Alternative titles; symbols
HGNC Approved Gene Symbol: DDX41
Cytogenetic location: 5q35.3 Genomic coordinates (GRCh38) : 5:177,511,577-177,516,961 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q35.3 | {Myeloproliferative/lymphoproliferative neoplasms, familial (multiple types), susceptibility to} | 616871 | Autosomal dominant | 3 |
The DDX41 gene encodes an RNA helicase. Evidence suggests that it also acts as a tumor suppressor gene (summary by Lewinsohn et al., 2016).
Irion and Leptin (1999) cloned DDX41, which they called ABS, by PCR of a HeLa cell cDNA library. The deduced 621-amino acid protein shares 64% identity with the Drosophila abstrakt protein, including 100% identity in 7 of the 8 motifs characteristic of DEAD box proteins.
Polprasert et al. (2015) reported expression of the DDX41 gene in CD14+, CD33+, and CD34+ myeloid cells, consistent with a function in hematopoiesis.
Gross (2016) mapped the DDX41 gene to chromosome 5q35.3 based on an alignment of the DDX41 sequence (GenBank BC015476) with the genomic sequence (GRCh38).
Using immunoprecipitation experiments, Polprasert et al. (2015) found that DDX41 interacted with several spliceosomal proteins.
In affected members of 7 unrelated families with multiple types of familial myeloproliferative/lymphoproliferative neoplasms (MPLPF; 616871), Polprasert et al. (2015) identified a heterozygous germline mutation in the DDX41 gene (see, e.g., 608170.0001; 608170.0003). Most of the patients had a recurrent germline truncating mutation (Asp140fs; 608170.0001). About half of the patients also carried a somatic heterozygous missense mutation in the DDX41 gene (R525H; 608170.0002) on the other allele. This missense mutation was shown to be a hypomorphic allele. Subsequent targeted sequencing of the DDX41 gene in 1,034 patients with MDS/AML identified 16 with heterozygous germline and/or somatic DDX41 mutations, including Asp140fs and R525H. Two of these patients were diagnosed with chromosome 5q- syndrome (153550). Overall, DDX41 mutations and deletions occurred more frequently in patients with advanced MDS and in patients with AML, and were associated with inferior overall survival compared to patients without DDX41 genetic alterations. Knockdown of the DDX41 gene in human hematopoietic cells resulted in enhanced proliferation, enhanced colony formation, and increased sensitivity to growth factor stimuli compared to controls. Knockdown of DDX41 also impaired cell differentiation and increased resistance to apoptosis. Forced expression of the gene resulted in growth inhibition; these overall findings suggested that DDX41 has tumor suppressor functions. In vitro functional expression studies indicated that the R525H mutation interfered with the ability of DDX41 to interact with several major spliceosomal components, and DDX41-deficient cells showed multiple splicing defects, including exon skipping in the ZMYM2 gene (602221). Deletions of chromosome 5q involving the DDX41 gene were found in 6% of all cases and in 26% of the del(5q) cases; these resulted in decreased DDX41 mRNA levels, suggesting that some cases of 5q deletion syndrome may result from deletion of the DDX41 gene.
In affected individuals from 10 unrelated families with MPLPF, Lewinsohn et al. (2016) identified germline heterozygous mutations in the DDX41 gene (see, e.g., 608170.0001-608170.0002; 608170.0004-608170.0006). Lymphoma was diagnosed in affected members from only 1 family (CCB 25476) with a missense mutation (R164W; 608170.0006). In some cases, studies of patient cells showed deleterious effects of the mutation on protein expression, but functional studies of the variants were not performed. In the entire cohort, the majority of mutation carriers had normal peripheral blood counts well into adulthood, suggesting that haploinsufficiency of DDX41 is sufficient for normal baseline hematopoiesis. The authors stated that 9 of the families were ascertained from a cohort of 289 families with inherited hematologic malignancies who underwent whole-exome sequencing, panel-based next-generation sequencing, or targeted sequencing of the DDX41 gene; they thus accounted for about 3% of families.
Using temperature-sensitive alleles, Irion and Leptin (1999) determined that abstrakt is essential for survival at all stages of the fly life cycle. Mutants showed specific defects in many developmental processes, including cell shape changes, localization of RNA, and apoptosis.
In affected members of 6 unrelated families with multiple types of familial myeloproliferative/lymphoproliferative neoplasms (MPLPF; 616871), Polprasert et al. (2015) identified a heterozygous germline 4-bp insertion (c.419insGATG) in the DDX41 gene, resulting in a frameshift (Asp140fs). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in 200 in-house controls. It was found in 1 of 12,518 alleles in the Exome Sequencing Project database. About half of the patients also carried a somatic heterozygous c.1574G-A transition in the DDX41 gene, resulting in an arg525-to-his (R525H; 608170.0002) substitution at a conserved residue in an ATP binding domain, that was confirmed to be on the other allele. A heterozygous germline Asp140fs mutation was also found in 6 additional unrelated patients with sporadic myeloproliferative neoplasms. One of these patients also carried the somatic R525H mutation. These patients were part of a large cohort of 1,034 individuals with MDS/AML.
In 4 patients from 3 unrelated families with MPLPF, Lewinsohn et al. (2016) identified a heterozygous germline 4-bp insertion (c.419insGATG, NM_016222.2) in the DDX41 gene, resulting in a frameshift and premature termination (Asp140fsTer2). One of the patients carried a somatic R525H mutation on the other allele. A fourth family (family UoC 127) with this mutation was reported in the supplementary material. There was evidence of incomplete penetrance in 2 of the families.
In 3 members of a family (CCB 31379) with MPLPF, Lewinsohn et al. (2016) identified a heterozygous germline c.1574G-A transition (c.1574G-A, NM_016222.2) in the DDX41 gene, resulting in an arg525-to-his (R525H) substitution. The patients were diagnosed between 44 and 56 years of age.
For discussion of the somatic c.1574G-A transition in the DDX41 gene, resulting in an arg525-to-his (R525H) substitution at a conserved residue in an ATP binding domain, that was found in compound heterozygous state in individuals with multiple types of familial myeloproliferative/lymphoproliferative neoplasms (MPLPF; 616871) by Polprasert et al. (2015), see (608170.0001).
Polprasert et al. (2015) found a heterozygous somatic R525X mutation in 6 of 1,034 unrelated patients with sporadic occurrence of MDS/AML. One of these patients carried a germline Asp140fs (608170.0001) on the other allele and another had a germline deletion of 5q including the DDX41 gene (see also 153550). In vitro functional expression studies indicated that the R525H mutation interfered with the ability of DDX41 to interact with several major spliceosomal components. Polprasert et al. (2015) concluded that it was a hypomorphic allele.
In a pair of twin brothers with multiple types of familial myeloproliferative/lymphoproliferative neoplasms (MPLPF; 616871), Polprasert et al. (2015) identified a germline heterozygous c.1187T-C transition (c.1187T-C, NM_016222.2) in the DDX41 gene, resulting in an ile396-to-thr (I396T) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project or Exome Sequencing Project databases or in 200 in-house controls. Each brother also carried a somatic R525X mutation (608170.0002) on the other allele; one also had a somatic variant in the JAK2 gene (V617F; 147796.0001).
In a man (family UoC 154) with familial myeloproliferative/lymphoproliferative neoplasms (MPLPF; 616871), Lewinsohn et al. (2016) identified a germline heterozygous del/ins mutation (c.435-2_435-1delAGinsCA, NM_016222.2) in the splice acceptor site of exon 6 of the DDX41 gene. Analysis of patient cells showed the presence of aberrant mRNA species that were predicted to result in frameshifts and prematurely terminated proteins. There was evidence of incomplete penetrance in this family.
In affected members of 2 unrelated families (CCB 20432 and UoC 236) with familial myeloproliferative/lymphoproliferative neoplasms (MPLPF; 616871), Lewinsohn et al. (2016) identified a germline heterozygous c.3G-A transition (c.3G-A, NM_016222.2) in the DDX41 gene, resulting in a met1-to-ile (M1I) substitution in the initiation codon. The mutation was predicted to result in a loss of function. There was evidence of incomplete penetrance in both families. In 1 family, a carrier of the mutation did not have a hematologic malignancy, but did have a history inflammatory-related disorders, including sarcoidosis and eczema. Analysis of patient cells showed that the mutation resulted in the production of a smaller protein from use of an alternative translation initiation site. The smaller isoform showed reduced nuclear localization, consistent with the loss of a predicted nuclear localization signal.
In affected members of a family (CCB 25476) of Dutch-Sri Lankan descent with familial myeloproliferative/lymphoproliferative neoplasms (MPLPF; 616871), Lewinsohn et al. (2016) identified a germline heterozygous c.490C-T transition (c.490C-T, NM_016222.2) in the DDX41 gene, resulting in an arg164-to-trp (R164W) substitution at a highly conserved residue adjacent to the Q motif. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project database; it was found at a very low frequency (0.014%) in the ExAC database. There was evidence of incomplete penetrance. The 4 patients with a confirmed mutation had lymphoma, and there was a family history of multiple myeloma in previous generations. Several variant-carrying family members had inflammatory-mediated disorders without overt hematologic malignancies. Functional studies of the variant were not performed, but it was predicted to affect DDX41 helicase activity.
Gross, M. B. Personal Communication. Baltimore, Md. 3/23/2016.
Irion, U., Leptin, M. Developmental and cell biological functions of the Drosophila DEAD-box protein Abstrakt. Curr. Biol. 9: 1373-1381, 1999. [PubMed: 10607561] [Full Text: https://doi.org/10.1016/s0960-9822(00)80082-2]
Lewinsohn, M., Brown, A. L., Weinel, L. M., Phung, C., Rafidi, G., Lee, M. K., Schreiber, A. W., Feng, J., Babic, M., Chong, C.-E., Lee, Y., Yong, A., and 18 others. Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. Blood 127: 1017-1023, 2016. [PubMed: 26712909] [Full Text: https://doi.org/10.1182/blood-2015-10-676098]
Polprasert, C., Schulze, I., Sekeres, M. A., Makishima, H., Przychodzen, B., Hosono, N., Singh, J., Padgett, R. A., Gu, X., Phillips, J. G., Clemente, M., Parker, Y., and 24 others. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell 27: 658-670, 2015. [PubMed: 25920683] [Full Text: https://doi.org/10.1016/j.ccell.2015.03.017]