Alternative titles; symbols
HGNC Approved Gene Symbol: DDX6
Cytogenetic location: 11q23.3 Genomic coordinates (GRCh38): 11:118,747,763-118,791,744 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.3 | Intellectual developmental disorder with impaired language and dysmorphic facies | 618653 | Autosomal dominant | 3 |
DDX6 belongs to the DEAD box family of putative RNA helicases that contain a characteristic asp-glu-ala-asp (DEAD) box motif (Seto et al., 1995). DDX6 localizes to cytoplasmic processing bodies (P bodies) involved in mRNA storage, processing, regulation, and degradation and is required for P-body formation (Scheller et al., 2007).
Akao et al. (1991) cloned the breakpoint of the t(11;14)(q23;q32) in B-cell lymphoma (Akao et al., 1990), as represented in the RC-K8 cell line, and named the locus RCK. Using a probe from the t(11;14) breakpoint, Akao et al. (1992) isolated a partial cDNA for the RCK gene, which detected a 7.5-kb mRNA. The predicted RCK protein has 472 amino acids and shares sequence homology with a translation initiation factor/helicase family.
Lu and Yunis (1992) cloned a putative human RNA helicase, p54, from a lymphoid cell line with chromosomal breakpoint 11q23.3. The predicted amino acid sequence shares 75% identity with the female germline-specific RNA helicase ME31B gene of Drosophila. Unlike ME31B, however, the human gene expressed an abundant transcript in a large number of adult tissues.
Seto et al. (1995) found that the RCK/p54 gene, which encodes a 472- to 483-amino acid peptide belonging to the RNA helicase/translation initiation factor family, is highly conserved in mouse. The mouse cDNA shows 93.7% nucleotide identity and 97.7% predicted amino acid identity with human RCK.
Using Northern blot analysis, Scheller et al. (2007) detected variable expression of a 7.5-kb RCK transcript in all human tissues examined. In HeLa cells, RCK colocalized with PATL1 (614660), LSM (607281), and CDP1 (see 607010) in cytoplasmic P bodies.
Balak et al. (2019) noted that expression of Ddx6 is regulated in a time-dependent manner in the mouse neocortex during development and plays a role in neuronal differentiation and migration.
By analysis of a B-cell lymphoma with t(11;14)(q23;q32), Akao et al. (1991) mapped the DDX6 gene to chromosome 11q23. Tunnacliffe et al. (1993) assigned the DDX6 gene more precisely using a panel of sequence tagged sites (STSs) representing 30 markers previously assigned to 11q23.
Using fluorescence in situ hybridization, Akao and Matsuda (1996) mapped the Ddx6 gene to mouse chromosome 9.
Akao et al. (1992) stated that by pulsed field gel electrophoresis, they had previously shown that the RCK locus was centromeric to the PBGD gene (HMBS; 609806) on chromosome 11q23, while the breakpoints of infantile leukemia cell lines with t(11;19)(q23;p13) were detected by a probe for CD3D (186790), which is centromeric to RCK. Akao et al. (1992) did long-range mapping from the CD3 genes to the PBGD gene on 11q23 to determine the relationship between RCK and MLL (159555). They showed that RCK and MLL are on different NotI fragments, indicating that 2 different genes are associated with 11q23 translocations in hematopoietic tumors.
Lu and Yunis (1992) found that the 5-prime noncoding region of p54 was split in a t(11;14)(q23.3;q32.3) cell line from a diffuse large B-cell lymphoma.
Using mass spectroscopy, Fenger-Gron et al. (2005) found that RCK, EDC3 (YJDC; 609842), and HEDLS (RCD8; 606030) coimmunopurified with DCP1A (607010) and DCP2 (609844) from HEK293 cell lysates. Overexpression of DCP2, RCK, or EDC3 in HeLa cells reduced the association of endogenous DCP1A and XRN1 (607994) with cytoplasmic P bodies.
Using small interfering RNAs, Scheller et al. (2007) found that knockdown of PATL1 or RCK reduced the number of P bodies in HeLa cells.
In 5 unrelated patients with intellectual developmental disorder with impaired language and dysmorphic facies (IDDILF; 618653), Balak et al. (2019) identified 5 different de novo heterozygous missense mutations in exon 11 of the DDX6 gene (600326.0001-600326.0005). The mutations, which were found by whole-exome, whole-genome, or next-generation sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. All mutations occurred at conserved residues in either the QxxR or V motifs within the second RecA-2 domain of the helicase core; this region is involved in RNA and/or ATP binding, suggesting functional consequences. Fibroblasts derived from 2 of the patients showed normal DDX6 protein expression, but they had decreased numbers of processing bodies (PBs) as well as defective functional response in PB assembly upon stimulation compared to controls. Immunoprecipitation studies showed that the variants had variably disrupted interactions with several protein partners, including LSM14A (610677) and PAT1B (614660). Further complementation studies in DDX6-null cells transfected with the other mutant variants showed similar defects in P-body assembly. Molecular modeling of the variants indicated that they clustered near known protein-binding regions. Transcriptome analysis of fibroblasts from the patient with the C390R mutation showed a significant difference in the expression of many genes compared to controls, particularly genes involved in ribosome and RNA processing, consistent with deregulation of DDX6-dependent mRNA processing.
In a 5-year-old girl (subject 1) with intellectual developmental disorder with impaired language and dysmorphic facies (IDDILF; 618653), Balak et al. (2019) identified a de novo heterozygous c.1118G-A transition (c.1118G-A, NM_004397.5) in exon 11 of the DDX6 gene, resulting in an arg373-to-gln (R373Q) substitution at a conserved residue in the QxxR motif within the second RecA-2 domain of the helicase core. This region is involved in RNA binding. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Patient-derived fibroblasts showed normal DDX6 protein expression, but decreased numbers of processing bodies (PBs) as well as defective functional response in PB assembly upon stimulation compared to controls.
In a 6-year-old boy (subject 2) with intellectual developmental disorder with impaired language and dysmorphic facies (IDDILF; 618653), Balak et al. (2019) identified a de novo heterozygous c.1168T-C transition (c.1168T-C, NM_004397.5) in exon 11 of the DDX6 gene, resulting in a cys390-to-arg (C390R) substitution at a conserved residue in the V motif within the second RecA-2 domain of the helicase core. This region is involved in RNA and ATP binding. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Patient-derived fibroblasts showed normal DDX6 protein expression, but decreased numbers of processing bodies (PBs) as well as defective functional response in PB assembly upon stimulation compared to controls.
In a patient (subject 3) with intellectual developmental disorder with impaired language and dysmorphic facies (IDDILF; 618653), Balak et al. (2019) identified a de novo heterozygous c.1172C-T transition (c.1172C-T, NM_004397.5) in exon 11 of the DDX6 gene, resulting in a thr391-to-ile (T391I) substitution at a conserved residue in the V motif within the second RecA-2 domain of the helicase core. This region is involved in RNA and ATP binding. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database.
In a 10-year-old boy (subject 4) with intellectual developmental disorder with impaired language and dysmorphic facies (IDDILF; 618653), Balak et al. (2019) identified a de novo heterozygous c.1171A-C transversion (c.1171A-C, NM_004397.5) in exon 11 of the DDX6 gene, resulting in a thr391-to-pro (T391P) substitution at a conserved residue in the V motif within the second RecA-2 domain of the helicase core. This region is involved in RNA and ATP binding. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database.
In a 13-year-old girl (subject 5) with intellectual developmental disorder with impaired language and dysmorphic facies (IDDILF; 618653), Balak et al. (2019) identified a de novo heterozygous c.1115A-G transition (c.1115A-G, NM_004397.5) in exon 11 of the DDX6 gene, resulting in a his372-to-arg (H372R) substitution at a conserved residue in the QxxR motif within the second RecA-2 domain of the helicase core. This region is involved in RNA binding. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database.
Akao, Y., Matsuda, Y. Identification and chromosome mapping of the mouse homologue of the human gene (DDX6) that encodes a putative RNA helicase of the DEAD box protein family. Cytogenet. Cell Genet. 75: 38-44, 1996. [PubMed: 8995487] [Full Text: https://doi.org/10.1159/000134454]
Akao, Y., Seto, M., Takahashi, T., Kubonishi, I., Miyoshi, I., Nakazawa, S., Tsujimoti, Y., Croce, C. M., Ueda, R. Molecular cloning of the chromosomal breakpoint of a B-cell lymphoma with the t(11;14)(q23;q32) chromosome translocation. Cancer Res. 51: 1574-1576, 1991. [PubMed: 1997200]
Akao, Y., Seto, M., Yamamoto, K., Iida, S., Nakazawa, S., Inazawa, J., Abe, T., Takahashi, T., Ueda, R. The RCK gene associated with t(11;14) translocation is distinct from the MLL/ALL-1 gene with t(4;11) and t(11;19) translocations. Cancer Res. 52: 6083-6087, 1992. [PubMed: 1394235]
Akao, Y., Tsujimoto, Y., Finan, J., Nowell, P. C., Croce, C. M. Molecular characterization of a t(11;14)(q23;q32) chromosome translocation in a B-cell lymphoma. Cancer Res. 50: 4856-4859, 1990. [PubMed: 2143098]
Balak, C., Benard, M., Schaefer, E., Iqbal, S., Ramsey, K., Ernoult-Lange, M., Mattioli, F., Llaci, L., Geoffroy, V., Courel, M., Naymik, M., Bachman, K. K., and 26 others. Rare de novo missense variants in RNA helicase DDX6 cause intellectual disability and dysmorphic features and lead to P-body defects and RNA dysregulation. Am. J. Hum. Genet. 105: 509-525, 2019. [PubMed: 31422817] [Full Text: https://doi.org/10.1016/j.ajhg.2019.07.010]
Fenger-Gron, M., Fillman, C., Norrild, B., Lykke-Andersen, J. Multiple processing body factors and the ARE binding protein TTP activate mRNA decapping. Molec. Cell 20: 905-915, 2005. [PubMed: 16364915] [Full Text: https://doi.org/10.1016/j.molcel.2005.10.031]
Lu, D., Yunis, J. J. Cloning, expression and localization of an RNA helicase gene from a human lymphoid cell line with chromosomal breakpoint 11q23.3. Nucleic Acids Res. 20: 1967-1972, 1992. [PubMed: 1579499] [Full Text: https://doi.org/10.1093/nar/20.8.1967]
Scheller, N., Resa-Infante, P., de la Luna, S., Galao, R. P., Albrecht, M., Kaestner, L., Lipp, P., Lengauer, T., Meyerhans, A., Diez, J. Identification of PatL1, a human homolog to yeast P body component Pat1. Biochim. Biophys. Acta 1773: 1786-1792, 2007. [PubMed: 17936923] [Full Text: https://doi.org/10.1016/j.bbamcr.2007.08.009]
Seto, M., Yamamoto, K., Takahashi, T., Ueda, R. Cloning and expression of a murine cDNA homologous to the human RCK/P54, a lymphoma-linked chromosomal translocation junction gene on 11q23. Gene 166: 293-296, 1995. [PubMed: 8543178] [Full Text: https://doi.org/10.1016/0378-1119(95)00559-5]
Tunnacliffe, A., Perry, H., Radice, P., Budarf, M. L., Emanuel, B. S. A panel of sequence tagged sites for chromosome band 11q23. Genomics 17: 744-747, 1993. [PubMed: 8244392] [Full Text: https://doi.org/10.1006/geno.1993.1397]