Alternative titles; symbols
HGNC Approved Gene Symbol: DDX3X
Cytogenetic location: Xp11.4 Genomic coordinates (GRCh38) : X:41,333,308-41,364,472 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.4 | Intellectual developmental disorder, X-linked syndromic, Snijders Blok type | 300958 | X-linked dominant; X-linked recessive | 3 |
The DDX3X gene encodes a conserved DEAD-box RNA helicase that is important in a variety of cellular processes, including transcription, splicing, RNA transport, and translation. The DDX3X gene in particular has been associated with cell cycle control, apoptosis, and tumorigenesis. It is thought to be an essential factor in the RNAi pathway, and is a key regulator of the WNT (see, e.g., WNT3A, 606359)/CTNNB1 (116806) pathway (summary by Snijders Blok et al., 2015).
DEAD box proteins are putative RNA helicases that have a characteristic asp-glu-ala-asp (DEAD) box as 1 of 8 highly conserved sequence motifs. Chung et al. (1995) cloned cDNAs encoding DDX3, a member of the DEAD box protein family.
Lahn and Page (1997) identified DDX3, which they called DBX, as 1 of 5 X-linked genes that have homologs located in the nonrecombining region of the Y chromosome (NRY). They determined that these 5 X-linked genes escape X inactivation. Lahn and Page (1997) postulated that these 5 genes are cases in which gene expression is maintained at comparable levels in males and females by preservation of homologous genes on both the X and the NRY, with male and female cells expressing both copies of each gene. Sequence analysis revealed that DBX shares 91% protein sequence identity with DBY (400010), the Y-linked homolog.
A single transcript in its unspliced and spliced forms directs synthesis of all human immunodeficiency virus (HIV)-1 proteins. Although nuclear export of intron-containing cellular transcripts is restricted in mammalian cells, HIV-1 has evolved the viral Rev protein to overcome this restriction for viral transcripts. CRM1 (XPO1; 602559) is a cellular cofactor for Rev-dependent export of intron-containing HIV-1 RNA. Yedavalli et al. (2004) presented evidence that Rev/CRM1 activity uses the ATP-dependent RNA helicase DDX3. They showed that DDX3 is a nucleocytoplasmic shuttling protein that binds CRM1 and localizes to nuclear membrane pores. Knockdown of DDX3 using either antisense vector or dominant-negative mutants suppressed Rev-RRE (Rev response element) function in the export of incompletely spliced HIV-1 RNAs. Yedavalli et al. (2004) concluded that DDX3 is the human RNA helicase that functions in the CRM1 RNA export pathway analogously to the postulated role for Dbp5 (605812) in yeast mRNA export.
Cruciat et al. (2013) identified the DEAD box RNA helicase DDX3 as a regulator of the Wnt (see 164820)-beta-catenin (116806)M network, where it acts as a regulatory subunit of CK1-epsilon (600863): in a Wnt-dependent manner, DDX3 binds CK1-epsilon and directly stimulates its kinase activity, and promotes phosphorylation of the scaffold protein dishevelled (see 601365). DDX3 is required for Wnt-beta-catenin signaling in mammalian cells and during Xenopus and C. elegans development. Cruciat et al. (2013) concluded that their results suggested that the kinase-stimulatory function extends to other DDX and CK1 members.
By integrating transcriptomewide analyses of translation, RNA structure, and Ded1p-RNA binding in S. cerevisiae, Guenther et al. (2018) showed that the effects of Ded1p (the yeast ortholog of DDX3) on the initiation of translation are connected to near-cognate initiation codons in 5-prime untranslated regions. Ded1p associates with the translation preinitiation complex at the mRNA entry channel, and repressing the activity of Ded1p leads to the accumulation of RNA structure in 5-prime untranslated regions, the initiation of translation from near-cognate start codons immediately upstream of these structures, and decreased protein synthesis from the corresponding main open reading frames. The data revealed a program for the regulation of translation that links Ded1p, the activation of near-cognate start codons, and mRNA structure. This program has a role in meiosis, in which a marked decrease in the levels of Ded1p is accompanied by the activation of the alternative translation initiation sites that are seen when the activity of Ded1p is repressed.
Samir et al. (2019) showed that the induction of stress granules specifically inhibits NLRP3 (606416) inflammasome activation, ASC (606838) speck formation, and pyroptosis. The stress granule protein DDX3X interacts with NLRP3 to drive inflammasome activation. Assembly of stress granules leads to the sequestration of DDX3X, and thereby the inhibition of NLRP3 inflammasome activation. Stress granules and the NLRP3 inflammasome compete for DDX3X molecules to coordinate the activation of innate responses and subsequent cell-fate decisions under stress conditions. Induction of stress granules or loss of DDX3X in the myeloid compartment leads to a decrease in the production of inflammasome-dependent cytokines in vivo. The findings of Samir et al. (2019) suggested that macrophages use the availability of DDX3X to interpret stress signals and choose between prosurvival stress granules and pyroptotic ASC specks. The authors concluded that their data demonstrated the role of DDX3X in driving NLRP3 inflammasome and stress granule assembly, and suggested a rheostat-like mechanistic paradigm for regulating live-or-die cell fate decisions under stress conditions.
Using knockdown analysis in hamster BHK-21 cells, Han et al. (2020) identified Rpl13 (113703) as an essential factor for replication of foot-and-mouth disease virus (FMDV). Rpl13 and Ddx3 interacted through the N-terminal region of Ddx3, and both proteins associated with the internal ribosome entry site (IRES) of the FMDV 5-prime UTR, thereby facilitating IRES-driven translation and promoting FMDV replication. The C-terminal region of Ddx3 was required for its association with the viral IRES. Rpl13 functioned downstream of Ddx3, and its interaction with the IRES was Ddx3 dependent. Ddx3 cooperated with Rpl13 to support assembly of 80S ribosomes for optimal translation initiation of FMDV mRNA, which also involved binding of Eif3e (602210) and Eif3j (603910) to the IRES. Further analysis demonstrated that the Rpl13 regulator function was also involved in infection of Seneca Valley virus and classical swine fever virus, but not vesicular stomatitis virus.
Using genomewide knockout screens in human cells, Cheng et al. (2019) showed that the NXF1 (602647)-NXT1 (605811) pathway mediated nuclear export of C9ORF72 (614260) GGGGCC repeat-containing RNA to the cytoplasm for translation, thereby influencing C9ORF72 dipeptide repeat (DPR) protein production. DDX3X was identified as a modifier of DPR protein production, as it suppressed repeat-associated non-AUG (RAN) translation of C9ORF72 (GGGGCC)n repeats by directly and selectively binding to GGGGCC repeat RNA. Binding to GGGGCC repeat RNA activated DDX3X ATPase activity for RNA structure unwinding, and translation repression required DDX3X helicase activity. Similarly, loss of Bel, the Drosophila ortholog of DDX3X, enhanced GGGGCC repeat toxicity in Drosophila, whereas ectopic expression of Bel partially rescued it, identifying Bel as a genetic modifier of GGGGCC repeat-mediated toxicity in vivo. ELISA revealed that DDX3X expression modulated repeat-mediated toxicity in amyotrophic lateral sclerosis (ALS; 105550) patient cells by regulating DPR production from RAN translation
By fluorescence in situ hybridization, Park et al. (1998) mapped the DDX3X gene to chromosome Xp11.3-p11.23.
Snijders Blok et al. (2015) identified 35 different de novo heterozygous mutations in the DDX3X gene (see, e.g., 300160.0001-300160.0004) in 38 girls with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MRXSSB; 300958). The mutations were found by whole-exome sequencing of 3 large cohorts of patients referred for testing (including the Deciphering Developmental Disorders Study, 2015); DDX3X mutations were found in 1 to 3% of these patient cohorts, rendering it one of the most common causes of intellectual disability in females. Nineteen of the mutations were predicted to result in complete loss of function, resulting in haploinsufficiency in the female patients. In vitro cellular functional expression studies and in vivo studies in zebrafish of some of the identified missense mutations showed that they caused a loss of function in the canonical WNT signaling pathway with a disruption of beta-catenin signaling. There was no evidence for a dominant-negative effect, and Snijders Blok et al. (2015) postulated haploinsufficiency as the disease mechanism. De novo variants were not found in any male patients who were part of the cohorts, but affected males in 3 unrelated families were found to carry hemizygous missense mutations in the DDX3X gene (see, e.g., 300160.0005) that were inherited from an unaffected mother. Functional studies indicated no differences between the male mutant alleles and wildtype, but Snijders Blok et al. (2015) speculated that they were pathogenic and that the effect of the mutant alleles was beyond the detection range of the assays. The results were consistent with the hypothesis that DDX3X is dosage sensitive and may have differential activity in females than in males.
By whole-exome sequencing, Kellaris et al. (2018) identified a maternally inherited missense mutation (R79K; 300160.0006) in the DDX3X gene in 2 brothers with MRXSSB. Functional testing of DDX3X activity in zebrafish embryos showed that the allele causes a partial loss of DDX3X function, indicating a hypomorphic variant.
In 3 unrelated males with MRXSSB, Nicola et al. (2019) identified hemizygous missense mutations in the DDX3X gene (see, e.g., R376H, 300160.0007 and V496M, 300160.0008). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, occurred de novo in 2 of the patients. Nicola et al. (2019) proposed that de novo DDX3X mutations are not necessarily male lethal and therefore should be considered as a cause of syndromic impaired intellectual development in both males and females.
By whole-exome sequencing, Scala et al. (2019) identified 3 different de novo heterozygous mutations in the DDX3X in 3 unrelated females with MRXSSB (300160.0009-300160.0011).
Beal et al. (2019) identified 5 novel heterozygous DDX3X mutations (4 frameshifts and 1 splice site) in 6 females with MRXSSB from 5 unrelated families. Two sibs had the same frameshift mutation (300160.0012); parental testing for this mutation was negative, suggesting germline mosaicism. Although both girls had impaired intellectual development, the older sister was more severely affected.
Using exome sequencing, Chanes et al. (2019) identified a de novo frameshift mutation (300160.0013) in the DDX3X gene in a 10-year-old girl with MRXSSB.
In 3 unrelated girls with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MRXSSB; 300958), Snijders Blok et al. (2015) identified a de novo heterozygous c.1126C-T transition (c.1126C-T, NM_001356.4) in the DDX3X gene, resulting in an arg376-to-cys (R376C) substitution in the helicase ATP-binding domain. The mutations were found by whole-exome sequencing of several large cohorts of patients with intellectual disability; R376C was not found in the ExAC or Exome Variant Server databases. In vitro cellular functional expression studies and in vivo studies in zebrafish indicated that the R376C mutation caused a loss of protein function, consistent with haploinsufficiency.
In a 3-year-old girl with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MRXSSB; 300958), Snijders Blok et al. (2015) identified a de novo heterozygous c.1520T-C transition (c.1520T-C, NM_001356.4) in the DDX3X gene, resulting in an ile507-to-thr (I507T) substitution in the helicase C terminal domain. The mutation, which was found by whole-exome sequencing of several large cohorts of patients with intellectual disability, was not found in the ExAC or Exome Variant Server databases. In vitro cellular functional expression studies and in vivo studies in zebrafish indicated that the I507T mutation caused a loss of protein function, consistent with haploinsufficiency.
In a 13-year-old girl with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MRXSSB; 300958), Snijders Blok et al. (2015) identified a de novo heterozygous c.977G-A transition (c.977G-A, NM_001356.4) in the DDX3X gene, resulting in an arg326-to-his (R326H) substitution in the helicase ATP-binding domain. The mutation, which was found by whole-exome sequencing of several large cohorts of patients with intellectual disability, was not found in the ExAC or Exome Variant Server databases. In vitro cellular functional expression studies and in vivo studies in zebrafish indicated that the R326H mutation caused a loss of protein function, consistent with haploinsufficiency.
In a 13-year-old girl with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MRXSSB; 300958), Snijders Blok et al. (2015) identified a de novo heterozygous c.873C-A transversion (c.873C-A, NM_001356.4) in the DDX3X gene, resulting in a tyr291-to-ter (Y291X) substitution. The mutation, which was found by whole-exome sequencing of several large cohorts of patients with intellectual disability, was not found in the ExAC or Exome Variant Server databases. The mutation was predicted to result in a loss of function, causing haploinsufficiency.
In 2 brothers and a maternal uncle with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MRXSSB; 300958), Snijders Blok et al. (2015) identified a hemizygous c.1084C-T transition (c.1084C-T, NM_001356.4) in the DDX3X gene, resulting in an arg362-to-cys (R362C) substitution in the helicase ATP-binding domain. The mutation, which was found by X-chromosome exome sequencing, was not found in the ExAC or Exome Variant Server databases. It segregated with the disorder in the family, and the unaffected mother was heterozygous for the mutation. The transmission pattern of the disorder in this family was consistent with X-linked recessive inheritance. In vitro and in vivo functional studies in zebrafish showed no difference of the mutant protein in WNT signaling compared to wildtype, but Snijders Blok et al. (2015) speculated that the variant was pathogenic and that the effect of the mutation was beyond the detection range of the assays.
By exome sequencing in 2 brothers with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MRXSSB; 300958), Kellaris et al. (2018) detected a maternally inherited c.236G-A transition in the DDX3X gene, resulting in an arg79-to-lys (R79K) substitution at a conserved residue located proximal to the helicase ATP-binding domain. Functional analysis in zebrafish embryos indicated that the discovered allele is likely a hypomorph. Both brothers had impaired intellectual development and progressive spasticity.
In a 9-year-old boy (patient 1; Decipher ID: 301323) with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MRXSSB; 300958), Nicola et al. (2019) identified a hemizygous c.1127G-A transition (c.1127G-A, NM_001356.4) in the DDX3X gene, resulting in an arg376-to-his (R376H) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was absent in the parents, suggesting a de novo mutation. A de novo mutation at the same codon (R376C; 300160.0001) was reported by Snijders Blok et al. (2015) in females with MRXSSB.
In an 8-year-old boy (patient 2) with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MRXSSB; 300958), Nicola et al. (2019) identified a de novo hemizygous c.1486G-A transition (c.1486G-A, NM_001356.4) in the DDX3X gene, resulting in a val496-to-met (V496M) substitution at a highly conserved reside in the helicase C-terminal domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. The patient had impaired intellectual development, cardiac defects, cataracts, and mild conductive hearing loss.
In an 11-year-old girl (patient 1) with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MRXSSB; 300958), Scala et al. (2019) identified a heterozygous c.1511G-A transition (c.1511G-A, NM_001356.3) in the DDX3X gene, resulting in a gly504-to-glu (G504E) substitution. The mutation, which was found by whole-exome sequencing, was confirmed by Sanger sequencing. The patient had a history of global developmental delay, absent speech, spastic tetraparesis, and severe scoliosis. She was incidentally diagnosed with a cerebellar pilocytic astrocytoma at age 8. The authors noted that DDX3X plays a crucial role in cell cycle progression and is involved in the Wnt/Beta-catenin signalling pathway and has been reported in Wnt-driven medulloblastoma.
In a 2-year-old girl (patient 2) with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MRXSSB; 300958), Scala et al. (2019) identified a heterozygous del/ins mutation (c.1436_1439delinsTCTC, NM_001356.3) in the DDX3X gene, resulting in an Asp479Arg480delinsValSer protein change. 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 girl (patient 3) with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MRXSSB; 300958), Scala et al. (2019) identified a heterozygous 3-bp deletion (c.641_643delTCA, NM_001356.3) in the DDX3X gene, resulting in deletion of an isoleucine residue (Ile214del). The patient had impaired intellectual development, microcephaly, hypotonia, and hand stereotypies.
In 2 sisters (patients 4 and 5) with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MRXSSB; 300958), Beal et al. (2019) identified a de novo heterozygous 4-bp deletion (c.828-831del, NM_001356.4) in the DDX3X gene, resulting in a frameshift and a premature termination codon (Arg276SerfsTer44). Parental testing for the mutation was negative, suggesting germline mosaicism. Although both girls had impaired intellectual development, the older sister was more severely affected.
By exome sequencing in a 10-year-old girl with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MRXSSB; 300958), Chanes et al. (2019) identified a de novo heterozygous 2-bp deletion (c.1535_1536del) in the DDX3X gene, resulting in a frameshift and a premature termination codon (His512ArgfsTer5). The patient, who was born prematurely at 25 weeks' gestation, had impaired intellectual development, behavioral problems, and minor dysmorphic features.
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