49662	631
GSDME	CASP8	Q14790	627
GSDME	AIM2	O14862	620
GSDME	IL18	Q14116	616
GSDME	NLRP3	Q96P20	608
GSDME	MLKL	Q8NB16	597
GSDME	NLRC4	Q9NPP4	597
GSDME	NLRP1	Q9C000	594
GSDME	SCAF11	Q99590	584

IntAct

54 interactions, top by confidence:

A	B	Type	Score
SCN2B	EXOC5	psi-mi:“MI:0914”(association)	0.640
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
GSDME	TIFA	psi-mi:“MI:0915”(physical association)	0.560
EPHA1	EXOC5	psi-mi:“MI:0914”(association)	0.530
GSDME	SLC27A2	psi-mi:“MI:0914”(association)	0.530
GPAT4	GSDME	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
HIDE1	GSDME	psi-mi:“MI:0914”(association)	0.530
CFTR	GSDME	psi-mi:“MI:0915”(physical association)	0.370
RUSF1	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.350
SIGLECL1	KIAA1324L	psi-mi:“MI:0914”(association)	0.350
ZSCAN29	GSDME	psi-mi:“MI:0914”(association)	0.350
CDKN2A	NHERF1	psi-mi:“MI:0914”(association)	0.350
HIDE1	TMEM120B	psi-mi:“MI:0914”(association)	0.350
GYPA	HYKK	psi-mi:“MI:0914”(association)	0.350
EFNB1	KRBA1	psi-mi:“MI:0914”(association)	0.350
TACSTD2	RIMOC1	psi-mi:“MI:0914”(association)	0.350
SIGLECL1	RBFOX3	psi-mi:“MI:0914”(association)	0.350
BTNL9	GPR89A	psi-mi:“MI:0914”(association)	0.350
KLC3	DCTN6	psi-mi:“MI:0914”(association)	0.350
HVCN1	CHEK1	psi-mi:“MI:0914”(association)	0.350
TPST2	NDC80	psi-mi:“MI:0914”(association)	0.350
OCIAD1	BTAF1	psi-mi:“MI:0914”(association)	0.350
B3GNT8	GSDME	psi-mi:“MI:0914”(association)	0.350

BioGRID (78): BIRC6 (Affinity Capture-MS), DFNA5 (Affinity Capture-MS), DFNA5 (Affinity Capture-MS), DFNA5 (Affinity Capture-MS), DFNA5 (Affinity Capture-MS), DFNA5 (Affinity Capture-MS), DFNA5 (Affinity Capture-MS), DFNA5 (Affinity Capture-MS), DFNA5 (Affinity Capture-MS), PLEC (Affinity Capture-MS), MUL1 (Affinity Capture-MS), DFNA5 (Affinity Capture-MS), SLC27A2 (Affinity Capture-MS), DFNA5 (Affinity Capture-MS), RPS3 (Affinity Capture-MS)

ESM2 similar proteins: A1A4V9, A4IFQ0, A6NFY4, A6QNT4, G3HKI1, O60443, P50747, Q13426, Q13769, Q14159, Q1JQA1, Q1RMS8, Q2HJ93, Q2HJB9, Q2KHT6, Q3T1H6, Q3ZK22, Q5E9K8, Q5FVM3, Q5M7Q1, Q5RFG8, Q5RFL7, Q5XI52, Q5ZJK1, Q641X7, Q68FX7, Q6NZQ0, Q6P1K2, Q7YS54, Q7Z6J8, Q8BX13, Q8C5K5, Q8CHQ0, Q8K2I9, Q8NFZ0, Q8QZS3, Q8TCJ0, Q8VE91, Q91WC1, Q91Z62

Diamond homologs: O60443, Q0ZLH2, Q0ZLH3, Q7YS54, Q9Z2D3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	2
Uncertain significance	216
Likely benign	93
Benign	77

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
179997	NM_001127453.2(GSDME):c.991-21TTC[2]	Pathogenic
2090	NG_011593.1:g.55397_56585delins59701_59837invGCCCA	Pathogenic
2092	NM_004403.3(GSDME):c.991-6C>G	Pathogenic
2093	NM_004403.3(GSDME):c.1183+4A>G	Pathogenic
2498199	NM_001127453.2(GSDME):c.1089_1113dup (p.Pro372fs)	Pathogenic
3651364	NM_001127453.2(GSDME):c.1183+1G>T	Pathogenic
1298356	NM_001127453.2(GSDME):c.1102C>G (p.Gln368Glu)	Likely pathogenic
228250	NM_004403.2(GSDME):c.(?863)-60(1257_?)+61del	Likely pathogenic

SpliceAI

1644 predictions. Top by Δscore:

Variant	Effect	Δscore
7:24706178:CCTTA:C	donor_loss	1.0000
7:24706179:CTTA:C	donor_loss	1.0000
7:24706180:TTACC:T	donor_loss	1.0000
7:24706181:TACC:T	donor_loss	1.0000
7:24706182:A:T	donor_loss	1.0000
7:24706372:TCGCA:T	acceptor_gain	1.0000
7:24706373:CGCA:C	acceptor_gain	1.0000
7:24706373:CGCAC:C	acceptor_gain	1.0000
7:24706374:GCA:G	acceptor_gain	1.0000
7:24706375:CA:C	acceptor_gain	1.0000
7:24706375:CAC:C	acceptor_gain	1.0000
7:24706377:C:CC	acceptor_gain	1.0000
7:24706378:T:C	acceptor_loss	1.0000
7:24708121:GCTCA:G	donor_loss	1.0000
7:24708122:CTCA:C	donor_loss	1.0000
7:24708123:TCACC:T	donor_loss	1.0000
7:24708124:CACCA:C	donor_loss	1.0000
7:24708126:CCA:C	donor_gain	1.0000
7:24708250:GGTCG:G	acceptor_gain	1.0000
7:24708251:GTCG:G	acceptor_gain	1.0000
7:24708252:TCG:T	acceptor_gain	1.0000
7:24708253:CG:C	acceptor_gain	1.0000
7:24708253:CGC:C	acceptor_gain	1.0000
7:24708253:CGCT:C	acceptor_loss	1.0000
7:24708254:GCTG:G	acceptor_loss	1.0000
7:24708255:C:CC	acceptor_gain	1.0000
7:24708255:C:CG	acceptor_loss	1.0000
7:24708257:G:C	acceptor_gain	1.0000
7:24710241:A:AC	donor_gain	1.0000
7:24710242:A:C	donor_gain	1.0000

AlphaMissense

3229 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:24717298:G:T	A218D	0.988
7:24717280:A:G	L224S	0.986
7:24719153:A:T	V157D	0.983
7:24749658:T:A	K39N	0.983
7:24749658:T:G	K39N	0.983
7:24717319:A:G	I211T	0.982
7:24717299:C:G	A218P	0.977
7:24710354:G:C	F244L	0.976
7:24710354:G:T	F244L	0.976
7:24710356:A:G	F244L	0.976
7:24744606:C:A	K120N	0.976
7:24744606:C:G	K120N	0.976
7:24717255:G:C	F232L	0.975
7:24717255:G:T	F232L	0.975
7:24717257:A:G	F232L	0.975
7:24749770:A:C	F2C	0.975
7:24719138:A:G	I162T	0.972
7:24749769:A:C	F2L	0.972
7:24749769:A:T	F2L	0.972
7:24749771:A:G	F2L	0.972
7:24749639:A:G	W46R	0.971
7:24749639:A:T	W46R	0.971
7:24719138:A:C	I162S	0.968
7:24719159:A:T	L155Q	0.965
7:24749624:A:C	Y51D	0.964
7:24749749:A:G	F9S	0.964
7:24749770:A:G	F2S	0.964
7:24717262:C:A	G230V	0.963
7:24717274:A:T	V226E	0.961
7:24744583:A:G	L128P	0.961

dbSNP variants (sampled 300 via entrez): RS1000024186 (7:24764605 A>C), RS1000050473 (7:24786720 T>C), RS1000065322 (7:24770715 C>A,G,T), RS1000079708 (7:24774463 A>G,T), RS1000086734 (7:24730651 C>G,T), RS1000090249 (7:24782203 C>A,T), RS1000143822 (7:24700004 T>G), RS1000226240 (7:24709536 C>A,T), RS1000249616 (7:24729188 C>T), RS1000254750 (7:24724926 C>A,G,T), RS1000268856 (7:24709262 C>G), RS1000274820 (7:24788692 G>C), RS1000358725 (7:24719626 C>A), RS1000359542 (7:24709833 A>C), RS1000373519 (7:24723860 G>A)

Disease associations

OMIM: gene MIM:608798 | disease phenotypes: MIM:600994

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant nonsyndromic hearing loss 5	Strong	Autosomal dominant
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	AD

Mondo (5): autosomal dominant nonsyndromic hearing loss 5 (MONDO:0010973), nonsyndromic genetic hearing loss (MONDO:0019497), hearing loss disorder (MONDO:0005365), sensorineural hearing loss disorder (MONDO:0020678), autosomal dominant nonsyndromic hearing loss (MONDO:0019587)

Orphanet (3): Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare genetic deafness (Orphanet:96210), Rare non-syndromic genetic deafness (Orphanet:87884)

HPO phenotypes

2 total (3 of 2 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000408	Progressive sensorineural hearing impairment
HP:0000407	Sensorineural hearing impairment

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002828_28	Urate levels in obese individuals	1.000000e-06
GCST004946_19	Schizophrenia	5.000000e-08
GCST006628_2	Systolic blood pressure	1.000000e-09
GCST006803_36	Schizophrenia	2.000000e-08
GCST007201_397	Schizophrenia	3.000000e-07
GCST007201_70	Schizophrenia	1.000000e-07
GCST008103_37	Bipolar disorder	9.000000e-08
GCST009600_137	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	7.000000e-11
GCST011102_10	Bipolar disorder	3.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0006335	systolic blood pressure

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C563410	Deafness, Autosomal Dominant 5 (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	3
Benzo(a)pyrene	increases expression	3
Cadmium	decreases expression, increases expression, decreases reaction, increases abundance, increases activity	3
Aflatoxin B1	affects expression, increases expression	3
Cadmium Chloride	increases expression, decreases reaction, increases abundance, increases activity, decreases expression	3
bisphenol A	decreases expression, increases methylation	2
sodium arsenite	decreases expression, increases expression	2
potassium chromate(VI)	affects cotreatment, decreases expression	2
entinostat	decreases expression, affects cotreatment	2
Acetaminophen	increases expression	2
Cisplatin	decreases reaction, increases cleavage, affects reaction, affects cotreatment, increases expression	2
Methotrexate	decreases expression, increases expression	2
Valproic Acid	decreases methylation, affects expression	2
Particulate Matter	increases abundance, affects cotreatment, increases cleavage, decreases expression	2
aristolochic acid I	decreases expression	1
SC-66 compound	increases cleavage, affects cotreatment, increases abundance	1
bisphenol F	increases expression	1
AKT activator SC79	increases cleavage, affects cotreatment, increases abundance	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
deoxynivalenol	decreases reaction, increases cleavage, decreases expression, affects cotreatment, increases secretion (+1 more)	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
nitidine	affects reaction, increases cleavage	1
thallium sulfate	increases cleavage	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
chloroquine diphosphate	decreases expression	1
artenimol	affects reaction, increases expression, increases secretion, decreases reaction, increases cleavage	1
epigallocatechin gallate	affects cotreatment, decreases expression	1

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D6AK	HyCyte A-549 KO-hGSDME	Cancer cell line	Male
CVCL_E0VN	Ubigene Huh-7 GSDME KO	Cancer cell line	Male
CVCL_E1VI	HAP1 DFNA5 (-) 1	Cancer cell line	Male
CVCL_E1VJ	HAP1 DFNA5 (-) 2	Cancer cell line	Male
CVCL_F1U2	HyCyte THP-1 KO-hGSDME	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound