TPK1

Summary

TPK1 (thiamin pyrophosphokinase 1, HGNC:17358) is a protein-coding gene on chromosome 7q35, encoding Thiamine pyrophosphokinase 1 (Q9H3S4). Catalyzes the phosphorylation of thiamine to thiamine pyrophosphate (TPP) utilizing UTP and therefore links the biosynthesis of TPP to pyrimidines metabolism.

The protein encoded by this gene functions as a homodimer and catalyzes the conversion of thiamine to thiamine pyrophosphate, a cofactor for some enzymes of the glycolytic and energy production pathways. Defects in this gene are a cause of thiamine metabolism dysfunction syndrome-5.

Source: NCBI Gene 27010 — RefSeq curated summary.

At a glance

• Gene–disease (curated): childhood encephalopathy due to thiamine pyrophosphokinase deficiency (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 337 total — 30 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 32
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_022445

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17358
Approved symbol	TPK1
Name	thiamin pyrophosphokinase 1
Location	7q35
Locus type	gene with protein product
Status	Approved
Aliases	HTPK1, PP20
Ensembl gene	ENSG00000196511
Ensembl biotype	protein_coding
OMIM	606370
Entrez	27010

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 13 protein_coding, 5 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000360057, ENST00000378098, ENST00000378099, ENST00000481645, ENST00000482940, ENST00000489798, ENST00000538212, ENST00000546806, ENST00000547966, ENST00000548460, ENST00000548831, ENST00000551062, ENST00000552881, ENST00000889989, ENST00000889990, ENST00000889991, ENST00000889992, ENST00000889993, ENST00000889994, ENST00000889995, ENST00000929247, ENST00000956436

RefSeq mRNA: 15 — MANE Select: NM_022445 NM_001042482, NM_001350879, NM_001350880, NM_001350881, NM_001350882, NM_001350883, NM_001350884, NM_001350885, NM_001350886, NM_001350887, NM_001350889, NM_001350893, NM_001350894, NM_001350895, NM_022445

CCDS: CCDS55178, CCDS5888

Canonical transcript exons

ENST00000360057 — 9 exons

Exon	Start	End
ENSE00001409274	144835967	144836053
ENSE00002223103	144765880	144765951
ENSE00002225661	144835560	144835618
ENSE00003507201	144623166	144623261
ENSE00003520736	144682909	144682978
ENSE00003528778	144548491	144548602
ENSE00003599390	144648807	144648879
ENSE00003601577	144591423	144591569
ENSE00003664702	144451941	144453663

Expression profiles

Bgee: expression breadth ubiquitous, 229 present calls, max score 89.73.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.3669 / max 124.2855, expressed in 1638 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86693	7.4864	1596
86692	0.8649	401
86691	0.0156	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	89.73	gold quality
jejunal mucosa	UBERON:0000399	89.67	gold quality
monocyte	CL:0000576	88.23	gold quality
mononuclear cell	CL:0000842	87.81	gold quality
leukocyte	CL:0000738	87.57	gold quality
duodenum	UBERON:0002114	87.49	gold quality
calcaneal tendon	UBERON:0003701	85.61	gold quality
blood	UBERON:0000178	84.94	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.66	gold quality
endothelial cell	CL:0000115	84.38	silver quality
oocyte	CL:0000023	84.35	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.97	gold quality
granulocyte	CL:0000094	83.43	gold quality
palpebral conjunctiva	UBERON:0001812	81.49	gold quality
left testis	UBERON:0004533	81.15	gold quality
tendon	UBERON:0000043	80.56	gold quality
rectum	UBERON:0001052	80.34	gold quality
testis	UBERON:0000473	80.26	gold quality
ileal mucosa	UBERON:0000331	80.23	gold quality
right testis	UBERON:0004534	80.21	gold quality
descending thoracic aorta	UBERON:0002345	79.94	gold quality
pigmented layer of retina	UBERON:0001782	79.61	gold quality
visceral pleura	UBERON:0002401	79.28	gold quality
spleen	UBERON:0002106	79.15	gold quality
thoracic aorta	UBERON:0001515	78.56	gold quality
vermiform appendix	UBERON:0001154	78.55	gold quality
ascending aorta	UBERON:0001496	78.43	gold quality
pleura	UBERON:0000977	78.14	gold quality
parietal pleura	UBERON:0002400	77.68	gold quality
aorta	UBERON:0000947	77.49	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.47

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1

miRNA regulators (miRDB)

86 targeting TPK1, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4760-5P	99.80	69.88	1619

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 10)

• This is the first report on the primary sequence for mammalian thiamin pyrophosphokinase, a protein that catalyzes the pyrophosphorylation of thiamin with adenosine 5’-triphosphate to form thiamin pyrophosphate. (PMID:10567383)
• findings indicate the importance of the Sp1 transcription factor cis-element in regulating the human thiamin pyrophosphokinase gene (hTPK1) gene expression (PMID:16262001)
• Genomic variations in either the fetal or maternal TPK1 gene could contribute to variability of birth weight in normal humans. (PMID:17295612)
• Mutation analysis of TPK1 uncovered three missense, one splice-site, and one frameshift mutation resulting in decreased TPK protein levels (PMID:22152682)
• These findings demonstrate that the genes involved in dictating thiamine homeostasis, such as SLC19A2, SLC25A19 and TPK-1, were significantly up-regulated in clinical tissues and breast cancer cell lines. (PMID:23642734)
• any disease mutants are directly or indirectly involved in thiamine binding. Thus, our study provided a novel rationale for thiamine supplementation, so far the major therapeutic intervention in TPK deficiency. (PMID:30483896)
• TPK1 as a predictive marker for the anti-tumour effects of simvastatin in gastric cancer. (PMID:31964553)
• Whole Exome Sequencing Identifies a Novel Mutation of TPK1 in a Chinese Family with Recurrent Ataxia. (PMID:32361878)
• Movement disorders associated with thiamine pyrophosphokinase deficiency: Intrafamilial variability in the phenotype. (PMID:33031988)
• The conserved Tpk1 regulates non-homologous end joining double-strand break repair by phosphorylation of Nej1, a homolog of the human XLF. (PMID:34244791)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tpk1	ENSDARG00000038040
mus_musculus	Tpk1	ENSMUSG00000029735
rattus_norvegicus	Tpk1	ENSRNOG00000029922
drosophila_melanogaster	CG14721	FBGN0037942
caenorhabditis_elegans		WBGENE00014027

Protein

Protein identifiers

Thiamine pyrophosphokinase 1 — Q9H3S4 (reviewed: Q9H3S4)

Alternative names: Placental protein 20, Thiamin pyrophosphokinase 1

All UniProt accessions (8): Q9H3S4, A0A090N8Y0, F5GZG6, F8VPB3, F8VRJ6, F8VVJ1, F8WCM7, Q6ZQX6

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the phosphorylation of thiamine to thiamine pyrophosphate (TPP) utilizing UTP and therefore links the biosynthesis of TPP to pyrimidines metabolism. By producing thiamine pyrophosphate, a cofactor of the mitochondrial pyruvate dehydrogenase indirectly regulates pyruvate oxidation and lipogenesis. Although it can also catalyze thiamine phosphorylation using ATP and CTP in vitro, it does so with significantly lower efficiency and without physiological relevance evidence.

Subunit / interactions. Homodimer.

Tissue specificity. Detected in heart, kidney, testis, small intestine and peripheral blood leukocytes, and at very low levels in a variety of tissues.

Disease relevance. Thiamine metabolism dysfunction syndrome 5, episodic encephalopathy type (THMD5) [MIM:614458] An autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Cofactor biosynthesis; thiamine diphosphate biosynthesis; thiamine diphosphate from thiamine: step 1/1.

Similarity. Belongs to the thiamine pyrophosphokinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H3S4-1	1	yes
Q9H3S4-2	2

RefSeq proteins (15): NP_001035947, NP_001337808, NP_001337809, NP_001337810, NP_001337811, NP_001337812, NP_001337813, NP_001337814, NP_001337815, NP_001337816, NP_001337818, NP_001337822, NP_001337823, NP_001337824, NP_071890* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006282	Thi_PPkinase	Family
IPR007371	TPK_catalytic	Domain
IPR007373	Thiamin_PyroPKinase_B1-bd	Domain
IPR016966	Thiamin_pyrophosphokinase_euk	Family
IPR036371	TPK_B1-bd_sf	Homologous_superfamily
IPR036759	TPK_catalytic_sf	Homologous_superfamily

Pfam: PF04263, PF04265

Enzyme classification (BRENDA):

• EC 2.7.6.2 — thiamine diphosphokinase (BRENDA: 15 organisms, 24 substrates, 34 inhibitors, 36 Km, 18 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
THIAMINE	0.0001–2.9	16
ATP	0.0041–18.3	14
GTP	0.021–2.6	2
CTP	7.6	1
PYRITHIAMINE	0.062	1
UTP	11.2	1
THIAMIN	—	0

Catalyzed reactions (Rhea), 1 shown:

• thiamine + UTP = thiamine diphosphate + UMP + H(+) (RHEA:79423)

UniProt features (38 total): strand 18, helix 8, sequence variant 3, splice variant 2, turn 2, mutagenesis site 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3S4Y	X-RAY DIFFRACTION	1.8
9HJC	ELECTRON MICROSCOPY	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H3S4-F1	97.92	0.98

Functional residue map

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

Mutagenesis-validated functional residues (2):

Position	Phenotype
100	loss of thiamine diphosphokinase activity.
101	loss of utp-specific thiamine diphosphokinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-196819	Vitamin B1 (thiamin) metabolism

MSigDB gene sets: 247 (showing top): BEGUM_TARGETS_OF_PAX3_FOXO1_FUSION_UP, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ACETYL_COA_METABOLIC_PROCESS, GOBP_KETONE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_FATTY_ACID_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_ERYTHROCYTE_UP

GO Biological Process (4): thiamine metabolic process (GO:0006772), thiamine diphosphate biosynthetic process (GO:0009229), regulation of pyruvate decarboxylation to acetyl-CoA (GO:0010510), thiamine-containing compound metabolic process (GO:0042723)

GO Molecular Function (10): thiamine diphosphokinase activity (GO:0004788), ATP binding (GO:0005524), kinase activity (GO:0016301), thiamine binding (GO:0030975), identical protein binding (GO:0042802), UTP thiamine diphosphokinase activity (GO:0141200), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (1): cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
diphosphotransferase activity	2
heterocyclic compound binding	2
primary alcohol metabolic process	1
thiamine-containing compound metabolic process	1
thiamine diphosphate metabolic process	1
thiamine-containing compound biosynthetic process	1
organophosphate biosynthetic process	1
pyruvate decarboxylation to acetyl-CoA	1
regulation of acyl-CoA biosynthetic process	1
sulfur compound metabolic process	1
pyrimidine-containing compound metabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transferase activity, transferring phosphorus-containing groups	1
vitamin binding	1
cation binding	1
alcohol binding	1
sulfur compound binding	1
protein binding	1
nucleoside phosphate binding	1
molecular_function	1
binding	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

948 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TPK1	TKTL2	Q9H0I9	984
TPK1	TKT	P29401	964
TPK1	TKTL1	P51854	943
TPK1	SLC19A3	Q9BZV2	780
TPK1	SLC19A2	O60779	748
TPK1	SLC25A19	Q9HC21	717
TPK1	HEBP2	Q9Y5Z4	621
TPK1	THTPA	Q9BU02	602
TPK1	LIPT1	Q9Y234	591
TPK1	LIPT2	A6NK58	542
TPK1	ENDOU	P21128	540
TPK1	PDHX	O00330	536
TPK1	PANK4	Q9NVE7	528
TPK1	LGALS13	Q9UHV8	505
TPK1	LIAS	O43766	476

IntAct

32 interactions, top by confidence:

A	B	Type	Score
TPK1	TPK1	psi-mi:“MI:0915”(physical association)	0.800
OPLAH	TPK1	psi-mi:“MI:0915”(physical association)	0.560
C1orf174	AHCYL1	psi-mi:“MI:0914”(association)	0.530
PARP2	TPK1	psi-mi:“MI:0557”(adp ribosylation reaction)	0.440
TPK1	PLS1	psi-mi:“MI:0915”(physical association)	0.400
TPK1	NSF	psi-mi:“MI:0915”(physical association)	0.400
PISD	IGLL5	psi-mi:“MI:0914”(association)	0.350
RHNO1	RAD1	psi-mi:“MI:0914”(association)	0.350
NOTCH2NLA	IGKC	psi-mi:“MI:0914”(association)	0.350
SERTAD1	IGKC	psi-mi:“MI:0914”(association)	0.350
TMEM18	GALT	psi-mi:“MI:0914”(association)	0.350
ZCCHC9	S100A10	psi-mi:“MI:0914”(association)	0.350
PTEN	DNAAF8	psi-mi:“MI:0914”(association)	0.350
ISX	GAPDHS	psi-mi:“MI:0914”(association)	0.350
TMEM69	ACOX3	psi-mi:“MI:0914”(association)	0.350
GALNT9	CTSV	psi-mi:“MI:0914”(association)	0.350
UBE2J2	ALOX12B	psi-mi:“MI:0914”(association)	0.350
PCGF3	MBL2	psi-mi:“MI:0914”(association)	0.350
RASL11A	MBL2	psi-mi:“MI:0914”(association)	0.350
SPIN4	MBL2	psi-mi:“MI:0914”(association)	0.350
DCK	KLK3	psi-mi:“MI:0914”(association)	0.350
EGLN3	KLK3	psi-mi:“MI:0914”(association)	0.350
OPLAH	TPK1	psi-mi:“MI:0915”(physical association)	0.000
TPK1	TPK1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (29): TPK1 (Two-hybrid), TPK1 (Two-hybrid), TPK1 (Two-hybrid), TPK1 (Negative Genetic), TPK1 (Proximity Label-MS), TPK1 (Affinity Capture-RNA), TPK1 (Affinity Capture-MS), TPK1 (Affinity Capture-MS), TPK1 (Affinity Capture-MS), TPK1 (Affinity Capture-MS), TPK1 (Affinity Capture-MS), TPK1 (Affinity Capture-MS), PLS1 (Affinity Capture-MS), TPK1 (Affinity Capture-MS), TPK1 (Affinity Capture-MS)

ESM2 similar proteins: B2GV54, D3K5L7, E2R222, O60656, O95803, P16152, P52848, Q08DW9, Q0VCJ8, Q0VD27, Q15645, Q1JQE6, Q2HJ19, Q3U129, Q3UA06, Q3UHN9, Q4R766, Q5E9T4, Q5R8Y5, Q5RCU5, Q5XHZ9, Q5XIJ5, Q5ZIN0, Q5ZMH6, Q67FW5, Q6AYT7, Q6DD70, Q6GL10, Q6GV29, Q6PIU2, Q8BGB7, Q8BK26, Q8BLF1, Q8BWB6, Q8MI29, Q8N2K0, Q8NFT2, Q8VDI9, Q99JW1, Q99LR1

Diamond homologs: B9DGU7, F4IV16, Q0JMW0, Q5E9T4, Q5JK24, Q60DX1, Q9H3S4, Q9R0M5, P30636, P41888, P0C026, P47173, Q8VXZ0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	12
Uncertain significance	131
Likely benign	116
Benign	27

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073305	NC_000007.13:g.(?144150618)(144532715_?)del	Pathogenic
1073306	NC_000007.13:g.(?144245564)(144532715_?)del	Pathogenic
1075880	NM_022445.4(TPK1):c.243del (p.Glu81fs)	Pathogenic
215275	NM_022445.4(TPK1):c.501+4A>T	Pathogenic
215277	NM_022445.4(TPK1):c.311del (p.Cys104fs)	Pathogenic
2426747	NC_000007.13:g.(?144532633)(144532695_?)del	Pathogenic
2426749	NC_000007.13:g.(?144245564)(144463064_?)del	Pathogenic
2426750	NC_000007.13:g.(?144288496)(144345992_?)del	Pathogenic
2426751	NC_000007.13:g.(?144288496)(144320374_?)del	Pathogenic
265278	NM_022445.4(TPK1):c.426G>C (p.Leu142Phe)	Pathogenic
2819348	NM_022445.4(TPK1):c.191dup (p.Leu64fs)	Pathogenic
2857481	NM_022445.4(TPK1):c.565G>T (p.Gly189Ter)	Pathogenic
30568	NM_022445.4(TPK1):c.148A>C (p.Asn50His)	Pathogenic
3245796	NC_000007.13:g.(?144462953)(144532695_?)del	Pathogenic
3363129	NM_022445.4(TPK1):c.355-2A>G	Pathogenic
3643694	NM_022445.4(TPK1):c.108G>A (p.Trp36Ter)	Pathogenic
3675841	NM_022445.4(TPK1):c.181_182del (p.Glu61fs)	Pathogenic
438734	NM_022445.4(TPK1):c.395T>C (p.Phe132Ser)	Pathogenic
438735	NM_022445.4(TPK1):c.614-1G>A	Pathogenic
4719345	NM_022445.4(TPK1):c.1A>G (p.Met1Val)	Pathogenic
583968	NC_000007.14:g.(?144623146)(144682998_?)del	Pathogenic
640613	NM_022445.4(TPK1):c.613+1G>C	Pathogenic
665627	NC_000007.14:g.(?144682889)(144682998_?)del	Pathogenic
686209	GRCh37/hg19 7q35(chr7:144274734-144331634)x1	Pathogenic
686732	GRCh37/hg19 7q35(chr7:144318728-144425718)x1	Pathogenic
687273	GRCh37/hg19 7q35(chr7:144272015-144331634)x1	Pathogenic
689063	GRCh37/hg19 7q35(chr7:144319985-144446894)x1	Pathogenic
832084	NC_000007.14:g.(?144682889)(144765971_?)del	Pathogenic
833116	NC_000007.14:g.(?144591403)(144835622_?)del	Pathogenic
944675	NM_022445.4(TPK1):c.405del (p.Met136fs)	Pathogenic

SpliceAI

4943 predictions. Top by Δscore:

Variant	Effect	Δscore
7:144453659:ATTTG:A	acceptor_gain	1.0000
7:144453660:TTTG:T	acceptor_gain	1.0000
7:144453661:TTG:T	acceptor_gain	1.0000
7:144453662:TG:T	acceptor_gain	1.0000
7:144453664:C:CC	acceptor_gain	1.0000
7:144551078:T:TA	donor_gain	1.0000
7:144591421:A:AC	donor_gain	1.0000
7:144591422:C:CC	donor_gain	1.0000
7:144623160:TATTA:T	donor_loss	1.0000
7:144623161:ATTAC:A	donor_loss	1.0000
7:144623162:TTA:T	donor_loss	1.0000
7:144623163:TA:T	donor_loss	1.0000
7:144623164:ACC:A	donor_loss	1.0000
7:144623165:C:CT	donor_loss	1.0000
7:144623259:TCC:T	acceptor_gain	1.0000
7:144623260:CC:C	acceptor_gain	1.0000
7:144623260:CCC:C	acceptor_gain	1.0000
7:144623261:CCTA:C	acceptor_gain	1.0000
7:144623264:A:C	acceptor_gain	1.0000
7:144623268:A:C	acceptor_gain	1.0000
7:144623269:T:TC	acceptor_gain	1.0000
7:144623274:G:GC	acceptor_gain	1.0000
7:144648880:C:CC	acceptor_gain	1.0000
7:144681805:A:AC	donor_gain	1.0000
7:144681806:C:CC	donor_gain	1.0000
7:144682903:GCATA:G	donor_loss	1.0000
7:144682904:CATA:C	donor_loss	1.0000
7:144682905:ATAC:A	donor_loss	1.0000
7:144682906:TA:T	donor_loss	1.0000
7:144682907:A:C	donor_loss	1.0000

AlphaMissense

1604 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:144623220:G:C	D100E	0.994
7:144623220:G:T	D100E	0.994
7:144453568:A:G	W237R	0.993
7:144453568:A:T	W237R	0.993
7:144453629:A:C	S216R	0.993
7:144453629:A:T	S216R	0.993
7:144453631:T:G	S216R	0.993
7:144548505:A:G	L200P	0.991
7:144648852:G:C	D71E	0.991
7:144648852:G:T	D71E	0.991
7:144623221:T:A	D100V	0.990
7:144623221:T:C	D100G	0.989
7:144623222:C:G	D100H	0.989
7:144453620:A:C	N219K	0.988
7:144453620:A:T	N219K	0.988
7:144623221:T:G	D100A	0.988
7:144648853:T:A	D71V	0.986
7:144648856:C:T	G70E	0.986
7:144453644:A:C	F211L	0.985
7:144453644:A:T	F211L	0.985
7:144453646:A:G	F211L	0.985
7:144682956:A:C	D46E	0.984
7:144682956:A:T	D46E	0.984
7:144548550:A:G	L185P	0.982
7:144623206:A:G	L105P	0.982
7:144648846:A:C	D73E	0.982
7:144648846:A:T	D73E	0.982
7:144648853:T:C	D71G	0.982
7:144548500:A:G	W202R	0.981
7:144548500:A:T	W202R	0.981

dbSNP variants (sampled 300 via entrez): RS1000001084 (7:144513614 T>C), RS1000002634 (7:144766799 C>G), RS1000009056 (7:144694586 G>A), RS1000022502 (7:144788528 C>G), RS1000038979 (7:144653061 A>C,T), RS1000055658 (7:144556905 A>G), RS1000062914 (7:144643762 G>A,C), RS1000067016 (7:144655811 C>T), RS1000072640 (7:144530487 C>T), RS1000094424 (7:144586618 T>A), RS1000098909 (7:144612028 G>A), RS1000101340 (7:144776208 G>A,C), RS1000106984 (7:144513077 C>T), RS1000110409 (7:144760399 A>G), RS1000115028 (7:144767048 A>G)

Disease associations

OMIM: gene MIM:606370 | disease phenotypes: MIM:614458, MIM:256000

GenCC curated gene-disease

Disease	Classification	Inheritance
childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Leigh syndrome	Moderate	AR

Mondo (2): childhood encephalopathy due to thiamine pyrophosphokinase deficiency (MONDO:0013761), Leigh syndrome (MONDO:0009723)

Orphanet (2): Childhood encephalopathy due to thiamine pyrophosphokinase deficiency (Orphanet:293955), Leigh syndrome (Orphanet:506)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000602	Ophthalmoplegia
HP:0000639	Nystagmus
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001288	Gait disturbance
HP:0001298	Encephalopathy
HP:0001332	Dystonia
HP:0001618	Dysphonia
HP:0001712	Left ventricular hypertrophy
HP:0002061	Lower limb spasticity
HP:0002066	Gait ataxia
HP:0002078	Truncal ataxia
HP:0002080	Intention tremor
HP:0002131	Episodic ataxia
HP:0002151	Increased circulating lactate concentration
HP:0002283	Global brain atrophy
HP:0002321	Vertigo
HP:0002371	Loss of speech
HP:0002376	Developmental regression
HP:0002490	Increased CSF lactate
HP:0003128	Lactic acidosis
HP:0003593	Infantile onset
HP:0011463	Childhood onset

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST007741_41	Iris color (b* coordinate)	3.000000e-06
GCST008667_10	Smoking status (heavy vs never)	2.000000e-07
GCST010136_23	Fruit consumption	5.000000e-08
GCST010136_24	Fruit consumption	1.000000e-48
GCST010397_39	Gut microbiota (bacterial taxa, rank normal transformation method)	2.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0009764	eye colour measurement
EFO:0006527	smoking status measurement
EFO:0008111	diet measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6155 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

1 measured of 1 human assays (76 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
2-[4-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]piperazin-1-yl]ethanol;hydrochloride	KI	146 nM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation	4
Aflatoxin B1	affects expression, decreases expression, increases methylation	4
Cisplatin	affects cotreatment, decreases expression	2
Estradiol	increases expression, decreases expression, affects cotreatment	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases methylation, affects cotreatment, affects methylation	1
arsenite	affects binding, decreases reaction	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	decreases expression	1
butylbenzyl phthalate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases methylation	1
jinfukang	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Fulvestrant	affects methylation, increases methylation, affects cotreatment	1
Arsenic	affects methylation	1
Cytarabine	decreases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL947913	Binding	Ratio of kcat to Km for thiamine pyrophospholipase	Non-charged thiamine analogs as inhibitors of enzyme transketolase. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells