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): 353 total — 8 pathogenic, 4 likely-pathogenic (top 9% of genes corpus-wide)
• GTEx eGene: eQTL in 15 tissues, sQTL in 3 (q < 0.05)
• Phenotypes (HPO): 171
• Cancer dependency (DepMap): dependent in 91.8% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.88 (unconstrained)
• 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: 28 — 19 protein_coding, 5 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000302787

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 3, TSL 3: 1

ENST00000302787, ENST00000466175, ENST00000505551, ENST00000510940, ENST00000511977, ENST00000512189, ENST00000512669, ENST00000872446, ENST00000872447, ENST00000872448, ENST00000872449, ENST00000872450, ENST00000872451, ENST00000872452, ENST00000872453, ENST00000872454, ENST00000917095, ENST00000957529, ENST00000957530, ENST00000957531, ENST00000957532, ENST00000957533, ENST00000957534, ENST00001021029, ENST00001021030, ENST00001076696, ENST00001115792, ENST00001134655

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.

Highest expression (Bgee): mucosa of transverse colon, sural nerve, buccal mucosa cell, lower esophagus mucosa, transverse colon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

LETM1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 15 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

18 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	4.7e-06	-0.34	4:1819924:C:T
Brain Cerebellum	eqtl	5.9e-05	-1.07	4:1819924:C:T
Whole Blood	eqtl	1.4e-04	+0.30	4:1805751:G:T
Testis	sqtl	1.0e-03	-1.83	4:1953289:C:T
Lung	eqtl	1.4e-03	-0.37	4:1806788:C:T
Esophagus Mucosa	eqtl	2.3e-03	+0.41	4:1265952:G:A
Thyroid	eqtl	3.5e-03	-0.18	4:1650557:C:T
Artery Tibial	eqtl	7.5e-03	-0.43	4:1819924:C:T
Small Intestine Terminal Ileum	sqtl	1.5e-02	-2.47	4:1334865:G:A
Cells EBV-transformed lymphocytes	eqtl	1.7e-02	-0.17	4:1833262:A:G
Adipose Subcutaneous	eqtl	2.1e-02	+0.08	4:2405569:A:G
Skin Sun Exposed Lower leg	eqtl	2.7e-02	-0.24	4:1819924:C:T
Cells Cultured fibroblasts	eqtl	2.9e-02	-0.12	4:1833262:A:G
Brain Cerebellar Hemisphere	eqtl	3.0e-02	+0.89	4:2279505:T:C
Pituitary	eqtl	3.2e-02	-0.78	4:1281535:C:CA
Cells Cultured fibroblasts	sqtl	3.3e-02	-0.79	4:1832939:T:C
Heart Left Ventricle	eqtl	3.9e-02	-0.26	4:1851624:C:G
Prostate	eqtl	3.9e-02	-0.39	4:1621951:A:G

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

showing 100 of 283 tissues 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
thymus	UBERON:0002370	86.46	gold quality
colon	UBERON:0001155	86.24	gold quality
metanephros cortex	UBERON:0010533	86.13	gold quality
duodenum	UBERON:0002114	86.05	gold quality
cerebellum	UBERON:0002037	86.02	gold quality
muscle of leg	UBERON:0001383	86.00	gold quality
tibial nerve	UBERON:0001323	85.99	gold quality
right lobe of liver	UBERON:0001114	85.98	gold quality
large intestine	UBERON:0000059	85.92	gold quality
gingival epithelium	UBERON:0001949	85.90	gold quality
left lobe of thyroid gland	UBERON:0001120	85.85	gold quality
skin of leg	UBERON:0001511	85.74	gold quality
right atrium auricular region	UBERON:0006631	85.65	gold quality
left testis	UBERON:0004533	85.61	gold quality
stomach	UBERON:0000945	85.49	gold quality
intestine	UBERON:0000160	85.48	gold quality
right testis	UBERON:0004534	85.35	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.31	gold quality
omental fat pad	UBERON:0010414	85.29	gold quality
peritoneum	UBERON:0002358	85.27	gold quality
granulocyte	CL:0000094	85.21	gold quality
thyroid gland	UBERON:0002046	85.19	gold quality
small intestine	UBERON:0002108	85.05	gold quality
middle temporal gyrus	UBERON:0002771	85.02	gold quality
body of pancreas	UBERON:0001150	84.98	gold quality
heart	UBERON:0000948	84.97	gold quality
adipose tissue of abdominal region	UBERON:0007808	84.93	gold quality
right ovary	UBERON:0002118	84.90	gold quality
adult mammalian kidney	UBERON:0000082	84.89	gold quality
nipple	UBERON:0002030	84.89	gold quality
testis	UBERON:0000473	84.88	gold quality
zone of skin	UBERON:0000014	84.81	gold quality
right frontal lobe	UBERON:0002810	84.72	gold quality
upper lobe of left lung	UBERON:0008952	84.66	gold quality
rectum	UBERON:0001052	84.62	gold quality
left ovary	UBERON:0002119	84.44	gold quality
globus pallidus	UBERON:0001875	84.31	gold quality
left uterine tube	UBERON:0001303	84.29	gold quality
cardiac atrium	UBERON:0002081	84.24	gold quality
gingiva	UBERON:0001828	84.15	gold quality
ovary	UBERON:0000992	84.05	gold quality
minor salivary gland	UBERON:0001830	83.71	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.70	gold quality
upper lobe of lung	UBERON:0008948	83.58	gold quality
mouth mucosa	UBERON:0003729	83.57	gold quality
vermiform appendix	UBERON:0001154	83.52	gold quality
tonsil	UBERON:0002372	83.46	gold quality
ectocervix	UBERON:0012249	83.39	gold quality
adipose tissue	UBERON:0001013	83.37	gold quality
anterior cingulate cortex	UBERON:0009835	83.36	gold quality
cingulate cortex	UBERON:0003027	83.23	gold quality
pancreatic ductal cell	CL:0002079	83.16	gold quality
renal medulla	UBERON:0000362	83.12	gold quality
nucleus accumbens	UBERON:0001882	83.10	gold quality
spleen	UBERON:0002106	82.97	gold quality
connective tissue	UBERON:0002384	82.96	gold quality
mucosa of stomach	UBERON:0001199	82.87	gold quality
lower esophagus	UBERON:0013473	82.87	gold quality
lower esophagus muscularis layer	UBERON:0035833	82.86	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	82.78	gold quality
amygdala	UBERON:0001876	82.69	gold quality
neocortex	UBERON:0001950	82.69	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.67	gold quality
left coronary artery	UBERON:0001626	82.65	gold quality
caecum	UBERON:0001153	82.62	gold quality
adenohypophysis	UBERON:0002196	82.62	gold quality
prefrontal cortex	UBERON:0000451	82.59	gold quality
body of uterus	UBERON:0009853	82.59	gold quality
colonic epithelium	UBERON:0000397	82.57	gold quality
fundus of stomach	UBERON:0001160	82.55	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

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Cerebral cortex	tissue	35.3	high
Motor cortex	tissue	35.3
Somatosensory cortex	tissue	34.2
Prefrontal cortex	tissue	33.4
Insular cortex	tissue	32.5
Hippocampal formation	tissue	30.7
Entorhinal cortex	tissue	30.7
Temporal cortex	tissue	30.7
Caudate putamen	tissue	29.7
Thalamus	tissue	29.3
Occipital cortex	tissue	28.8
Hippocampus	tissue	28.7	medium
Putamen	tissue	28.5
Retrosplenial and cingulate cortex	tissue	28.5
Nucleus accumbens	tissue	28.4
Retrosplenial cortex	tissue	28.4
Frontal cortex	tissue	28.1
Postcentral gyrus	tissue	27.6
Amygdala	tissue	27.5
Locus coeruleus	tissue	27.4
Superior colliculi	tissue	27.2
Midbrain	tissue	26.7
Basal ganglia	tissue	26.6	medium
Pons	tissue	26.4
Choroid plexus	tissue	25.8
Ventral forebrain	tissue	25.2
Medulla oblongata	tissue	24.2
Thymus	tissue	23.9
Substantia nigra	tissue	23.7
Cerebellum	tissue	23.5	high
Spinal cord	tissue	22.7
Hypothalamus	tissue	22.6
Septum	tissue	22.1
Periaqueductal gray	tissue	18.6
Corpus callosum	tissue	18.4
Olfactory bulb	tissue	16.9
Colon	tissue	15.4	medium
Duodenum	tissue	13.1	high
Skin 1	tissue	11.8	high
Esophagus	tissue	11.8	medium
Parathyroid gland	tissue	10.7	high
Adipose tissue	tissue	10.6	medium
Vagina	tissue	10.3	medium
Tongue	tissue	10.2
Small intestine	tissue	10.2	high
Stomach 1	tissue	10.1	high
Rectum	tissue	10.1	medium
Heart muscle	tissue	10.0	medium
Skeletal muscle	tissue	10.0	medium
Pancreas	tissue	9.5	medium
Kidney	tissue	9.2	high
Pituitary gland	tissue	8.6
Testis	tissue	7.6	high
Adrenal gland	tissue	7.5	high
Appendix	tissue	7.4	high
Tonsil	tissue	7.3	high
Bone marrow	tissue	7.1	high
Spleen	tissue	6.7	high
Thyroid gland	tissue	6.6	medium
Lymph node	tissue	6.5	high

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Posterior thalamic nucleus (34.6), Ventromedial nucleus (34.2), Medial geniculate body (33.0), Olfactory area (32.9), Lateral amygdala (32.7).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting LETM1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 71 miRNAs:

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

gnomAD constraint: pLI 1.37e-11, LOEUF 0.881, missense Z 1.71 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000302787 splits into 4 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
4:1,814,427–1,822,183	161 / 252.7	0.64	no
4:1,822,184–1,823,765	172 / 170.7	1.01	no
4:1,823,766–1,841,505	269 / 348.8	0.77	no
4:1,841,506–1,855,950	222 / 195.6	1.14	no
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.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): NCI-H82 (-2.847), TUHR14TKB (-2.188), SNU-620 (-2.057), LN-319 (-2.049), Capan-1 (-1.985), PANC-1 (-1.955), TE-10 (-1.896), KELLY (-1.862), SNU-1077 (-1.851), C2BBe1 (-1.816), M059K (-1.76), HT-144 (-1.756), JURL-MK1 (-1.737), Hs 294T (-1.715), U-251 MG (-1.711).

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1932557) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 18 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal liver physiology	1
abnormal embryo development	1
decreased embryo size	1
abnormal glucose homeostasis	1
abnormal kidney morphology	1
abnormal brain morphology	1
decreased heart weight	1
increased susceptibility to pharmacologically induced seizures	1
embryonic growth retardation	1
decreased oxygen consumption	1
abnormal enzyme/coenzyme activity	1
abnormal mitochondrial physiology	1
embryonic lethality, complete penetrance	1
preweaning lethality, complete penetrance	1
embryonic lethality during organogenesis, incomplete penetrance	1
abnormal amino acid metabolism	1
abnormal glucose metabolism	1
decreased glucose oxidation	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q0VCA3	79.2%	Diamond
Gallus gallus	Q5ZK33	72.3%	Diamond
Xenopus tropicalis	Q0VA06	71.8%	Diamond
Saccharomyces cerevisiae S288C	Q06493	50.3%	Diamond
Drosophila melanogaster	P91927	50.0%	Diamond
Schizosaccharomyces pombe 972h-	O13920	47.5%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR943	ncRNA	100126332
FGFR3	protein-coding	2261
SCARNA22	ncRNA	677770
NSD2	protein-coding	7468
NELFA	protein-coding	7469
TACC3	protein-coding	10460
TMEM129	protein-coding	92305
NICOL1	protein-coding	401115

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)

• 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 by resolution:

PDB	Title	Method	Resolution (Å)
9BA1	Solution NMR structure of the human LETM1 F-EF-hand domain in the presence of calcium	SOLUTION NMR
9DMR	Solution NMR structure of the calcium insensitive human LETM1 F-EF-hand domain mutant in …	SOLUTION NMR

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Transporters, Electrochemical Potential-driven transporters, Predicted membrane proteins, Human disease related genes, Other congenital disorders, Chromosomal abnormalities, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria

Antibody reliability (HPA): IH supported · IF supported

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)

Position	Role
676	Ca(2+)
678	Ca(2+)
680	Ca(2+)
682	Ca(2+)
687	Ca(2+)

Post-translational modifications (2)

Type	Positions
Phosphothreonine	192
N6-acetyllysine	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 growth of …
382	loss of ability to complement growth defects and morphologic defects of mitochondria in letm1-deficient yeast mutant; when associated with …
383	loss of ability to complement growth defects and morphologic defects of mitochondria in letm1-deficient yeast mutant; when associated with …
384	loss of ability to complement growth defects and morphologic defects of mitochondria in letm1-deficient yeast mutant; when associated with …

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 11; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

11 pathways:

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

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 (2): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743)

Reactome top-level categories

8 top-level categories:

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

28 GO namespaces:

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

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 12 of 23 annotations. The rest are phylogenetic / computational / electronic (IEA).

12 experimentally-supported GO terms:

GO term	NS	Evidence
calcium export from the mitochondrion	BP	direct assay
calcium ion transport	BP	mutant phenotype
cristae formation	BP	mutant phenotype
inner mitochondrial membrane organization	BP	mutant phenotype
mitochondrial calcium ion homeostasis	BP	direct assay
mitochondrial calcium ion transmembrane transport	BP	direct assay
mitochondrial potassium ion transmembrane transport	BP	mutant phenotype
negative regulation of mitochondrial calcium ion concentration	BP	mutant phenotype
regulation of cellular hyperosmotic salinity response	BP	mutant phenotype
mitochondrial inner membrane	CC	direct assay
mitochondrion	CC	direct assay
calcium:proton antiporter activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,473 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LETM1	TRAPPC10	P48553	901
LETM1	NSD2	O96028	840
LETM1	MICU1	Q9BPX6	802
LETM1	MCU	Q8NE86	795
LETM1	SLC8B1	Q6J4K2	784
LETM1	MICU2	Q8IYU8	735
LETM1	MCUR1	Q96AQ8	655
LETM1	MCUB	Q9NWR8	648
LETM1	NELFA	Q9H3P2	613
LETM1	SMDT1	Q9H4I9	583
LETM1	MSX1	P28360	568
LETM1	IMMT	Q16891	536
LETM1	MICU3	Q86XE3	536
LETM1	MPV17L2	Q567V2	524
LETM1	OXA1L	Q15070	480

IntAct

Human interaction partners of LETM1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

15 partners by confidence:

Partner	Interaction type	MIscore	Records
KRTAP6-2	physical association	0.560	3
PSMA3	physical association	0.560	3
ZNF76	physical association	0.560	3
BCS1L	physical association	0.560	1
CALR	physical association	0.400	1
PPL	physical association	0.400	1
CEP43	association	0.350	1
IL5RA	association	0.350	1
LETM2	association	0.350	1
LRRC14B	association	0.350	1
MLC1	association	0.350	1
OR2T10	association	0.350	1
UBE2Q2	association	0.350	1
MCC	physical association	0.000	1
SGK1	physical association	0.000	1

BioGRID (312 interactions; top human partners by supporting records): CYP1A1 (Affinity Capture-MS; 3 records), AIFM1 (Proximity Label-MS; 2 records), C17orf80 (Proximity Label-MS; 2 records), CLPP (Proximity Label-MS; 2 records), CS (Proximity Label-MS; 2 records), FGB (Affinity Capture-MS; 2 records), GRSF1 (Proximity Label-MS; 2 records), ICT1 (Proximity Label-MS; 2 records), KIAA1429 (Affinity Capture-RNA; 2 records), OGDH (Co-fractionation; 2 records), PCDHGB4 (Affinity Capture-MS; 2 records), PCNA (Cross-Linking-MS (XL-MS); 2 records), PHB2 (Proximity Label-MS; 2 records), PRNP (Affinity Capture-MS; 2 records), SFXN1 (Proximity Label-MS; 2 records)

SIGNOR signaling

8 signaling 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

Disease & clinical

Genetic variants

Variant evidence for LETM1: 353 ClinVar records (12 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	4
Uncertain significance	163
Likely benign	135
Benign	23

Top pathogenic / likely-pathogenic (12)

Showing all 12 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1300217	NM_012318.3(LETM1):c.898C>T (p.Pro300Ser)	Likely pathogenic	criteria provided, single submitter	2
3381225	NM_012318.3(LETM1):c.1791delinsAA (p.Tyr598fs)	Likely pathogenic	criteria provided, single submitter	1
4849458	NM_012318.3(LETM1):c.1456del (p.Gln486fs)	Likely pathogenic	criteria provided, single submitter	1
3062779	GRCh37/hg19 4p16.3-16.2(chr4:68345-4611819)x1	Pathogenic	criteria provided, single submitter	1
1300216	NM_012318.3(LETM1):c.878T>A (p.Ile293Asn)	Pathogenic	no assertion criteria provided	2
1300218	NM_012318.3(LETM1):c.2094del (p.Asp699fs)	Pathogenic	no assertion criteria provided	2
1300221	NM_012318.3(LETM1):c.881G>A (p.Arg294Gln)	Pathogenic	no assertion criteria provided	2
1300225	NM_012318.3(LETM1):c.2071-9C>G	Pathogenic	no assertion criteria provided	2
1300220	NM_012318.3(LETM1):c.751AAG[1] (p.Lys252del)	Pathogenic	no assertion criteria provided	1
1300222	NM_012318.3(LETM1):c.1072G>A (p.Asp358Asn)	Pathogenic	no assertion criteria provided	1
1300224	NM_012318.3(LETM1):c.1139G>C (p.Arg380Pro)	Pathogenic	no assertion criteria provided	1
152442	GRCh38/hg38 4p16.3(chr4:1825301-1859026)x1	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore LETM1’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 39 predictions of 1,552):

Position(s)	Effect	Δscore	Sites
4:1814574–1814575	acceptor_loss	1.0000	3
4:1815662–1815663	donor_loss	1.0000	5
4:1816725–1816726	donor_loss	1.0000	5
4:1816915–1816916	acceptor_loss	1.0000	5
4:1819336–1819337	donor_loss	1.0000	5
4:1819473–1819474	acceptor_loss	1.0000	5
4:1819478	acceptor_gain	1.0000
4:1819484	acceptor_gain	1.0000
4:1822986–1822987	donor_loss	1.0000	4
4:1823132–1823133	acceptor_loss	1.0000	5

AlphaMissense

1,439 missense substitutions predicted likely pathogenic (of 4,827 scored), across 401 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M384	9	0.886	0.996
F312	8	0.993	0.999
D359	8	0.992	0.998
D205	8	0.989	0.994
F232	8	0.981	0.996
F215	8	0.976	0.996
F240	8	0.974	0.998
F263	8	0.961	0.999
D174	8	0.959	0.993
D358	8	0.953	0.991
D314	8	0.952	0.991
F286	8	0.951	0.990
H163	8	0.949	0.993
F207	8	0.930	0.969
H405	8	0.930	0.986
D582	8	0.919	0.966
F289	8	0.916	0.993
F220	8	0.906	0.968
D319	8	0.900	0.965
F212	8	0.887	0.975

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Papillary Cell Carcinoma (TCGA)	favorable	7.47e-05
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000378
Colon Adenocarcinoma (TCGA)	favorable	0.000562
Lung Squamous Cell Carcinoma (validation)	favorable	0.000982

Disease associations

OMIM: gene MIM:604407 | disease phenotypes: MIM:620089

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction	Strong	Autosomal recessive	4

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (19 panels, 19 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

19 panels:

Panel	Rating
Ataxia and cerebellar anomalies - childhood onset	green
Bilateral congenital or childhood onset cataracts	green
Congenital myopathy	green
DDG2P	green
Early onset or syndromic epilepsy	green
Hereditary ataxia and cerebellar anomalies, childhood onset	green
Hereditary spastic paraplegia, childhood onset	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Mitochondrial disorders	green
Monogenic hearing loss	green
Optic neuropathy	green
Other rare neuromuscular disorders	green
Paediatric disorders	green
Paediatric or syndromic cardiomyopathy	green
Possible mitochondrial disorder, nuclear genes	green
Unexplained death in infancy and sudden unexplained death in childhood	green

Mondo (1): neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction (MONDO:0859304)

HPO phenotypes

showing 60 of 171 phenotypes (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
HP:0000377	Abnormal pinna morphology
HP:0000384	Preauricular skin tag
HP:0000389	Chronic otitis media
HP:0000402	Stenosis of the external auditory canal
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000431	Wide nasal bridge
HP:0000444	Convex nasal ridge
HP:0000465	Webbed neck
HP:0000485	Megalocornea
HP:0000486	Strabismus
HP:0000488	Retinopathy
HP:0000494	Downslanted palpebral fissures
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000520	Proptosis
HP:0000558	Rieger anomaly
HP:0000612	Iris coloboma
HP:0000639	Nystagmus
HP:0000647	Sclerocornea
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000679	Taurodontia
HP:0000684	Delayed eruption of teeth
HP:0000733	Motor stereotypy
HP:0000765	Abnormal thorax morphology
HP:0000776	Congenital diaphragmatic hernia
HP:0000826	Precocious puberty

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066991 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC55 Mitochondrial cation/proton exchangers

Binding affinities (BindingDB)

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

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

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	decreases expression, increases abundance, increases expression	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	affects cotreatment, decreases expression	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	increases expression, decreases expression, affects cotreatment, affects localization	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)

Via MONDO — disease-level, not drug-specific.

showing 60 of 102 trials:

NCT	Phase	Status	Title
NCT00517959	Phase 3	UNKNOWN	SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors
NCT01096368	Phase 3	COMPLETED	Maintenance Chemotherapy or Observation Following Induction Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Ependymoma
NCT00003479	Phase 2	TERMINATED	Antineoplaston Therapy in Treating Patients With Ependymoma
NCT00520936	Phase 2	COMPLETED	A Study of Pemetrexed in Children With Recurrent Cancer
NCT00840047	Phase 2	ACTIVE_NOT_RECRUITING	Methionine PET/CT Studies In Patients With Cancer
NCT01088035	Phase 2	TERMINATED	Carboplatin as a Radiosensitizer in Treating Childhood Ependymoma
NCT01247922	Phase 2	TERMINATED	Single-agent Erlotinib in Patients Previously Treated With Oral Etoposide in Protocol OSI-774-205
NCT01288235	Phase 2	COMPLETED	Proton Radiotherapy for Pediatric Brain Tumors Requiring Partial Brain Irradiation
NCT01295944	Phase 2	COMPLETED	Carboplatin and Bevacizumab for Recurrent Ependymoma
NCT01356290	Phase 2	RECRUITING	Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma, ATRT and Rare CNS Tumors
NCT01836549	Phase 2	TERMINATED	Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors
NCT02125786	Phase 2	ACTIVE_NOT_RECRUITING	A Trial of Surgery and Fractionated Re-Irradiation for Recurrent Ependymoma
NCT02689336	Phase 2	WITHDRAWN	Erlotinib in Combination With Temozolomide in Treating Relapsed/Recurrent/Refractory Pediatric Solid Tumors
NCT03095248	Phase 2	TERMINATED	Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors
NCT03155620	Phase 2	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	Phase 2	TERMINATED	Immune Checkpoint Inhibitor Nivolumab in People With Recurrent Select Rare CNS Cancers
NCT03194906	Phase 2	COMPLETED	Memantine for Prevention of Cognitive Late Effects in Pediatric Patients Receiving Cranial Radiation Therapy for Localized Brain Tumors
NCT03210714	Phase 2	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	Phase 2	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	Phase 2	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	Phase 2	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	Phase 2	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	Phase 2	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	Phase 2	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	Phase 2	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	Phase 2	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	Phase 2	TERMINATED	Marizomib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial, and Spinal Cord Ependymoma
NCT04049669	Phase 2	ACTIVE_NOT_RECRUITING	Pediatric Trial of Indoximod With Chemotherapy and Radiation for Relapsed Brain Tumors or Newly Diagnosed DIPG
NCT04195555	Phase 2	ACTIVE_NOT_RECRUITING	Ivosidenib in Treating Patients With Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With IDH1 Mutations (A Pediatric MATCH Treatment Trial)
NCT04284774	Phase 2	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	Phase 2	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	Phase 2	RECRUITING	Innovative Trial for Understanding the Impact of Targeted Therapies in NF2-Related Schwannomatosis (INTUITT-NF2)
NCT04743661	Phase 2	ACTIVE_NOT_RECRUITING	131I-Omburtamab, in Recurrent Medulloblastoma and Ependymoma
NCT06804655	Phase 2	RECRUITING	Pharmacoscopy for Patients With Refractory Primary Brain Tumors
NCT07424092	Phase 2	RECRUITING	Intratumoral DNX-2401 for High Grade Pediatric Brain Tumors
NCT07707947	Phase 2	NOT_YET_RECRUITING	Selumetinib for NF2-Related Schwannomatosis
NCT07713745	Phase 2	NOT_YET_RECRUITING	Platform Research for Innovative Medicines in NF2-SWN (PRIME-NF2)
NCT00634231	Phase 1	COMPLETED	A Phase I Study of AdV-tk + Prodrug Therapy in Combination With Radiation Therapy for Pediatric Brain Tumors
NCT00994071	Phase 1	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	Phase 1	COMPLETED	Vaccination With Dendritic Cells Loaded With Brain Tumor Stem Cells for Progressive Malignant Brain Tumor
NCT01331135	Phase 1	COMPLETED	Aflac ST0901 CHOANOME - Sirolimus in Solid Tumors
NCT01498783	Phase 1	COMPLETED	Phase I Study of 5-Fluorouracil in Children and Young Adults With Recurrent Ependymoma
NCT01795313	Phase 1	TERMINATED	Immunotherapy for Recurrent Ependymomas in Children Using Tumor Antigen Peptides With Imiquimod
NCT02271711	Phase 1	COMPLETED	Expanded Natural Killer Cell Infusion in Treating Younger Patients With Recurrent/Refractory Brain Tumors
NCT02359565	Phase 1	ACTIVE_NOT_RECRUITING	Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, Hypermutated Brain Tumors, Ependymoma or Medulloblastoma
NCT02502708	Phase 1	COMPLETED	Study of the IDO Pathway Inhibitor, Indoximod, and Temozolomide for Pediatric Patients With Progressive Primary Malignant Brain Tumors
NCT02722512	Phase 1	TERMINATED	Trial of Heat Shock Protein Peptide Complex-96 (HSPPC-96) Vaccine
NCT03043391	Phase 1	COMPLETED	Phase 1b Study PVSRIPO for Recurrent Malignant Glioma in Children
NCT03128047	Phase 1	COMPLETED	HUMC 1612: Optune NovoTTF-200A System
NCT03152318	Phase 1	ACTIVE_NOT_RECRUITING	A Study of the Treatment of Recurrent Malignant Glioma With rQNestin34.5v.2
NCT03434262	Phase 1	COMPLETED	SJDAWN: St. Jude Children’s Research Hospital Phase 1 Study Evaluating Molecularly-Driven Doublet Therapies for Children and Young Adults With Recurrent Brain Tumors
NCT03500991	Phase 1	ACTIVE_NOT_RECRUITING	HER2-specific CAR T Cell Locoregional Immunotherapy for HER2-positive Recurrent/Refractory Pediatric CNS Tumors
NCT03572530	Phase 1	COMPLETED	Infusion of 5-Azacytidine (5-AZA) Into the Fourth Ventricle in Patients With Recurrent Posterior Fossa Ependymoma
NCT03638167	Phase 1	COMPLETED	EGFR806-specific CAR T Cell Locoregional Immunotherapy for EGFR-positive Recurrent or Refractory Pediatric CNS Tumors
NCT03750513	Phase 1	RECRUITING	LET Optimized IMPT in Treating Pediatric Patients With Ependymoma
NCT03990597	Phase 1	WITHDRAWN	StrataXRT in Preventing Radiation Dermatitis in Pediatric Patients Undergoing Radiation Therapy to the Brain or Spinal Cord
NCT04185038	Phase 1	RECRUITING	Study of B7-H3-Specific CAR T Cell Locoregional Immunotherapy for Diffuse Intrinsic Pontine Glioma/Diffuse Midline Glioma and Recurrent or Refractory Pediatric Central Nervous System Tumors
NCT04541082	Phase 1	RECRUITING	Phase I Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms
NCT04661384	Phase 1	ACTIVE_NOT_RECRUITING	Brain Tumor-Specific Immune Cells (IL13Ralpha2-CAR T Cells) for the Treatment of Leptomeningeal Glioblastoma, Ependymoma, or Medulloblastoma
NCT04732065	Phase 1	RECRUITING	ONC206 for Treatment of Newly Diagnosed, Recurrent Diffuse Midline Gliomas, and Other Recurrent Malignant CNS Tumors

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for LETM1 across ~30M SureChEMBL compounds — explore on Sugi Predict.