Contrast of phenotypes in animal vs human studies
| . | Animal studies . | Human observations . |
|---|---|---|
| Effect on HSPCs | Hypomorphic zebrafish ddx41 mutants display aberrant HSPC expansion, with deregulation of type I IFN pathway components and targets31 | Patients present with leukopenia, hypocellular bone marrow, and erythroid dysplasia1 |
| Mouse Ddx41 KO HSPC show diminished survival and transplantation capacity32,33 | ||
| Mouse HSPCs with Ddx41 heterozygous KO show competitive advantage33 | ||
| Mice with Ddx41 heterozygous KO show age-dependent hematopoietic defects including anemia, thrombocytopenia, and BM hypocellularity33 | ||
| Animals with heterozygous KO of Ddx41 function do not develop hematopoietic malignancies31-33 | Patients with deleterious germ line DDX41 variants develop hematopoietic malignancies, mostly of myeloid lineage, with late onset1-17,20,22-24 | |
| DDX41-interacting proteins | Spliceosomal components (C elegans)34 | Spliceosomal components7 |
| R-loop–interacting proteins35,36 | ||
| Alternative splicing changes in DDX41-mutant or knockdown cells | Increased alternative exon usage, intron retention, alternative 5' and 3' splice site usage (C elegans, zebrafish, mice)31,34,37 | Increased exon inclusion and intron retention7 |
| Mutual exclusivity with splicing mutations? | Yes. C elegans sacy-1 mutants show synthetic lethality with germ line splicing factor mutants34 | Yes. Co-occurrence of somatic mutations in genes encoding splicing factors is rare, suggesting that DDX41's splicing function is critical7 |
| Role in ribosome biogenesis (snoRNA and pre-rRNA processing) | Ddx41-deficient HSPCs display increased snoRNA levels33 | Cells overexpressing DDX41 R525H display defects in pre-rRNA processing and had diminished cellular proliferation30 |
| DDX41-interacting RNAs are enriched for snoRNAs, suggesting that DDX41 could remove snoRNA-containing introns via splicing regulation33 | ||
| R-loop interactions | Increased RNA:DNA hybrids result from insufficient Ddx41 levels, which induces a cGAS-STING-mediated inflammatory response that directs HSPC expansion (zebrafish)31 | Increased RNA:DNA hybrids and consequently elevated dsDNA breaks result from insufficient DDX41 levels35 |
| cGAS-STING interactions | Murine fetal liver Ddx41-null HSPCs display diminished inflammatory gene expression32 | Loss of DDX41 in monocytic cells lowered dsDNA-triggered activation of the cGAS-STING pathway. However, expression of DDX41 R525H, with intact dsDNA binding but dampened helicase activity, activates the STING pathway38 |
| Human hematopoietic cells show paradoxical increased type I IFN signaling upon DDX41 knockdown35 |
| . | Animal studies . | Human observations . |
|---|---|---|
| Effect on HSPCs | Hypomorphic zebrafish ddx41 mutants display aberrant HSPC expansion, with deregulation of type I IFN pathway components and targets31 | Patients present with leukopenia, hypocellular bone marrow, and erythroid dysplasia1 |
| Mouse Ddx41 KO HSPC show diminished survival and transplantation capacity32,33 | ||
| Mouse HSPCs with Ddx41 heterozygous KO show competitive advantage33 | ||
| Mice with Ddx41 heterozygous KO show age-dependent hematopoietic defects including anemia, thrombocytopenia, and BM hypocellularity33 | ||
| Animals with heterozygous KO of Ddx41 function do not develop hematopoietic malignancies31-33 | Patients with deleterious germ line DDX41 variants develop hematopoietic malignancies, mostly of myeloid lineage, with late onset1-17,20,22-24 | |
| DDX41-interacting proteins | Spliceosomal components (C elegans)34 | Spliceosomal components7 |
| R-loop–interacting proteins35,36 | ||
| Alternative splicing changes in DDX41-mutant or knockdown cells | Increased alternative exon usage, intron retention, alternative 5' and 3' splice site usage (C elegans, zebrafish, mice)31,34,37 | Increased exon inclusion and intron retention7 |
| Mutual exclusivity with splicing mutations? | Yes. C elegans sacy-1 mutants show synthetic lethality with germ line splicing factor mutants34 | Yes. Co-occurrence of somatic mutations in genes encoding splicing factors is rare, suggesting that DDX41's splicing function is critical7 |
| Role in ribosome biogenesis (snoRNA and pre-rRNA processing) | Ddx41-deficient HSPCs display increased snoRNA levels33 | Cells overexpressing DDX41 R525H display defects in pre-rRNA processing and had diminished cellular proliferation30 |
| DDX41-interacting RNAs are enriched for snoRNAs, suggesting that DDX41 could remove snoRNA-containing introns via splicing regulation33 | ||
| R-loop interactions | Increased RNA:DNA hybrids result from insufficient Ddx41 levels, which induces a cGAS-STING-mediated inflammatory response that directs HSPC expansion (zebrafish)31 | Increased RNA:DNA hybrids and consequently elevated dsDNA breaks result from insufficient DDX41 levels35 |
| cGAS-STING interactions | Murine fetal liver Ddx41-null HSPCs display diminished inflammatory gene expression32 | Loss of DDX41 in monocytic cells lowered dsDNA-triggered activation of the cGAS-STING pathway. However, expression of DDX41 R525H, with intact dsDNA binding but dampened helicase activity, activates the STING pathway38 |
| Human hematopoietic cells show paradoxical increased type I IFN signaling upon DDX41 knockdown35 |
BM, bone marrow; DDX41, DEAD-box helicase 41; KO, knockout.