DTHD1

Summary

DTHD1 (death domain containing 1, HGNC:37261) is a protein-coding gene on chromosome 4p14, encoding Death domain-containing protein 1 (Q6ZMT9).

This gene encodes a protein which contains a death domain. Death domain-containing proteins function in signaling pathways and formation of signaling complexes, as well as the apoptosis pathway. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 401124 — RefSeq curated summary.

At a glance

• Gene–disease (curated): LCAT deficiency (Limited, GenCC)
• GWAS associations: 11
• Clinical variants (ClinVar): 540 total
• Phenotypes (HPO): 1
• MANE Select transcript: NM_001170700

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:37261
Approved symbol	DTHD1
Name	death domain containing 1
Location	4p14
Locus type	gene with protein product
Status	Approved
Aliases	FLJ16686
Ensembl gene	ENSG00000197057
Ensembl biotype	protein_coding
OMIM	616979
Entrez	401124

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000357504, ENST00000456874, ENST00000503528, ENST00000506008, ENST00000507598, ENST00000639862, ENST00000903020, ENST00000903021

RefSeq mRNA: 3 — MANE Select: NM_001170700 NM_001136536, NM_001170700, NM_001378435

CCDS: CCDS54754

Canonical transcript exons

ENST00000639862 — 10 exons

Exon	Start	End
ENSE00001402457	36290373	36290703
ENSE00001418004	36339112	36339169
ENSE00001422831	36308204	36308493
ENSE00001427566	36294795	36295039
ENSE00001429919	36306191	36306352
ENSE00001431109	36293526	36293705
ENSE00003473308	36316242	36316486
ENSE00003808628	36283976	36284591
ENSE00003810985	36281616	36282029
ENSE00003903788	36343502	36347511

Expression profiles

Bgee: expression breadth ubiquitous, 128 present calls, max score 94.65.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.6101 / max 184.5102, expressed in 144 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47286	1.5044	141
47287	0.1057	42

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	94.65	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.67	gold quality
bronchial epithelial cell	CL:0002328	82.19	gold quality
bronchus	UBERON:0002185	80.32	gold quality
granulocyte	CL:0000094	76.74	gold quality
oviduct epithelium	UBERON:0004804	71.47	gold quality
right lung	UBERON:0002167	71.25	gold quality
fallopian tube	UBERON:0003889	71.25	gold quality
lymph node	UBERON:0000029	68.24	gold quality
right testis	UBERON:0004534	67.57	gold quality
mucosa of paranasal sinus	UBERON:0005030	67.44	silver quality
left testis	UBERON:0004533	66.70	gold quality
testis	UBERON:0000473	65.19	gold quality
vermiform appendix	UBERON:0001154	64.30	gold quality
nasal cavity mucosa	UBERON:0001826	64.28	gold quality
spleen	UBERON:0002106	62.64	gold quality
left uterine tube	UBERON:0001303	60.65	gold quality
upper lobe of left lung	UBERON:0008952	60.07	gold quality
blood	UBERON:0000178	59.62	gold quality
gall bladder	UBERON:0002110	59.24	gold quality
caecum	UBERON:0001153	59.06	gold quality
upper lobe of lung	UBERON:0008948	58.93	gold quality
caput epididymis	UBERON:0004358	58.01	gold quality
bone marrow cell	CL:0002092	57.96	gold quality
lung	UBERON:0002048	56.85	gold quality
colonic epithelium	UBERON:0000397	56.68	gold quality
corpus callosum	UBERON:0002336	56.58	gold quality
tonsil	UBERON:0002372	54.83	gold quality
endometrium	UBERON:0001295	53.41	gold quality
caudate nucleus	UBERON:0001873	52.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-114	yes	60.77
E-ANND-3	yes	10.32

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

46 targeting DTHD1, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-409-3P	99.50	66.33	1192
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-3160-5P	99.28	69.07	1938
HSA-MIR-4635	98.74	67.63	1339
HSA-MIR-3938	98.72	66.07	834
HSA-MIR-216B-3P	98.55	67.19	1223
HSA-MIR-6881-5P	98.16	67.38	665

Literature-anchored findings (GeneRIF, showing 1)

• human genome-wide gene expression profile assay was used to screen the targets of miR-3131. The overexpressed miR-3131 could lead to a significant decrease of DTHD1 and XAF1 mRNA level. (PMID:28034876)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	dthd1	ENSDARG00000086452
mus_musculus	Dthd1	ENSMUSG00000090326

Paralogs (1): PSMD10 (ENSG00000101843)

Protein

Protein identifiers

Death domain-containing protein 1 — Q6ZMT9 (reviewed: Q6ZMT9)

All UniProt accessions (3): A0A1W2PR94, Q6ZMT9, D6RB49

Isoforms (2)

UniProt ID	Names	Canonical?
Q6ZMT9-1	1	yes
Q6ZMT9-2	2

RefSeq proteins (3): NP_001130008, NP_001164171, NP_001365364 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000488	Death_dom	Domain
IPR000906	ZU5_dom	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily

Pfam: PF00531

UniProt features (11 total): sequence variant 4, domain 3, splice variant 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZMT9-F1	69.99	0.28

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 0 (showing top):

GO Biological Process (1): signal transduction (GO:0007165)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
binding	1

Protein interactions and networks

STRING

538 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DTHD1	IFT38	Q96AJ1	561
DTHD1	RD3	Q7Z3Z2	489
DTHD1	AIPL1	Q9NZN9	476
DTHD1	SPATA7	Q9P0W8	464
DTHD1	IFT140	Q96RY7	463
DTHD1	KCNJ13	O60928	455
DTHD1	MORN5	Q5VZ52	445
DTHD1	LMNTD1	Q8N9Z9	439
DTHD1	TULP1	O00294	437
DTHD1	IQCB1	Q15051	436
DTHD1	LRRC74B	Q6ZQY2	436
DTHD1	CABP4	P57796	434
DTHD1	RDH12	Q96NR8	430
DTHD1	PRPH2	P23942	425
DTHD1	CIMAP1B	A8MYP8	410

IntAct

2 interactions, top by confidence:

A	B	Type	Score
M		psi-mi:“MI:0914”(association)	0.350

BioGRID (2): DTHD1 (Affinity Capture-MS), DTHD1 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A6H5X4, B2RX14, D0QMC3, D3ZF42, F6QRE9, O14862, O35368, P0C6Y7, P0DOV1, P0DOV2, P23497, P41218, Q13342, Q15361, Q16666, Q17RS7, Q3KRF1, Q504N7, Q5H9K5, Q5I0E2, Q5RD14, Q5RF97, Q5T4T6, Q5VYS8, Q5W0A0, Q62187, Q66JT0, Q6K0P9, Q6NYJ3, Q6ZMT9, Q7RTT4, Q80VH0, Q86X53, Q8BUH8, Q8BV49, Q8BVK9, Q8C0V1, Q8CGE8, Q8NDB2, Q8SPH9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	380
Likely benign	131
Benign	21

Top pathogenic / likely-pathogenic (0)

SpliceAI

1894 predictions. Top by Δscore:

Variant	Effect	Δscore
4:36284592:G:GG	donor_gain	1.0000
4:36284589:GGA:G	donor_gain	0.9900
4:36284590:GA:G	donor_gain	0.9900
4:36284590:GAG:G	donor_gain	0.9900
4:36293587:A:AG	acceptor_gain	0.9900
4:36293588:G:GG	acceptor_gain	0.9900
4:36339110:A:AG	acceptor_gain	0.9900
4:36339111:G:GG	acceptor_gain	0.9900
4:36284510:A:AG	donor_gain	0.9800
4:36284588:AGGA:A	donor_gain	0.9800
4:36284589:GGAG:G	donor_gain	0.9800
4:36293588:GAAA:G	acceptor_gain	0.9800
4:36308489:TTCAA:T	donor_gain	0.9800
4:36308492:AA:A	donor_gain	0.9800
4:36308492:AAGT:A	donor_loss	0.9800
4:36308493:AG:A	donor_loss	0.9800
4:36308494:G:GG	donor_gain	0.9800
4:36308495:TA:T	donor_loss	0.9800
4:36308496:AAGTA:A	donor_loss	0.9800
4:36343500:A:AG	acceptor_gain	0.9800
4:36343501:G:GG	acceptor_gain	0.9800
4:36343501:GAA:G	acceptor_gain	0.9800
4:36284587:AAGGA:A	donor_gain	0.9700
4:36290476:A:G	donor_gain	0.9700
4:36306323:ATC:A	donor_gain	0.9700
4:36308271:G:C	acceptor_gain	0.9700
4:36308490:TCAA:T	donor_gain	0.9700
4:36308491:CAA:C	donor_gain	0.9700
4:36308497:AGTAT:A	donor_loss	0.9700
4:36339111:GC:G	acceptor_gain	0.9700

AlphaMissense

5993 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:36290515:A:C	S219R	0.997
4:36290517:C:A	S219R	0.997
4:36290517:C:G	S219R	0.997
4:36294870:A:C	S367R	0.997
4:36294872:C:A	S367R	0.997
4:36294872:C:G	S367R	0.997
4:36290516:G:T	S219I	0.992
4:36293572:T:A	V297D	0.992
4:36306276:T:A	W452R	0.992
4:36306276:T:C	W452R	0.992
4:36290479:A:C	S207R	0.984
4:36290481:T:A	S207R	0.984
4:36290481:T:G	S207R	0.984
4:36290587:T:C	F243L	0.984
4:36290589:T:A	F243L	0.984
4:36290589:T:G	F243L	0.984
4:36293536:C:A	A285D	0.984
4:36316364:G:C	G615R	0.984
4:36343666:T:A	W730R	0.983
4:36343666:T:C	W730R	0.983
4:36316342:C:A	N607K	0.982
4:36316342:C:G	N607K	0.982
4:36343721:T:C	L748P	0.981
4:36308482:T:A	I570K	0.980
4:36306278:G:C	W452C	0.979
4:36306278:G:T	W452C	0.979
4:36290416:T:C	C186R	0.978
4:36290627:T:A	V256E	0.978
4:36293650:T:A	I323K	0.978
4:36293661:T:G	Y327D	0.978

dbSNP variants (sampled 300 via entrez): RS1000013407 (4:36308029 T>C), RS1000026541 (4:36306692 G>A), RS10000657 (4:36345569 G>A), RS1000071937 (4:36347711 C>G), RS1000137057 (4:36300346 G>T), RS1000165112 (4:36328161 C>T), RS1000190718 (4:36343483 T>A,C,G), RS10001947 (4:36303025 C>A,G), RS1000231728 (4:36312226 T>A), RS1000296491 (4:36337507 T>C), RS10003169 (4:36315929 G>A,T), RS1000331016 (4:36318807 G>A,C,T), RS1000379246 (4:36279813 C>A,T), RS1000489920 (4:36324754 C>T), RS1000507674 (4:36296950 T>C)

Disease associations

OMIM: gene MIM:616979 | disease phenotypes: MIM:204000

GenCC curated gene-disease

Disease	Classification	Inheritance
LCAT deficiency	Limited	Autosomal recessive

Mondo (5): inherited retinal dystrophy (MONDO:0019118), optic atrophy (MONDO:0003608), Leber congenital amaurosis (MONDO:0018998), muscular dystrophy (MONDO:0020121), LCAT deficiency (MONDO:0018999)

Orphanet (5): OBSOLETE: Inherited retinal disorder (Orphanet:71862), Leber congenital amaurosis (Orphanet:65), Muscular dystrophy (Orphanet:98473), LCAT deficiency (Orphanet:650), Familial LCAT deficiency (Orphanet:79293)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000556	Retinal dystrophy

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST005951_144	Body mass index	2.000000e-08
GCST006369_2	Body mass index	4.000000e-06
GCST006904_11	Cerebral amyloid deposition (PET imaging)	6.000000e-06
GCST006993_5	Hippocampal volume in Alzheimer’s disease dementia	4.000000e-07
GCST010724_7	HOMA-B (corrected for HOMA-IR)	2.000000e-07
GCST90002380_145	Basophil percentage of white cells	5.000000e-09
GCST90002389_38	Lymphocyte percentage of white cells	2.000000e-11
GCST90002393_219	Monocyte count	3.000000e-15
GCST90002398_445	Neutrophil count	8.000000e-28
GCST90002399_414	Neutrophil percentage of white cells	2.000000e-11
GCST90002407_425	White blood cell count	5.000000e-26

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007707	cerebral amyloid deposition measurement
EFO:0005035	hippocampal volume
EFO:0004469	HOMA-B
EFO:0007992	basophil percentage of leukocytes
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0005091	monocyte count
EFO:0004833	neutrophil count
EFO:0007990	neutrophil percentage of leukocytes

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D009136	Muscular Dystrophies	C05.651.534.500; C10.668.491.175.500; C16.320.577
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation	1
Folic Acid	decreases expression	1
Smoke	increases abundance, increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	increases expression	1
Permethrin	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01882400	PHASE4	COMPLETED	Assessment of Response to Treatment of Osteoporosis With Oral Bisphosphonates in Patients With Muscular Dystrophy
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT00999609	PHASE3	ACTIVE_NOT_RECRUITING	Safety and Efficacy Study in Subjects With Leber Congenital Amaurosis
NCT06891443	PHASE3	RECRUITING	Study to Evaluate Sepofarsen in Subjects With Leber Congenital Amaurosis (LCA) Type 10 (HYPERION)
NCT01254019	PHASE3	COMPLETED	A Clinical Study to Assess the Efficacy and Safety of GSK2402968 in Subjects With Duchenne Muscular Dystrophy
NCT01480245	PHASE3	TERMINATED	Open Label Study of GSK2402968 in Subjects With Duchenne Muscular Dystrophy
NCT01803412	PHASE3	TERMINATED	A Study of the Safety, Tolerability & Efficacy of Long-term Administration of Drisapersen in US & Canadian Subjects
NCT01826487	PHASE3	COMPLETED	Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
NCT01890798	PHASE3	WITHDRAWN	Drisapersen Duchenne Muscular Dystrophy (DMD) Treatment Protocol
NCT02090959	PHASE3	TERMINATED	An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy
NCT02432885	PHASE3	COMPLETED	Myocardial Fibrosis Progression in Duchenne and Becker Muscular Dystrophy - ACE Inhibitor Therapy Trial
NCT03179631	PHASE3	COMPLETED	Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy
NCT05126758	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Deramiocel (CAP-1002) in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT07587242	PHASE3	NOT_YET_RECRUITING	A Phase 3 Study to Evaluate the Safety and Efficacy of AOC 1044 (Also Referred to as Delpacibart Zotadirsen) in Participants With DMD With Gene Mutations Amenable to Exon 44 Skipping
NCT07608432	PHASE3	RECRUITING	Efficacy, Safety, and Tolerability of Zeleciment Rostudirsen (DYNE-251) Administered Intravenously Every 4 Weeks in Ambulatory Participants With Duchenne Muscular Dystrophy (FORZETTO)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT01153932	PHASE2	COMPLETED	Phase II Doubleblind Exploratory Study of GSK2402968 in Ambulant Subjects With Duchenne Muscular Dystrophy
NCT01462292	PHASE2	COMPLETED	A Clinical Study to Assess Two Doses of GSK2402968 in Subjects With Duchenne Muscular Dystrophy (DMD)
NCT01910649	PHASE2	TERMINATED	A Phase I/II, Open Label, Escalating Dose, Pilot Study to Assess Effect, Safety, Tolerability and PK of Multiple SC Doses of Drisapersen in Patients With Duchenne Muscular Dystrophy and to Assess the Potential for IV Dosing as an Alternative Route of Administration
NCT03406780	PHASE2	COMPLETED	A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT06290713	PHASE2	RECRUITING	Vasodilator and Exercise Study for DMD (VASO-REx)
NCT06547216	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Open-label Extension Study of AOC 1020 in Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT07287189	PHASE2	RECRUITING	Phase 2 Study of SAT-3247 in Pediatric Ambulatory Patients
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT01064505	PHASE1	COMPLETED	Safety Study of a Single IVT Injection of QPI-1007 in Chronic Optic Nerve Atrophy and Recent Onset NAION Patients
NCT05147701	PHASE1	RECRUITING	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for NAION
NCT00516477	PHASE1	COMPLETED	Safety Study in Subjects With Leber Congenital Amaurosis
NCT00821340	PHASE1	COMPLETED	Clinical Trial of Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations
NCT00494195	PHASE1	COMPLETED	Gene Transfer Therapy for Treating Children and Adults With Limb Girdle Muscular Dystrophy Type 2D (LGMD2D)
NCT00674843	PHASE1	UNKNOWN	The Efficacy of Using Far Infrared Radiation to Manage Muscular Dystrophies
NCT00873782	PHASE1	COMPLETED	Safety Study of Transvenous Limb Perfusion in Human Muscular Dystrophy
NCT01128855	PHASE1	COMPLETED	A Double-blind, Escalating Dose, Randomized, Placebo-controlled Study Assessing PK, Safety, Tolerability in Non-ambulant DMD Subjects
NCT02241928	PHASE1	WITHDRAWN	Stem Cell Therapy in Muscular Dystrophy
NCT03627494	PHASE1	COMPLETED	First Time in Human (FTIH) Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Single and Repeat Doses of GSK3439171A in Healthy Subjects and to Assess Food Effect