DDX41: A DEAD-Box RNA Helicase in Myeloid Neoplasia and Innate Immunity
Comprehensive genomic and functional overview of DDX41, a tumor suppressor gene implicated in familial myelodysplastic syndrome and acute myeloid leukemia.
Gene Information Card
| Symbol | DDX41 |
|---|---|
| Full Name | DEAD-box helicase 41 |
| Gene Type | Protein-coding |
| Chromosomal Location | 5q35.3 |
| NCBI Gene ID | 51428 ncbi.nlm.nih.gov/gene/51428 |
| Ensembl ID | ENSG00000183287 |
| UniProt ID | Q9UJV9 |
| OMIM ID | 608170 |
| HGNC ID | 18674 |
| Aliases | ABS, DEAD-box protein 41, DEAD box protein abstrakt, MDS2 |
Description
DDX41 encodes a DEAD-box RNA helicase involved in pre-mRNA splicing, ribosome biogenesis, and innate immune sensing of double-stranded DNA. Germline loss-of-function mutations in DDX41 predispose to late-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), often with additional somatic mutations in the wild-type allele. The protein also participates in the STING-dependent interferon response.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Myelodysplastic syndrome (MDS) | Germline DDX41 mutations cause haploinsufficiency; somatic second-hit mutations lead to complete loss of function, driving clonal hematopoiesis and MDS. | ClinVar, OMIM #608170 |
| Acute myeloid leukemia (AML) | Same mechanism as MDS; DDX41-mutant AML often presents with normal karyotype and older age at diagnosis. | ClinVar, COSMIC |
| Familial AML with mutated DDX41 | Autosomal dominant inheritance with incomplete penetrance; germline mutations in DDX41 are a known cause of familial MDS/AML. | OMIM #616871 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Bone marrow | 15.2 | Medium |
| Spleen | 12.8 | Medium |
| Lymph node | 11.5 | Medium |
| Whole blood | 9.3 | Low |
| Testis | 8.7 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| K562 (leukemia) | 18.4 | High expression |
| HL-60 (promyelocytic leukemia) | 16.1 | High expression |
| HEK293 (embryonic kidney) | 12.3 | Medium expression |
| HeLa (cervical carcinoma) | 10.5 | Medium expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.157G>A (p.Asp53Asn) | Missense | Germline; recurrent in familial MDS/AML | Loss of helicase activity; reduced protein stability |
| c.404G>A (p.Arg135His) | Missense | Germline; reported in MDS/AML | Impaired RNA binding and splicing |
| c.1114C>T (p.Arg372*) | Nonsense | Somatic; second hit in germline carriers | Truncation; complete loss of function |
| c.1433_1434del (p.Glu478Glyfs*2) | Frameshift | Somatic | Loss of C-terminal domain; protein degradation |
Mutation functional classification
Loss of Function (LOF)
Germline and somatic truncating, frameshift, and missense mutations that reduce helicase activity, RNA binding, or protein stability lead to haploinsufficiency or complete loss of DDX41 function.
Gain of Function (GOF)
No evidence of gain-of-function mutations; all reported pathogenic variants are loss-of-function.
Dominant Negative (DN)
Not established; current evidence supports haploinsufficiency rather than dominant-negative effects.
View complete mutation data：
Gene Ontology (GO)
| • ATP binding | • RNA helicase activity |
| • pre-mRNA splicing | • innate immune response |
| • cytoplasmic pattern recognition receptor signaling pathway | • ribosome biogenesis |
Pathways
• Spliceosome (Reactome: R-HSA-72163)
• STING-mediated induction of type I IFNs (Reactome: R-HSA-1834949)
• Cytosolic DNA-sensing pathway (KEGG: hsa04623)
Protein Summary
DDX41 is a 622-amino acid DEAD-box RNA helicase with conserved helicase domains (DEXDc, HELICc) and a zinc finger motif. It localizes to the nucleus and cytoplasm, where it functions in pre-mRNA splicing as part of the U2 snRNP complex and in cytosolic DNA sensing by binding DNA and activating STING. The protein is ubiquitously expressed, with highest levels in hematopoietic tissues. Loss of DDX41 disrupts splicing fidelity and innate immune signaling, contributing to leukemogenesis.
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