LYRM4: LYR Motif Containing 4, a Key Iron-Sulfur Cluster Biogenesis Factor
Essential mitochondrial protein involved in Fe-S cluster assembly and cellular iron homeostasis
Gene Information Card
| Symbol | LYRM4 |
|---|---|
| Full Name | LYR Motif Containing 4 |
| Gene Type | Protein coding |
| Chromosomal Location | 6p25.1 |
| NCBI Gene ID | 57128 ncbi.nlm.nih.gov/gene/57128 |
| Ensembl ID | ENSG00000112742 |
| UniProt ID | Q9HD34 |
| OMIM ID | 613311 |
| HGNC ID | 25616 |
| Aliases | ISD11, CGI-128, MDS010 |
Description
LYRM4 encodes a mitochondrial protein that is a component of the iron-sulfur (Fe-S) cluster assembly complex. It forms a stable subcomplex with NFS1 (cysteine desulfurase) and is essential for the desulfurase activity of NFS1, providing sulfur for Fe-S cluster biogenesis. The protein contains a LYR (leucine-tyrosine-arginine) motif that mediates protein-protein interactions within the mitochondrial matrix. LYRM4 is critical for cellular respiration, DNA repair, and iron homeostasis.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Combined oxidative phosphorylation deficiency 19 (COXPD19) | Loss-of-function mutations in LYRM4 impair Fe-S cluster assembly, leading to mitochondrial respiratory chain defects and multiple enzyme deficiencies (e.g., complex I, II, III). | ClinVar, OMIM |
| Mitochondrial encephalopathy | Disrupted Fe-S cluster biogenesis affects energy metabolism in neural tissues, causing neurological symptoms. | OMIM, PubMed |
| Iron-sulfur cluster deficiency | Reduced LYRM4 activity leads to cytosolic iron overload and mitochondrial iron depletion, disrupting cellular iron sensing. | UniProt, NCBI |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 12.5 | Medium |
| Heart | 10.8 | Medium |
| Skeletal Muscle | 9.2 | Medium |
| Brain | 6.1 | Low |
| Kidney | 8.4 | Medium |
| Testis | 7.3 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 14.2 | High expression |
| HEK293 | 11.5 | Medium expression |
| K562 | 9.8 | Medium expression |
| HepG2 | 13.1 | High expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.205C>T (p.Arg69Trp) | Missense | Rare | Loss of function; disrupts interaction with NFS1, reducing Fe-S cluster assembly |
| c.287G>A (p.Gly96Asp) | Missense | Rare | Impaired protein stability and complex formation |
| c.1A>G (p.Met1Val) | Start loss | Very rare | Complete loss of translation; associated with COXPD19 |
Mutation functional classification
Loss of Function (LOF)
Most LYRM4 mutations are loss-of-function, reducing Fe-S cluster biogenesis and mitochondrial respiration.
Gain of Function (GOF)
No gain-of-function mutations reported.
Dominant Negative (DN)
No dominant-negative mutations described; disease is typically autosomal recessive.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Mitochondrial iron-sulfur cluster biogenesis (Reactome: R-HSA-1369007)
• Sulfur relay system (KEGG: hsa04122)
• Metabolism of iron and heme (Reactome: R-HSA-917937)
Protein Summary
LYRM4 (ISD11) is a 10.8 kDa mitochondrial protein (88 amino acids) that functions as an essential cofactor for NFS1 cysteine desulfurase. It stabilizes the NFS1 homodimer and is required for sulfur transfer to the scaffold protein ISCU. The protein is ubiquitously expressed with highest levels in liver and heart. Defects in LYRM4 cause combined oxidative phosphorylation deficiency 19 (COXPD19), characterized by lactic acidosis, hypotonia, and encephalopathy. The protein contains a conserved LYR motif that mediates binding to other Fe-S assembly factors such as ISD11 and FXN.
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