TMLHE

Summary

TMLHE (trimethyllysine hydroxylase, epsilon, HGNC:18308) is a protein-coding gene on chromosome Xq28, encoding Trimethyllysine dioxygenase, mitochondrial (Q9NVH6). Converts trimethyllysine (TML) into hydroxytrimethyllysine (HTML).

This gene encodes the protein trimethyllysine dioxygenase which is the first enzyme in the carnitine biosynthesis pathway. Carnitine play an essential role in the transport of activated fatty acids across the inner mitochondrial membrane. The encoded protein converts trimethyllysine into hydroxytrimethyllysine. A pseudogene of this gene is found on chromosome X. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 55217 — RefSeq curated summary.

At a glance

• Gene–disease (curated): epsilon-trimethyllysine hydroxylase deficiency (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 166 total — 1 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 12
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_018196

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18308
Approved symbol	TMLHE
Name	trimethyllysine hydroxylase, epsilon
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	TMLH, FLJ10727, BBOX2, XAP130
Ensembl gene	ENSG00000185973
Ensembl biotype	protein_coding
OMIM	300777
Entrez	55217

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 16 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000334398, ENST00000369439, ENST00000449645, ENST00000461075, ENST00000487422, ENST00000675642, ENST00000902548, ENST00000902549, ENST00000902550, ENST00000902551, ENST00000902552, ENST00000902553, ENST00000902554, ENST00000902555, ENST00000902556, ENST00000902557, ENST00000960922, ENST00000960923, ENST00000960924

RefSeq mRNA: 2 — MANE Select: NM_018196 NM_001184797, NM_018196

CCDS: CCDS14768, CCDS55547

Canonical transcript exons

ENST00000334398 — 8 exons

Exon	Start	End
ENSE00001335160	155489011	155491666
ENSE00001335163	155506898	155507134
ENSE00001335164	155511673	155511792
ENSE00001335165	155513986	155514265
ENSE00001335167	155524456	155524632
ENSE00001361355	155612792	155612952
ENSE00001770767	155492357	155492495
ENSE00003660615	155545096	155545277

Expression profiles

Bgee: expression breadth ubiquitous, 136 present calls, max score 89.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.2701 / max 50.0734, expressed in 1683 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
201088	2.6746	1364
201089	2.5956	1383

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue	UBERON:0001134	89.60	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.34	gold quality
muscle of leg	UBERON:0001383	89.18	gold quality
gastrocnemius	UBERON:0001388	88.93	gold quality
adrenal tissue	UBERON:0018303	88.18	gold quality
muscle tissue	UBERON:0002385	87.98	gold quality
blood	UBERON:0000178	86.82	gold quality
heart left ventricle	UBERON:0002084	86.29	gold quality
monocyte	CL:0000576	85.55	gold quality
islet of Langerhans	UBERON:0000006	85.49	gold quality
ventricular zone	UBERON:0003053	85.42	gold quality
leukocyte	CL:0000738	85.40	gold quality
heart	UBERON:0000948	85.34	gold quality
ganglionic eminence	UBERON:0004023	85.13	gold quality
smooth muscle tissue	UBERON:0001135	84.58	gold quality
right adrenal gland	UBERON:0001233	84.47	gold quality
rectum	UBERON:0001052	84.37	gold quality
right adrenal gland cortex	UBERON:0035827	84.23	gold quality
right atrium auricular region	UBERON:0006631	84.17	gold quality
colonic epithelium	UBERON:0000397	84.07	gold quality
calcaneal tendon	UBERON:0003701	83.81	gold quality
adrenal gland	UBERON:0002369	83.75	gold quality
duodenum	UBERON:0002114	83.63	gold quality
endometrium	UBERON:0001295	83.53	gold quality
left adrenal gland	UBERON:0001234	83.42	gold quality
tonsil	UBERON:0002372	83.42	gold quality
left adrenal gland cortex	UBERON:0035825	83.28	gold quality
adult mammalian kidney	UBERON:0000082	83.10	gold quality
kidney	UBERON:0002113	82.71	gold quality
popliteal artery	UBERON:0002250	82.63	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.10

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

99 targeting TMLHE, 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-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-202-5P	99.78	67.65	991
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-3659	99.70	67.97	694
HSA-MIR-548M	99.70	68.87	1749

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 7)

• C-terminal region of trimethyllysine hydroxylase, epsilon contains the main determinants for its enzymatic activity including a key H389 residue (PMID:15754339)
• By 5’ and 3’ RACE, we identified and mapped two alternative 5’ TMLH first exons and seven alternative 3’-splice variants. (PMID:17408883)
• Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE. (PMID:21865298)
• TMLHE deficiency is common in control males and was not significantly increased in frequency in probands from simplex autism families, however, it was 2.82-fold more frequent in probands from male-male multiplex autism families. (PMID:22566635)
• Study found 3 mutations in TMLHE to be associated with autism spectrum disorder, c.229C>T/p.Arg77X, c.730G>C/p.Asp244His, and c.1107G>T/p.Glu369Asp. (PMID:23092983)
• Case Report: complex recombination with deletion in the F8 and duplication in the TMLHE mediated by int22h copies during early embryogenesis in proband’s mother. (PMID:28492696)
• This work demonstrates the importance of the recognition sites that contribute to the enzymatic activity of TMLH: the Fe(II)-binding H242-D244-H389 residues, R391-R398 involved in 2OG binding and several residues (D231, N334 and the aromatic cage comprised of W221, Y217 and Y234) associated with binding of (2S)-N (epsilon)-trimethyllysine. (PMID:30898847)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmlhe	ENSDARG00000077547
rattus_norvegicus	Tmlhe	ENSRNOG00000000729
drosophila_melanogaster	Tmlh	FBGN0038795
caenorhabditis_elegans		WBGENE00001523

Paralogs (1): BBOX1 (ENSG00000129151)

Protein

Protein identifiers

Trimethyllysine dioxygenase, mitochondrial — Q9NVH6 (reviewed: Q9NVH6)

Alternative names: Epsilon-trimethyllysine 2-oxoglutarate dioxygenase, Epsilon-trimethyllysine hydroxylase, TML hydroxylase, TML-alpha-ketoglutarate dioxygenase

All UniProt accessions (1): Q9NVH6

UniProt curated annotations — full annotation on UniProt →

Function. Converts trimethyllysine (TML) into hydroxytrimethyllysine (HTML).

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion matrix.

Tissue specificity. All isoforms, but isoform 8, are widely expressed in adult and fetal tissues. Isoform 8 is restricted to heart and skeletal muscle.

Disease relevance. Autism, X-linked 6 (AUTSX6) [MIM:300872] A form of autism, a complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Most individuals with autism also manifest moderate intellectual disability. AUTSX6 patients may respond favorably to carnitine supplementation. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 Fe(2+) ion per subunit.

Pathway. Amine and polyamine biosynthesis; carnitine biosynthesis.

Miscellaneous. Produced by alternative splicing. Lacks enzymatic activity. Produced by alternative splicing. Lacks enzymatic activity. Produced by alternative splicing. Lacks enzymatic activity. Produced by alternative splicing. Lacks enzymatic activity. Produced by alternative splicing. Lacks the mitochondrial transit signal. Produced by alternative splicing. Produced by alternative promoter usage. Although the expression of the alternative 5’ exon has been detected by PCR in heart and skeletal muscle, the identification of the alternative promoter leading to this form remains elusive.

Similarity. Belongs to the gamma-BBH/TMLD family.

Isoforms (8)

UniProt ID	Names	Canonical?
Q9NVH6-1	1, TMLHa, TMLH1a	yes
Q9NVH6-3	2, TMLHb
Q9NVH6-4	3, TMLHc
Q9NVH6-2	4, TMLHd
Q9NVH6-5	5, TMLHe
Q9NVH6-6	6, TMLHf
Q9NVH6-7	7, TMLHg
Q9NVH6-8	8, TMLH1b

RefSeq proteins (2): NP_001171726, NP_060666* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003819	TauD/TfdA-like	Domain
IPR010376	GBBH-like_N	Domain
IPR012776	Trimethyllysine_dOase	Family
IPR038492	GBBH-like_N_sf	Homologous_superfamily
IPR042098	GlaH-like_sf	Homologous_superfamily
IPR050411	AlphaKG_dependent_hydroxylases	Family

Pfam: PF02668, PF06155

Enzyme classification (BRENDA):

• EC 1.14.11.8 — trimethyllysine dioxygenase (BRENDA: 6 organisms, 17 substrates, 12 inhibitors, 18 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
N6,N6,N6-TRIMETHYL-L-LYSINE	0.13–1.47	9
2-OXOGLUTARATE	0.109–1.97	6
ALPHA-KETOGLUTARATE	0.22	1
TRIMETHYLLYSINE	1.6	1

Catalyzed reactions (Rhea), 1 shown:

• N(6),N(6),N(6)-trimethyl-L-lysine + 2-oxoglutarate + O2 = (3S)-3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine + succinate + CO2 (RHEA:14181)

UniProt features (20 total): splice variant 8, binding site 3, sequence variant 2, sequence conflict 2, modified residue 2, transit peptide 1, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NVH6-F1	89.10	0.85

Functional residue map

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

Ligand- & substrate-binding residues (3): 242; 244; 389

Post-translational modifications (2): 179, 236

Mutagenesis-validated functional residues (1):

Position	Phenotype
389	no catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-71262	Carnitine synthesis

MSigDB gene sets: 153 (showing top): MODULE_255, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, MODULE_317, KEGG_LYSINE_DEGRADATION, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, GOBP_AMINO_ACID_BETAINE_METABOLIC_PROCESS, GOBP_MODIFIED_AMINO_ACID_METABOLIC_PROCESS, GOCC_MITOCHONDRIAL_MATRIX, MODULE_69, STAT5A_01, GOMF_DIOXYGENASE_ACTIVITY, GOMF_IRON_ION_BINDING, chrXq28

GO Biological Process (1): carnitine biosynthetic process (GO:0045329)

GO Molecular Function (5): iron ion binding (GO:0005506), trimethyllysine dioxygenase activity (GO:0050353), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), dioxygenase activity (GO:0051213)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
amino-acid betaine biosynthetic process	1
carnitine metabolic process	1
transition metal ion binding	1
2-oxoglutarate-dependent dioxygenase activity	1
catalytic activity	1
cation binding	1
oxidoreductase activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1508 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMLHE	TRAT1	Q6PIZ9	930
TMLHE	TRIM36	Q9NQ86	831
TMLHE	TRIM5	Q9C035	772
TMLHE	TRIM45	Q9H8W5	765
TMLHE	TRIM31	Q9BZY9	755
TMLHE	TRIM17	Q9Y577	715
TMLHE	BBX	Q8WY36	651
TMLHE	ALDH9A1	P49189	610
TMLHE	FLNA	P21333	584
TMLHE	PRY	O14603	583
TMLHE	MID1	O15344	582
TMLHE	SPRY1	O43609	548
TMLHE	SLC22A5	O76082	544
TMLHE	SPRY3	O43610	528
TMLHE	MID2	Q9UJV3	479

IntAct

61 interactions, top by confidence:

A	B	Type	Score
MED10	MED19	psi-mi:“MI:0914”(association)	0.910
MED29	MED19	psi-mi:“MI:0914”(association)	0.890
MED9	MED19	psi-mi:“MI:0914”(association)	0.790
HSPD1	NUDT19	psi-mi:“MI:0914”(association)	0.710
STIM2	PRKAB2	psi-mi:“MI:0914”(association)	0.640
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
RPUSD3	HSPD1	psi-mi:“MI:0914”(association)	0.530
ARHGEF26	CPS1	psi-mi:“MI:0914”(association)	0.530
BTG3	TMLHE	psi-mi:“MI:0915”(physical association)	0.400
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
RBL2	GSTM3	psi-mi:“MI:0914”(association)	0.350
SDHAF4	GPX4	psi-mi:“MI:0914”(association)	0.350
	AP3B1	psi-mi:“MI:0914”(association)	0.350
IMMP1L	EIF1AY	psi-mi:“MI:0914”(association)	0.350
SQSTM1	CHEK1	psi-mi:“MI:0914”(association)	0.350
MRM2	ZZEF1	psi-mi:“MI:0914”(association)	0.350
ISCA1	BACH1	psi-mi:“MI:0914”(association)	0.350
TRMU	IFT56	psi-mi:“MI:0914”(association)	0.350
MRM2	VWA8	psi-mi:“MI:0914”(association)	0.350
TRIM43	VWA8	psi-mi:“MI:0914”(association)	0.350
SHC2	VWA8	psi-mi:“MI:0914”(association)	0.350
YARS2	VWA8	psi-mi:“MI:0914”(association)	0.350
MRPS24	VWA8	psi-mi:“MI:0914”(association)	0.350
AMACR	VWA8	psi-mi:“MI:0914”(association)	0.350
ACSM5	VWA8	psi-mi:“MI:0914”(association)	0.350
RASL10B	VWA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (60): TMLHE (Affinity Capture-MS), TMLHE (Affinity Capture-MS), TMLHE (Affinity Capture-MS), TMLHE (Proximity Label-MS), TMLHE (Proximity Label-MS), TMLHE (Affinity Capture-MS), TMLHE (Proximity Label-MS), TMLHE (Proximity Label-MS), TMLHE (Proximity Label-MS), CSNK1E (Affinity Capture-MS), RPS21 (Affinity Capture-MS), TMLHE (Affinity Capture-MS), TMLHE (Proximity Label-MS), TMLHE (Reconstituted Complex), TMLHE (Affinity Capture-MS)

ESM2 similar proteins: B4G0F3, B5DEQ3, B7ZMP1, B8BKI7, B9SQI7, C1BYA3, C6JS30, E0CSI1, E0CTF3, E9Q4Z2, O00763, O14832, O15229, O18778, O35386, O62515, O88867, O94851, P09925, P0CF52, P28492, P37287, P57093, Q08C93, Q0IIB1, Q0VC74, Q1RLY6, Q2R483, Q571F8, Q5BJP9, Q5F4B3, Q5R5T5, Q5R9W8, Q5SRE7, Q64323, Q6DIZ8, Q6GQI7, Q6IQE9, Q812G0, Q91WN4

Diamond homologs: A5DCB6, Q0VC74, Q5F4B3, Q91ZE0, Q91ZW6, Q96UB1, Q9NVH6, P80193, O75936, Q5R5D8

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
TMLHE	“down-regulates quantity”	N(6),N(6),N(6)-trimethyl-L-lysine	“chemical modification”
TMLHE	“down-regulates quantity”	2-oxoglutarate(2-)	“chemical modification”
TMLHE	“up-regulates quantity”	succinate(2-)	“chemical modification”
TMLHE	“up-regulates quantity”	3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	6
Uncertain significance	69
Likely benign	13
Benign	4

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
225231	NM_018196.4(TMLHE):c.961_962del (p.Ile321fs)	Pathogenic
1299348	NM_018196.4(TMLHE):c.638+2del	Likely pathogenic
1808573	GRCh37/hg19 Xq28(chrX:154697070-155233731)x0	Likely pathogenic
4845897	NM_018196.4(TMLHE):c.224G>A (p.Trp75Ter)	Likely pathogenic
545381	NC_000023.11:g.(?155530103)(155550495_?)del	Likely pathogenic
545382	NC_000023.11:g.(?155531678)(155556173_?)del	Likely pathogenic
632605	NM_018196.4(TMLHE):c.277C>T (p.Arg93Cys)	Likely pathogenic

SpliceAI

1343 predictions. Top by Δscore:

Variant	Effect	Δscore
X:155506893:CTCA:C	donor_loss	1.0000
X:155506894:TCA:T	donor_loss	1.0000
X:155506895:CA:C	donor_loss	1.0000
X:155506896:A:AC	donor_gain	1.0000
X:155506896:AC:A	donor_gain	1.0000
X:155506897:C:CA	donor_gain	1.0000
X:155506897:CC:C	donor_gain	1.0000
X:155506897:CCT:C	donor_gain	1.0000
X:155506897:CCTG:C	donor_gain	1.0000
X:155506897:CCTGA:C	donor_gain	1.0000
X:155507133:TG:T	acceptor_gain	1.0000
X:155507135:C:CC	acceptor_gain	1.0000
X:155511671:A:AC	donor_gain	1.0000
X:155511671:AC:A	donor_gain	1.0000
X:155511672:C:CC	donor_gain	1.0000
X:155511672:CC:C	donor_gain	1.0000
X:155511672:CCCA:C	donor_gain	1.0000
X:155513981:ATTAC:A	donor_loss	1.0000
X:155513982:TTAC:T	donor_loss	1.0000
X:155513983:TACCT:T	donor_loss	1.0000
X:155513984:A:C	donor_loss	1.0000
X:155514265:CCT:C	acceptor_gain	1.0000
X:155514267:T:C	acceptor_gain	1.0000
X:155514269:T:C	acceptor_gain	1.0000
X:155524454:A:AC	donor_gain	1.0000
X:155524455:C:CC	donor_gain	1.0000
X:155524633:C:CC	acceptor_gain	1.0000
X:155492404:A:C	donor_gain	0.9900
X:155507130:GAATG:G	acceptor_gain	0.9900
X:155507131:AATG:A	acceptor_gain	0.9900

AlphaMissense

2772 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:155491609:G:T	R398S	0.998
X:155491629:C:A	R391M	0.998
X:155511700:T:A	D244V	0.998
X:155511707:G:C	H242D	0.998
X:155514170:A:G	W152R	0.998
X:155514170:A:T	W152R	0.998
X:155491629:C:G	R391T	0.997
X:155491644:C:G	R386P	0.997
X:155491645:G:T	R386S	0.997
X:155491649:G:C	N384K	0.997
X:155491649:G:T	N384K	0.997
X:155492437:A:G	W352R	0.997
X:155492437:A:T	W352R	0.997
X:155492478:C:G	R338P	0.997
X:155511699:G:C	D244E	0.997
X:155511699:G:T	D244E	0.997
X:155511701:C:G	D244H	0.997
X:155491628:C:A	R391S	0.996
X:155491628:C:G	R391S	0.996
X:155491632:C:T	G390D	0.996
X:155491636:G:C	H389D	0.996
X:155492415:A:G	L359P	0.996
X:155507075:T:A	D273V	0.996
X:155507076:C:G	D273H	0.996
X:155511700:T:C	D244G	0.996
X:155511700:T:G	D244A	0.996
X:155514061:C:A	G188V	0.996
X:155514061:C:T	G188E	0.996
X:155524537:G:T	R93S	0.996
X:155524584:C:G	R77P	0.996

dbSNP variants (sampled 300 via entrez): RS1000047456 (X:155577006 A>C), RS1000084847 (X:155601543 G>C), RS1000183292 (X:155606277 A>C,G), RS1000450473 (X:155522909 T>G), RS1000478706 (X:155597783 A>C), RS1000630983 (X:155543081 C>G,T), RS1000767669 (X:155597467 G>A), RS10007922 (X:155510711 C>T), RS1000792504 (X:155509864 G>A), RS1000941966 (X:155578811 G>A), RS1001021731 (X:155548736 A>G), RS1001103878 (X:155555040 C>A), RS1001182064 (X:155547336 G>A,C,T), RS1001304534 (X:155538048 T>C), RS1001350219 (X:155512217 G>T)

Disease associations

OMIM: gene MIM:300777 | disease phenotypes: MIM:300872, MIM:181500, MIM:213000, MIM:217990

GenCC curated gene-disease

Disease	Classification	Inheritance
epsilon-trimethyllysine hydroxylase deficiency	Limited	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
autism spectrum disorder	Disputed	XL

Mondo (5): epsilon-trimethyllysine hydroxylase deficiency (MONDO:0010469), intellectual disability (MONDO:0001071), schizophrenia (MONDO:0005090), isolated cerebellar hypoplasia/agenesis (MONDO:0008939), corpus callosum, agenesis of (MONDO:0009022)

Orphanet (5): Isolated cerebellar agenesis (Orphanet:1398), Isolated corpus callosum agenesis (Orphanet:200), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

12 total (13 of 12 shown, HPO-id order):

HPO	Term
HP:0000160	Narrow mouth
HP:0000322	Short philtrum
HP:0000430	Underdeveloped nasal alae
HP:0000508	Ptosis
HP:0000717	Autism
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001419	X-linked recessive inheritance
HP:0001513	Obesity
HP:0002003	Large forehead
HP:0002376	Developmental regression
HP:0100753	Schizophrenia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007445_43	Factor VIII levels	3.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004630	factor VIII measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D061085	Agenesis of Corpus Callosum	C10.500.034; C16.131.666.034; C23.300.008
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C562568	Cerebellar Hypoplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	5
bisphenol A	decreases expression, increases methylation, affects expression	2
bisphenol F	increases expression	1
methylmercuric chloride	decreases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	decreases expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Amiodarone	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	affects expression	1
Tunicamycin	increases expression	1
Zinc	decreases expression	1
Aflatoxin B1	decreases methylation	1
Copper Sulfate	decreases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia