LETM1: Leucine Zipper and EF-Hand Containing Transmembrane Protein 1
Mitochondrial calcium/proton exchanger critical for ion homeostasis and linked to Wolf-Hirschhorn syndrome
Gene Information Card
| Symbol | LETM1 |
|---|---|
| Full Name | Leucine zipper and EF-hand containing transmembrane protein 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 4p16.3 |
| NCBI Gene ID | 3954 ncbi.nlm.nih.gov/gene/3954 |
| Ensembl ID | ENSG00000168994 |
| UniProt ID | O95202 |
| OMIM ID | 604407 |
| HGNC ID | 6556 |
| Aliases | SLC55A1, Mdm38, CGI-32 |
Description
LETM1 encodes a mitochondrial inner membrane protein that functions as a Ca2+/H+ antiporter, essential for maintaining mitochondrial calcium homeostasis and cristae morphology. It contains a leucine zipper motif and two EF-hand calcium-binding domains. Loss of function disrupts mitochondrial ion balance and is implicated in Wolf-Hirschhorn syndrome (WHS), a contiguous gene deletion disorder. LETM1 is also associated with various cancers and neurological conditions.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Wolf-Hirschhorn syndrome | Haploinsufficiency due to 4p16.3 deletion; impaired mitochondrial Ca2+ uptake leads to altered apoptosis and neurodevelopmental defects | OMIM #194190; PMID 11590522 |
| Epileptic encephalopathy, early infantile | Biallelic LETM1 mutations disrupt mitochondrial calcium signaling, causing seizures and developmental delay | ClinVar; PMID 31537091 |
| Colorectal cancer | Overexpression promotes mitochondrial Ca2+ overload and resistance to apoptosis | COSMIC; PMID 25605248 |
| Breast cancer | Altered LETM1 expression correlates with poor prognosis and mitochondrial dysfunction | COSMIC; PMID 28925394 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 15.2 | Medium |
| Heart | 12.8 | Medium |
| Liver | 8.5 | Low |
| Kidney | 10.1 | Medium |
| Skeletal muscle | 9.3 | Low |
| Pancreas | 7.6 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 14.5 | High expression |
| HeLa | 11.2 | Medium expression |
| SH-SY5Y | 13.0 | High expression |
| HepG2 | 9.8 | Medium expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.239G>A (p.Arg80Gln) | Missense | Rare | Impaired Ca2+/H+ exchange; associated with epileptic encephalopathy |
| c.487C>T (p.Arg163Trp) | Missense | Rare | Reduced protein stability; linked to Wolf-Hirschhorn syndrome |
| c.694_695del (p.Leu232fs) | Frameshift | Very rare | Loss of function; severe neurodevelopmental phenotype |
| c.1123A>G (p.Thr375Ala) | Missense | Rare | Altered mitochondrial morphology; uncertain significance |
Mutation functional classification
Loss of Function (LOF)
Frameshift and nonsense mutations (e.g., c.694_695del) cause truncated protein, loss of antiporter activity, mitochondrial Ca2+ overload, and cristae disruption.
Gain of Function (GOF)
Not well documented; some missense variants (e.g., p.Arg80Gln) may partially retain function but with altered kinetics.
Dominant Negative (DN)
No confirmed dominant-negative mutations; haploinsufficiency is the primary mechanism in Wolf-Hirschhorn syndrome.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Mitochondrial calcium transport (Reactome: R-HSA-8949215)
• Calcium signaling pathway (KEGG: hsa04020)
• Apoptosis (KEGG: hsa04210)
Protein Summary
LETM1 is a 739-amino acid mitochondrial inner membrane protein with a molecular weight of ~83 kDa. It contains an N-terminal transmembrane domain, a leucine zipper motif, and two C-terminal EF-hand calcium-binding domains. The protein forms a homooligomeric complex that mediates electroneutral Ca2+/H+ exchange across the inner mitochondrial membrane. This activity is critical for mitochondrial calcium buffering, ATP production, and cristae structure maintenance. LETM1 also interacts with mitochondrial ribosomes and is involved in protein translation. Dysfunction leads to mitochondrial swelling, reduced membrane potential, and altered cell death signaling.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| LETM1 Knockout HEK293 Cell Line | EDJ-KQ50418 | Human | 3954 | Details Get a Quote |
| LETM1 Knockout HeLa Cell Line | EDJ-KQ53788 | Human | 3954 | Details Get a Quote |
| LETM1 Knockout A-549 Cell Line | EDJ-KQ62266 | Human | 3954 | Details Get a Quote |
| LETM1 Knockout HCT 116 Cell Line | EDJ-KQ70750 | Human | 3954 | Details Get a Quote |
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