LETM1

Summary

LETM1 (leucine zipper and EF-hand containing transmembrane protein 1, HGNC:6556) is a protein-coding gene on chromosome 4p16.3, encoding Mitochondrial proton/calcium exchanger protein (O95202). Plays an important role in maintenance of mitochondrial morphology and in mediating either calcium or potassium/proton antiport. It is a common-essential gene (DepMap: required in 91.8% of cancer cell lines).

This gene encodes a protein that is localized to the inner mitochondrial membrane. The protein functions to maintain the mitochondrial tubular shapes and is required for normal mitochondrial morphology and cellular viability. Mutations in this gene cause Wolf-Hirschhorn syndrome, a complex malformation syndrome caused by the deletion of parts of the distal short arm of chromosome 4. Related pseudogenes have been identified on chromosomes 8, 15 and 19.

Source: NCBI Gene 3954 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction (Strong, GenCC)
• Clinical variants (ClinVar): 348 total — 7 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 171
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 91.8% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_012318

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6556
Approved symbol	LETM1
Name	leucine zipper and EF-hand containing transmembrane protein 1
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Aliases	SLC55A1, Mdm38
Ensembl gene	ENSG00000168924
Ensembl biotype	protein_coding
OMIM	604407
Entrez	3954

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 17 protein_coding, 5 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000302787, ENST00000466175, ENST00000505551, ENST00000510940, ENST00000511977, ENST00000512189, ENST00000512669, ENST00000872446, ENST00000872447, ENST00000872448, ENST00000872449, ENST00000872450, ENST00000872451, ENST00000872452, ENST00000872453, ENST00000872454, ENST00000917095, ENST00000957529, ENST00000957530, ENST00000957531, ENST00000957532, ENST00000957533, ENST00000957534

RefSeq mRNA: 1 — MANE Select: NM_012318 NM_012318

CCDS: CCDS3355

Canonical transcript exons

ENST00000302787 — 14 exons

Exon	Start	End
ENSE00001164678	1815664	1815802
ENSE00001164686	1816727	1816914
ENSE00001164692	1819338	1819472
ENSE00001164699	1822181	1822312
ENSE00001164703	1822988	1823131
ENSE00001164728	1832744	1832947
ENSE00001164778	1855869	1856156
ENSE00001292753	1811479	1814573
ENSE00002721649	1834845	1834982
ENSE00003527879	1823644	1823775
ENSE00003614625	1841347	1841797
ENSE00003646754	1836429	1836572
ENSE00003656048	1825564	1825683
ENSE00003687209	1849149	1849209

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 95.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.5683 / max 274.7540, expressed in 1811 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51094	24.4715	1808
51096	0.5380	277
51093	0.3977	154
51095	0.1449	33
51092	0.0162	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	95.00	gold quality
sural nerve	UBERON:0015488	94.41	gold quality
buccal mucosa cell	CL:0002336	91.95	gold quality
lower esophagus mucosa	UBERON:0035834	90.70	gold quality
transverse colon	UBERON:0001157	90.55	gold quality
apex of heart	UBERON:0002098	90.20	gold quality
esophagus mucosa	UBERON:0002469	90.14	gold quality
epithelium of nasopharynx	UBERON:0001951	88.55	gold quality
stromal cell of endometrium	CL:0002255	88.22	gold quality
right adrenal gland	UBERON:0001233	88.03	gold quality
right adrenal gland cortex	UBERON:0035827	87.64	gold quality
right lobe of thyroid gland	UBERON:0001119	87.57	gold quality
left adrenal gland cortex	UBERON:0035825	87.51	gold quality
colonic mucosa	UBERON:0000317	87.46	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.39	gold quality
left adrenal gland	UBERON:0001234	87.37	gold quality
heart left ventricle	UBERON:0002084	87.18	gold quality
cortical plate	UBERON:0005343	87.15	gold quality
adrenal cortex	UBERON:0001235	87.08	gold quality
cardiac ventricle	UBERON:0002082	86.90	gold quality
body of stomach	UBERON:0001161	86.82	gold quality
gastrocnemius	UBERON:0001388	86.77	gold quality
skin of abdomen	UBERON:0001416	86.76	gold quality
cerebellar hemisphere	UBERON:0002245	86.72	gold quality
adrenal gland	UBERON:0002369	86.69	gold quality
mucosa of sigmoid colon	UBERON:0004993	86.69	gold quality
cerebellar cortex	UBERON:0002129	86.68	gold quality
esophagus	UBERON:0001043	86.62	gold quality
vagina	UBERON:0000996	86.52	gold quality
medial globus pallidus	UBERON:0002477	86.49	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	654.59
E-ANND-3	yes	8.62

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

71 targeting LETM1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-7156-5P	99.64	68.81	1369

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 91.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 36)

• LETM1 is evolutionarily conserved throughout the eukaryotic kingdom and located in the mitochondria. (PMID:14706454)
• Here, we present cellular and biochemical analysis of Letm1 (PMID:17606466)
• Study shows that human LETM1 is located in the inner membrane, exposed to the matrix and oligomerized in higher molecular weight complexes of unknown composition; down-regulation of LETM1 caused ’necrosis-like’ death, without activation of caspases. (PMID:17925330)
• the LETM1-mediated regulation of the mitochondrial volume and its interaction with the mitochondrial AAA-ATPase BCS1L that is responsible for three different human disorders (PMID:18628306)
• LETM1 protein is a novel binding partner for Carboxyl-terminal modulator protein that may play an important role in mitochondrial fragmentation via optic atrophy type 1-cleavage. (PMID:19168126)
• Data suggest that LETM1 serves as an anchor protein for complex formation with the mitochondrial ribosome and regulates mitochondrial biogenesis. Increased expression of LETM1 in human cancer suggests that dysregulation of LETM1 features in tumorigenesis. (PMID:19318571)
• Letm1, was found to specifically mediate coupled Ca2+/H+ exchange; RNAi knockdown, overexpression, and liposome reconstitution of the purified Letm1 protein demonstrate that Letm1 is a mitochondrial Ca2+/H+ antiporter (PMID:19797662)
• LETM1 suppressed lung cancer cell growth in vitro and in vivo. (PMID:20824095)
• Letm1 and UCP2/3 independently contribute to two distinct, mitochondrial Ca(2+) uptake pathways in intact endothelial cells. (PMID:21613221)
• we have identified a novel submicroscopic duplication involving dosage sensitive genes TACC3, FGFR3, and LETM1. (PMID:21815251)
• Summarizes the current state of the art about the functions of LETM1 and its role in pathophysiology, with some emphasis on whether it is a feasible candidate for regulation of mitochondrial Ca2+ homeostasis. (PMID:22641639)
• Letm1 expression is decreased in patients with intractable TLE and a rat model of epilepsy. Down-regulation of Letm1 leads to increases mitochondrial swelling and decreased MT-CYB expression, which is associated with susceptibility to seizures. (PMID:23645710)
• Data indicate that loss of Letm1 contributes to the pathology of Wolf-Hirschhorn syndrome and may contribute to seizure phenotypes by reducing glucose oxidation and other specific metabolic alterations. (PMID:23716663)
• Haploinsufficiency of WHSC1 and/or LETM1 contributes to Wolf-Hirschhorn Syndrome, but that loss of distinct and/or additional genes in 4p16.3 is necessary for the expression of the core Wolf-Hirschhorn Syndrome phenotype. (PMID:23963300)
• Functional properties of Letm1 described in study are remarkably similar to those of the H(+)-dependent Ca(2+) transport mechanism identified in intact mitochondria. (PMID:24344246)
• These findings identify novel cellular phenotypes in Wolf-Hirschhorn syndrome attributable to a 50% reduction in LETM1 expression level. (PMID:24626991)
• LETM1 plays an important role in the progression of head and neck squamous cell carcinoma. (PMID:24689060)
• NCLX, but not LETM1, mediates Ca(2+) extrusion from mitochondria. By controlling the duration of matrix Ca(2+) elevations, NCLX contributes to the regulation of NAD(P)H production and to the conversion of Ca(2+) signals into redox changes. (PMID:24898248)
• Reconstitution of LETM1 or antioxidant overexpression rescued mitochondrial Ca(2+) transport and bioenergetics (PMID:25077561)
• LETM1 protein overexpression is associated with Triple negative breast cancer progression, and may be a potential biomarker for poor prognostic evaluation of Triple negative breast cancer. (PMID:25617527)
• LETM1 plays an important role in the progression of breast cancer (PMID:26722481)
• Data indicate a positive association between LETM1 up-regulation, YAP1 nuclear localization and high PDGFB expression. (PMID:27556512)
• these results revealed that the knockdown of LETM1 exhibited tumor suppressive effects, possibly by controlling the downstream Wnt/beta-catenin signaling pathway. (PMID:29048663)
• Here, the authors show that LETM1 is associated with mitochondrial ribosomes, is required for mitochondrial DNA distribution and expression, and regulates the activity of an ancillary metabolic enzyme, pyruvate dehydrogenase. (PMID:30012579)
• High expression of LETM1 indicates poor prognosis and may be a potential cancer stem cell marker in esophageal squamous cell carcinoma. (PMID:30031102)
• Data show that LETM1 is a transporter protein localized to the inner mitochondrial membrane shown to have a Ca(2+)/H exchanger activity. The role of LETM1 to Ca(2+) regulation is evident from Wolf-Hirschhorn syndrome patients that harbor a haploinsuficiency in LETM1 expression, leading to dysfunctional mitochondrial Ca(2+) handling and from many types of cancer cells that show an upregulation of its expression. [review] (PMID:30642051)
• LETM1 expression was remarkably upregulated in human fetal sagittal sections and colorectal adenocarcinoma tissues. The expression of LETM1 in colorectal adenocarcinoma tissue was correlated with clinical stage, lymph node metastasis, distant metastasis, and microvessel density. (PMID:31101574)
• LETM1 is a potential prognostic biomarker of lung non-small cell carcinoma. (PMID:31500591)
• LETM1 could serve as a potential prognostic biomarker and a therapeutic target for the better clinical management of gastric adenocarcinoma (PMID:31705880)
• The mitochondrial inner membrane protein LETM1 modulates cristae organization through its LETM domain. (PMID:32139798)
• MiR-613 blocked the progression of cervical cancer by targeting LETM1. (PMID:32633345)
• Wholeexome sequencing identifies a novel mutation of SLC20A2 (c.C1849T) as a possible cause of hereditary multiple exostoses in a Chinese family. (PMID:32705272)
• Suppression of LETM1 inhibits the proliferation and stemness of colorectal cancer cells through reactive oxygen species-induced autophagy. (PMID:33314691)
• The leucine zipper EF-hand containing transmembrane protein-1 EF-hand is a tripartite calcium, temperature, and pH sensor. (PMID:33576522)
• LETM1 (leucine zipper-EF-hand-containing transmembrane protein 1) silence reduces the proliferation, invasion, migration and angiogenesis in esophageal squamous cell carcinoma via KIF14 (kinesin family member 14). (PMID:34605738)
• Circ_0061140 Contributes to Ovarian Cancer Progression by Targeting miR-761/LETM1 Signaling. (PMID:36056285)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	letm1	ENSDARG00000056978
mus_musculus	Letm1	ENSMUSG00000005299
rattus_norvegicus	Letm1	ENSRNOG00000016427

Paralogs (2): LETMD1 (ENSG00000050426), LETM2 (ENSG00000165046)

Protein

Protein identifiers

Mitochondrial proton/calcium exchanger protein — O95202 (reviewed: O95202)

Alternative names: Electroneutral mitochondrial K(+)/H(+)exchanger, Leucine zipper-EF-hand-containing transmembrane protein 1

All UniProt accessions (1): O95202

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in maintenance of mitochondrial morphology and in mediating either calcium or potassium/proton antiport. Mediates proton-dependent calcium efflux from mitochondrion. Also functions as an electroneutral mitochondrial proton/potassium exchanger. Crucial for the maintenance of mitochondrial tubular networks and for the assembly of the supercomplexes of the respiratory chain. Required for the maintenance of the tubular shape and cristae organization.

Subunit / interactions. Homohexamer. Can form 2 complexes: a major (300 kDa) and a minor complex (500-600 kDa). Interacts with BCS1L. Interacts with GHITM.

Subcellular location. Mitochondrion inner membrane.

Post-translational modifications. PINK1-mediated phosphorylation at Thr-192, positively regulates its mitochondrial calcium transport activity.

Disease relevance. Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction (CONDMIM) [MIM:620089] An autosomal recessive disorder characterized primarily by global developmental delay and variably impaired intellectual development with speech delay apparent from infancy. Affected individuals have hypotonia, poor feeding, poor overall growth, and respiratory distress early in life. Other features include visual impairment due to optic atrophy, sensorineural hearing loss, and neuromuscular abnormalities. Features suggestive of a mitochondrial disorder include cataracts, cardiomyopathy, diabetes mellitus, combined oxidative phosphorylation deficiency, and increased lactate. Some patients develop seizures, some have dysmorphic facial features, and some have non-specific abnormalities on brain imaging. Death in childhood may occur. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by ruthenium red or its derivative Ru360.

Miscellaneous. May be due to intron retention. May be due to intron retention.

Similarity. Belongs to the LETM1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
O95202-1	1	yes
O95202-2	2
O95202-3	3

RefSeq proteins (1): NP_036450* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR033122	LETM1-like_RBD	Domain
IPR044202	LETM1/MDM38-like	Family
IPR059005	LETM1_C	Domain

Pfam: PF07766, PF26561

Catalyzed reactions (Rhea), 2 shown:

• K(+)(in) + H(+)(out) = K(+)(out) + H(+)(in) (RHEA:29467)
• Ca(2+)(in) + 2 H(+)(out) = Ca(2+)(out) + 2 H(+)(in) (RHEA:72199)

UniProt features (42 total): sequence variant 9, mutagenesis site 6, binding site 5, coiled-coil region 4, splice variant 3, helix 3, modified residue 2, topological domain 2, strand 2, domain 2, transit peptide 1, chain 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9BA1	SOLUTION NMR
9DMR	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95202-F1	67.36	0.05

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 (5): 676; 678; 680; 682; 687

Post-translational modifications (2): 192, 597

Mutagenesis-validated functional residues (6):

Position	Phenotype
192	loss of phosphorylation by pink1.
192	phosphomimetic mutant. increased rate of calcium export from mitochondria.
359	loss of ability to complement morphologic defects of mitochondria in letm1-deficient yeast mutant. slightly supports gro
382	loss of ability to complement growth defects and morphologic defects of mitochondria in letm1-deficient yeast mutant; wh
383	loss of ability to complement growth defects and morphologic defects of mitochondria in letm1-deficient yeast mutant; wh
384	loss of ability to complement growth defects and morphologic defects of mitochondria in letm1-deficient yeast mutant; wh

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-8949215	Mitochondrial calcium ion transport
R-HSA-9013408	RHOG GTPase cycle
R-HSA-9865881	Complex III assembly
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-382551	Transport of small molecules
R-HSA-611105	Respiratory electron transport
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 0 (showing top):

GO Biological Process (15): calcium ion transport (GO:0006816), mitochondrial calcium ion transmembrane transport (GO:0006851), mitochondrion organization (GO:0007005), inner mitochondrial membrane organization (GO:0007007), protein hexamerization (GO:0034214), cristae formation (GO:0042407), protein homooligomerization (GO:0051260), mitochondrial calcium ion homeostasis (GO:0051560), negative regulation of mitochondrial calcium ion concentration (GO:0051562), calcium export from the mitochondrion (GO:0099093), mitochondrial potassium ion transmembrane transport (GO:0140141), regulation of cellular hyperosmotic salinity response (GO:1900069), monoatomic ion transport (GO:0006811), potassium ion transport (GO:0006813), proton transmembrane transport (GO:1902600)

GO Molecular Function (6): calcium ion binding (GO:0005509), calcium:proton antiporter activity (GO:0015369), ribosome binding (GO:0043022), protein binding (GO:0005515), antiporter activity (GO:0015297), metal ion binding (GO:0046872)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Transport of small molecules	1
RHO GTPase cycle	1
Respiratory electron transport	1
Metabolism	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Aerobic respiration and respiratory electron transport	1
Signaling by Rho GTPases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metal ion transport	2
protein complex oligomerization	2
calcium ion transmembrane transport	1
organelle organization	1
mitochondrial membrane organization	1
inner mitochondrial membrane organization	1
mitochondrion	1
intracellular calcium ion homeostasis	1
mitochondrial calcium ion homeostasis	1
mitochondrial calcium ion transmembrane transport	1
release of sequestered calcium ion into cytosol	1
potassium ion transmembrane transport	1
cellular hyperosmotic salinity response	1
regulation of cellular response to osmotic stress	1
regulation of response to salt stress	1
transport	1
monoatomic cation transmembrane transport	1
metal ion binding	1
calcium:monoatomic cation antiporter activity	1
metal cation:proton antiporter activity	1
ribonucleoprotein complex binding	1
binding	1
secondary active transmembrane transporter activity	1
cation binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1591 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LETM1	TRAPPC10	P48553	905
LETM1	SLC8B1	Q6J4K2	864
LETM1	NSD2	O96028	854
LETM1	MICU1	Q9BPX6	838
LETM1	MICU2	Q8IYU8	764
LETM1	MCU	Q8NE86	752
LETM1	IMMT	Q16891	721
LETM1	MCUR1	Q96AQ8	708
LETM1	NELFA	Q9H3P2	671
LETM1	MCUB	Q9NWR8	657
LETM1	SMDT1	Q9H4I9	650
LETM1	MRPL36	Q9P0J6	593
LETM1	CHCHD3	Q9NX63	582
LETM1	MSX1	P28360	560
LETM1	OXA1L	Q15070	557

IntAct

153 interactions, top by confidence:

A	B	Type	Score
TBK1	TBKBP1	psi-mi:“MI:0914”(association)	0.860
STX12	SNAP23	psi-mi:“MI:0914”(association)	0.640
LETM1	PSMA3	psi-mi:“MI:0915”(physical association)	0.560
PSMA3	LETM1	psi-mi:“MI:0915”(physical association)	0.560
LETM1	ZNF76	psi-mi:“MI:0915”(physical association)	0.560
LETM1	KRTAP6-2	psi-mi:“MI:0915”(physical association)	0.560
LETM1	BCS1L	psi-mi:“MI:0915”(physical association)	0.560
SNRNP27	UBA6	psi-mi:“MI:0914”(association)	0.530
USP47	DENR	psi-mi:“MI:0914”(association)	0.530
HSD3B2	NARS1	psi-mi:“MI:0914”(association)	0.530
CYP1A1	SNX3	psi-mi:“MI:0914”(association)	0.530
TIMMDC1	NDUFS8	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
UNC93B1	GPR89A	psi-mi:“MI:0914”(association)	0.530
HTRA2	HAX1	psi-mi:“MI:2364”(proximity)	0.420
Lats2	MPDZ	psi-mi:“MI:0914”(association)	0.420
PPL	LETM1	psi-mi:“MI:0915”(physical association)	0.400
LETM1	CALR	psi-mi:“MI:0915”(physical association)	0.400
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
MAPK6		psi-mi:“MI:0914”(association)	0.350
IFITM3	STX12	psi-mi:“MI:0914”(association)	0.350
UNC93B1		psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
ATP6V0D1		psi-mi:“MI:0914”(association)	0.350
PCDHGB4	FAM171A2	psi-mi:“MI:0914”(association)	0.350

BioGRID (285): PSMA3 (Two-hybrid), LETM1 (Affinity Capture-MS), LETM1 (Affinity Capture-MS), LETM1 (Affinity Capture-MS), LETM1 (Affinity Capture-MS), LETM1 (Affinity Capture-MS), LETM1 (Affinity Capture-MS), LETM1 (Affinity Capture-MS), LETM1 (Affinity Capture-MS), LETM1 (Affinity Capture-MS), LETM1 (Affinity Capture-MS), LETM1 (Affinity Capture-MS), LETM1 (Affinity Capture-MS), LETM1 (Affinity Capture-MS), LETM1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I3P7X4, A7S641, A8WG88, A9ULY7, B0R034, B0W6N3, B5DFC8, B5ME19, D6WIX5, E7EXT2, F7AEX0, O60308, O95202, P0C204, P45433, P53569, Q03701, Q0VA06, Q173M7, Q1L987, Q28HX4, Q3SYW6, Q3ZC50, Q4QR58, Q5RAT8, Q5RCI4, Q5U2X6, Q5XGZ8, Q5XIN6, Q5ZK33, Q66I12, Q6AZI2, Q6IVW0, Q6P1V4, Q6PFQ2, Q6PGY6, Q7PGE8, Q7SYB2, Q8BZN6, Q8R1B4

Diamond homologs: O13920, O95202, P91927, Q06493, Q08179, Q0VA06, Q0VCA3, Q1LY46, Q28DA8, Q2VYF4, Q5PQQ5, Q5XIN6, Q5ZK33, Q7TNU7, Q9Z2I0

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
BCS1L	“up-regulates activity”	LETM1	binding
LETM1	up-regulates	Mitochondrial_biogenesis
LETM1	up-regulates	“CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III”
LETM1	up-regulates	“NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I”
LETM1	up-regulates	“Cytochrome c oxidase-Mitochondrial respiratory chain complex IV”
LETM1	“up-regulates quantity”	calcium(2+)	relocalization
LETM1	“up-regulates quantity”	potassium(1+)	relocalization
PINK1	“up-regulates activity”	LETM1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 193 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrion organization	8	7.1×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	4
Uncertain significance	162
Likely benign	132
Benign	25

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1300216	NM_012318.3(LETM1):c.878T>A (p.Ile293Asn)	Pathogenic
1300218	NM_012318.3(LETM1):c.2094del (p.Asp699fs)	Pathogenic
1300220	NM_012318.3(LETM1):c.751AAG[1] (p.Lys252del)	Pathogenic
1300221	NM_012318.3(LETM1):c.881G>A (p.Arg294Gln)	Pathogenic
1300222	NM_012318.3(LETM1):c.1072G>A (p.Asp358Asn)	Pathogenic
1300224	NM_012318.3(LETM1):c.1139G>C (p.Arg380Pro)	Pathogenic
1300225	NM_012318.3(LETM1):c.2071-9C>G	Pathogenic
1300217	NM_012318.3(LETM1):c.898C>T (p.Pro300Ser)	Likely pathogenic
152442	GRCh38/hg38 4p16.3(chr4:1825301-1859026)x1	Likely pathogenic
3381225	NM_012318.3(LETM1):c.1791delinsAA (p.Tyr598fs)	Likely pathogenic
4849458	NM_012318.3(LETM1):c.1456del (p.Gln486fs)	Likely pathogenic

SpliceAI

2997 predictions. Top by Δscore:

Variant	Effect	Δscore
4:1814574:C:CA	acceptor_loss	1.0000
4:1814575:T:A	acceptor_loss	1.0000
4:1815660:CCAC:C	donor_loss	1.0000
4:1815661:CACC:C	donor_loss	1.0000
4:1815662:A:C	donor_loss	1.0000
4:1815663:C:CG	donor_loss	1.0000
4:1815695:T:TA	donor_gain	1.0000
4:1815803:C:CC	acceptor_gain	1.0000
4:1816723:TCACC:T	donor_loss	1.0000
4:1816724:CA:C	donor_loss	1.0000
4:1816725:AC:A	donor_gain	1.0000
4:1816725:ACC:A	donor_gain	1.0000
4:1816725:ACCC:A	donor_gain	1.0000
4:1816726:CC:C	donor_gain	1.0000
4:1816726:CCC:C	donor_gain	1.0000
4:1816726:CCCC:C	donor_gain	1.0000
4:1816911:AGTC:A	acceptor_gain	1.0000
4:1816912:GTC:G	acceptor_gain	1.0000
4:1819334:CCA:C	donor_loss	1.0000
4:1819335:CA:C	donor_loss	1.0000
4:1819336:A:T	donor_loss	1.0000
4:1819337:C:CA	donor_loss	1.0000
4:1819337:CCTCG:C	donor_gain	1.0000
4:1819346:AGT:A	donor_gain	1.0000
4:1819348:T:TA	donor_gain	1.0000
4:1819357:T:TA	donor_gain	1.0000
4:1819360:T:TA	donor_gain	1.0000
4:1819468:TCCTC:T	acceptor_gain	1.0000
4:1819469:CCTCC:C	acceptor_gain	1.0000
4:1819470:CTC:C	acceptor_gain	1.0000

AlphaMissense

4827 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:1823775:A:G	W401R	1.000
4:1823775:A:T	W401R	1.000
4:1823773:C:A	W401C	0.999
4:1823773:C:G	W401C	0.999
4:1832781:A:G	L348P	0.999
4:1832847:A:G	L326P	0.999
4:1832862:A:G	L321P	0.999
4:1832888:A:C	F312L	0.999
4:1832888:A:T	F312L	0.999
4:1832890:A:G	F312L	0.999
4:1834930:A:G	L264P	0.999
4:1834932:G:C	F263L	0.999
4:1834932:G:T	F263L	0.999
4:1834934:A:G	F263L	0.999
4:1815776:A:G	L653P	0.998
4:1823732:A:G	L415P	0.998
4:1823765:A:G	L404P	0.998
4:1825571:A:G	L398P	0.998
4:1825616:C:T	G383D	0.998
4:1825640:A:G	L375P	0.998
4:1832749:C:G	D359H	0.998
4:1832769:A:G	L352P	0.998
4:1832793:A:G	L344P	0.998
4:1832838:A:G	L329P	0.998
4:1832889:A:C	F312C	0.998
4:1832900:A:C	F308L	0.998
4:1832900:A:T	F308L	0.998
4:1832902:A:G	F308L	0.998
4:1834939:G:T	A261D	0.998
4:1834940:C:G	A261P	0.998

dbSNP variants (sampled 300 via entrez): RS1000058784 (4:1813423 C>T), RS1000179606 (4:1835993 T>C), RS1000240556 (4:1839020 T>C), RS1000272076 (4:1848829 C>T), RS1000393325 (4:1838163 G>A), RS1000398791 (4:1821760 G>C,T), RS1000498264 (4:1855371 G>A,T), RS1000583733 (4:1844080 G>A,C), RS1000607729 (4:1849853 CCTT>C), RS1000660988 (4:1812076 G>A), RS1000725523 (4:1811114 C>T), RS1000790035 (4:1844311 T>C), RS1000790980 (4:1829893 C>T), RS1000847396 (4:1833657 G>A), RS1000858860 (4:1843369 C>T)

Disease associations

OMIM: gene MIM:604407 | disease phenotypes: MIM:194190, MIM:620089, MIM:612379

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction	Strong	Autosomal recessive

Mondo (5): Wolf-Hirschhorn syndrome (MONDO:0008684), neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction (MONDO:0859304), optic nerve disorder (MONDO:0002135), SRD5A3-congenital disorder of glycosylation (MONDO:0012885), ependymoma (MONDO:0016698)

Orphanet (3): Wolf-Hirschhorn syndrome (Orphanet:280), SRD5A3-CDG (Orphanet:324737), Ependymoma (Orphanet:251636)

HPO phenotypes

171 total (30 of 171 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000077	Abnormality of the kidney
HP:0000078	Abnormality of the genital system
HP:0000079	Abnormality of the urinary system
HP:0000119	Abnormality of the genitourinary system
HP:0000151	Aplasia of the uterus
HP:0000153	Abnormality of the mouth
HP:0000159	Abnormal lip morphology
HP:0000175	Cleft palate
HP:0000188	Short upper lip
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000288	Abnormality of the philtrum
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D004806	Ependymoma	C04.557.465.625.600.380.290; C04.557.470.670.380.290; C04.557.580.625.600.380.290
D009901	Optic Nerve Diseases	C10.292.700; C11.640
D054877	Wolf-Hirschhorn Syndrome	C16.131.077.944; C16.131.260.985; C16.320.180.985

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066991 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC55 Mitochondrial cation/proton exchangers

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression, increases expression	4
Valproic Acid	affects expression, increases expression, increases methylation	3
Cadmium Chloride	increases expression, decreases expression, increases abundance	3
bisphenol A	increases expression	2
Estradiol	increases expression	2
aristolochic acid I	increases expression	1
afuresertib	decreases expression	1
bisphenol F	increases expression	1
dicrotophos	increases expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
trichostatin A	decreases expression, affects cotreatment	1
tetrahydropalmatine	decreases expression	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
bisphenol B	increases expression	1
abrine	decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
bisphenol AF	increases expression	1
Decitabine	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases abundance, increases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	decreases expression	1
Furaldehyde	affects cotreatment, affects localization, increases expression, decreases expression	1
Hydrogen Peroxide	affects 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
CHEMBL5651689	Binding	Binding affinity to human LETM1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00517959	PHASE3	UNKNOWN	SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors
NCT01096368	PHASE3	COMPLETED	Maintenance Chemotherapy or Observation Following Induction Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Ependymoma
NCT00003479	PHASE2	TERMINATED	Antineoplaston Therapy in Treating Patients With Ependymoma
NCT00520936	PHASE2	COMPLETED	A Study of Pemetrexed in Children With Recurrent Cancer
NCT00840047	PHASE2	ACTIVE_NOT_RECRUITING	Methionine PET/CT Studies In Patients With Cancer
NCT01088035	PHASE2	TERMINATED	Carboplatin as a Radiosensitizer in Treating Childhood Ependymoma
NCT01247922	PHASE2	TERMINATED	Single-agent Erlotinib in Patients Previously Treated With Oral Etoposide in Protocol OSI-774-205
NCT01288235	PHASE2	COMPLETED	Proton Radiotherapy for Pediatric Brain Tumors Requiring Partial Brain Irradiation
NCT01295944	PHASE2	COMPLETED	Carboplatin and Bevacizumab for Recurrent Ependymoma
NCT01356290	PHASE2	RECRUITING	Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma, ATRT and Rare CNS Tumors
NCT01836549	PHASE2	TERMINATED	Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors
NCT02125786	PHASE2	ACTIVE_NOT_RECRUITING	A Trial of Surgery and Fractionated Re-Irradiation for Recurrent Ependymoma
NCT02689336	PHASE2	WITHDRAWN	Erlotinib in Combination With Temozolomide in Treating Relapsed/Recurrent/Refractory Pediatric Solid Tumors
NCT03095248	PHASE2	TERMINATED	Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03173950	PHASE2	COMPLETED	Immune Checkpoint Inhibitor Nivolumab in People With Recurrent Select Rare CNS Cancers
NCT03194906	PHASE2	COMPLETED	Memantine for Prevention of Cognitive Late Effects in Pediatric Patients Receiving Cranial Radiation Therapy for Localized Brain Tumors
NCT03210714	PHASE2	ACTIVE_NOT_RECRUITING	Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213652	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03213665	PHASE2	COMPLETED	Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)
NCT03213678	PHASE2	COMPLETED	Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213704	PHASE2	ACTIVE_NOT_RECRUITING	Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)
NCT03220035	PHASE2	COMPLETED	Vemurafenib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With BRAF V600 Mutations (A Pediatric MATCH Treatment Trial)
NCT03233204	PHASE2	COMPLETED	Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)
NCT03526250	PHASE2	COMPLETED	Palbociclib in Treating Patients With Relapsed or Refractory Rb Positive Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Activating Alterations in Cell Cycle Genes (A Pediatric MATCH Treatment Trial)
NCT03698994	PHASE2	ACTIVE_NOT_RECRUITING	Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)
NCT03727841	PHASE2	TERMINATED	Marizomib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial, and Spinal Cord Ependymoma
NCT04049669	PHASE2	ACTIVE_NOT_RECRUITING	Pediatric Trial of Indoximod With Chemotherapy and Radiation for Relapsed Brain Tumors or Newly Diagnosed DIPG
NCT04195555	PHASE2	ACTIVE_NOT_RECRUITING	Ivosidenib in Treating Patients With Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With IDH1 Mutations (A Pediatric MATCH Treatment Trial)
NCT04284774	PHASE2	ACTIVE_NOT_RECRUITING	Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial
NCT04320888	PHASE2	ACTIVE_NOT_RECRUITING	Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediatric MATCH Treatment Trial
NCT04374305	PHASE2	RECRUITING	Innovative Trial for Understanding the Impact of Targeted Therapies in NF2-Related Schwannomatosis (INTUITT-NF2)
NCT04743661	PHASE2	ACTIVE_NOT_RECRUITING	131I-Omburtamab, in Recurrent Medulloblastoma and Ependymoma
NCT06804655	PHASE2	NOT_YET_RECRUITING	Pharmacoscopy for Patients With Refractory Primary Brain Tumors
NCT07424092	PHASE2	RECRUITING	Intratumoral DNX-2401 for High Grade Pediatric Brain Tumors
NCT00634231	PHASE1	COMPLETED	A Phase I Study of AdV-tk + Prodrug Therapy in Combination With Radiation Therapy for Pediatric Brain Tumors
NCT00994071	PHASE1	COMPLETED	A Phase I Study of ABT-888, an Oral Inhibitor of Poly(ADP-ribose) Polymerase and Temozolomide in Children With Recurrent/Refractory CNS Tumors
NCT01171469	PHASE1	COMPLETED	Vaccination With Dendritic Cells Loaded With Brain Tumor Stem Cells for Progressive Malignant Brain Tumor
NCT01331135	PHASE1	COMPLETED	Aflac ST0901 CHOANOME - Sirolimus in Solid Tumors
NCT01498783	PHASE1	COMPLETED	Phase I Study of 5-Fluorouracil in Children and Young Adults With Recurrent Ependymoma