Alternative titles; symbols
HGNC Approved Gene Symbol: EIF4A3
SNOMEDCT: 723998001;
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38): 17:80,134,369-80,147,128 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.3 | Robin sequence with cleft mandible and limb anomalies | 268305 | Autosomal recessive | 3 |
DDX48 is a component of the exon junction complex (EJC), which assembles near exon-exon junctions of mRNAs as a result of splicing. EJC proteins play roles in postsplicing events, including mRNA export, cytoplasmic localization, and nonsense-mediated decay (Chan et al., 2004).
By sequencing clones obtained from a size-fractionated immature myeloid cell line cDNA library, Nagase et al. (1995) cloned DDX48, which they designated KIAA0111. The deduced protein contains 411 amino acids. Northern blot analysis detected DDX48 expression in all tissues and cell lines examined. Highest expression was in heart, brain, placenta, lung, liver, skeletal muscle, kidney, and thymus, and lowest expression was in peripheral blood leukocytes.
Holzmann et al. (2000) purified DDX48, which they called NMP265, from nuclear matrix proteins isolated from various human tissues and cells. The protein had an apparent molecular mass of 47 kD by 2-dimensional electrophoresis. The deduced protein contains 8 DEAD-box motifs that correspond to those of ATP-dependent RNA helicases. DDX48 shares 66% amino acid identity with EIF4A1 (602641) and 71% identity with EIF4A2 (601102), although the N termini differ between the 3 proteins. DDX48 shares 61 to 96% amino acid identity with its rodent, frog, nematode, and yeast homologs. Northern blot analysis detected an mRNA of about 1.7 kb in 3 human cell lines. RNA dot blot analysis detected expression in all adult and fetal tissues examined. Immunofluorescence and confocal microscopy detected fluorescence-tagged DDX48 in a punctate nuclear staining pattern preferentially at perinucleolar sites. Mutation analysis indicated that the N-terminal 23 amino acids of DDX48 were involved in nuclear localization.
To characterize the CG-rich 5-prime untranslated region (UTR) of the EIF4A3 gene, Favaro et al. (2014) sequenced 140 alleles from 70 unrelated Brazilian controls and discovered multiple allelic patterns that varied in size and organization of motifs, which contained 18 or 20 nucleotides. There were 3 motifs present, including a 20-nucleotide motif which the authors designated CACA-20-nt; an 18-nucleotide motif, termed CA-18-nt; and another 20-nucleotide motif identical to the first except for an A-to-G substitution, designated CGCA-20-nt. The most prevalent pattern among controls (97%) involved a total of 5 to 12 repeats, consisting of an initial CACA-20-nt repeated between 2 and 9 times followed by 1 CA-18-nt, another CACA-20-nt, and 1 final CA-18-nt, ending 43 bases upstream of the first ATG.
By examining human-rodent hybrid cell lines, Nagase et al. (1995) mapped the DDX48 gene to chromosome 17.
Chan et al. (2004) showed that EIF4A3 is a component of the EJC. EIF4A3 preferentially associated with the nuclear EJC complex proteins MAGOH (602603) and Y14 (605313), and it interacted with these components indirectly through interactions with TAP (602647) and ALY (604171). Furthermore, EIF4A3, but not EIF4A1 or EIF4A2, preferentially associated with spliced mRNA. EIF4A3 did not bind intronless mRNA. In vitro splicing and mapping experiments demonstrated that EIF4A3 bound mRNAs at the EJC. Chan et al. (2004) concluded that EIF4A3 provides a splicing-dependent influence on the translation of mRNAs.
Using a library of endoribonuclease-prepared short interfering RNAs (esiRNAs), Kittler et al. (2004) identified 37 genes required for cell division, one of which was DDX48. These 37 genes included several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown.
In 20 affected individuals from 17 Brazilian families with Robin sequence, cleft mandible, and limb anomalies (Richieri-Costa-Pereira syndrome, or RCPS; 268305) mapping to chromosome 17q25.3, Favaro et al. (2014) analyzed the candidate gene EIF4A3 and identified homozygosity for an expanded 16-repeat allele (608546.0001) in 17 of the patients and compound heterozygosity for the 16-repeat allele and a 15-repeat allele (608546.0002) in 3 of them. Analysis of an additional 5 Brazilian RCPS patients identified homozygosity for the 16-repeat allele in 4 of them; the fifth patient was a compound heterozygote for a 14-repeat expanded allele (608546.0003) and a missense mutation (D270G; 608546.0004). Unaffected family members either lacked an expanded allele or were heterozygous for the 16-repeat allele; the expanded alleles were not found in 520 Brazilian controls, who had only 3 to 12 repeats. Transcript analysis showed no evidence for altered splicing, but EIF4A3 transcript abundance was 30 to 40% lower in patient cells than in control cells.
Favaro et al. (2014) generated zebrafish deficient in Eif4a3 and observed underdevelopment of craniofacial cartilage, bone alterations, and clefting of the lower jaw. In addition, morphants displayed underdevelopment of the third through sixth pharyngeal arches.
In 21 affected individuals from 18 Brazilian families with Robin sequence, cleft mandible, and limb anomalies (RCPS; 268305), Favaro et al. (2014) identified homozygosity for an expanded 16-repeat allele of the EIF4A3 gene, consisting of an initial CACA-20-nt motif followed by 13 repeats of CGCA-20-nt, 1 CACA-20-nt, and 1 final CA-18-nt motif. In 3 more Brazilian patients, including a distant cousin of 1 of the homozygous patients, Favaro et al. (2014) identified compound heterozygosity for the 16-repeat allele and a 15-repeat allele (608546.0002) that was identical to the 16-repeat allele except for the presence of 1 fewer CGCA-20-nt repeat. Unaffected family members either lacked an expanded allele or were heterozygous for the 16-repeat allele; the expanded alleles were not found in 520 Brazilian controls, who had only 3 to 12 repeats. Transcript analysis showed no evidence for altered splicing, but EIF4A3 transcript abundance was 30 to 40% lower in patient cells than in control cells. All but 1 of the patients had been previously reported (Richieri-Costa and Pereira, 1992; Richieri-Costa and Pereira, 1993; Tabith and Bento-Goncalves, 1996; Guion-Almeida and Richieri-Costa, 1998; Tabith and Bento-Goncalves, 2003; Favaro et al., 2011; Souza et al., 2011; Raskin et al., 2013), and haplotype analysis was consistent with a common origin for the expanded 15- and 16-repeat alleles. Favaro et al. (2014) noted that the phenotype of the 3 compound heterozygous patients was very similar to that of the homozygotes.
For discussion of the 15-repeat expansion in the EIF4A3 gene that was found in compound heterozygous state in patients with Robin sequence, cleft mandible, and limb anomalies (RCPS; 268305) by Favaro et al. (2014), see 608546.0001.
In a Brazilian man with micrognathia, abnormal larynx, and radial ray and tibial abnormalities (RCPS; 268305), Favaro et al. (2014) identified compound heterozygosity for an expanded 14-repeat allele of the EIF4A3 gene, consisting of 2 initial CACA-20-nt motifs followed by 10 repeats of CGCA-20-nt, 1 CACA-20-nt, and 1 final CA-18-nt motif, and a c.809A-G transition in exon 8, resulting in an asp270-to-gly (D270G) substitution at a highly conserved residue within the C-terminal helicase RecA2 domain (608546.0004). Compared to patients homozygous for the EIF4A3 16-repeat allele (608546.0001) or compound heterozygous for the 16-repeat allele and a 15-repeat allele (608546.0002), this patient exhibited a milder phenotype and had fusion of the mandible. The 14-repeat allele was embedded in the same 42-kb haplotype observed in the recombinant 16-repeat alleles, whereas the c.809A-G mutation was embedded in a distinct haplotype.
For discussion of the asp270-to-gly (D270G) mutation in the EIF4A3 gene that was found in compound heterozygous state in a patient with micrognathia, abnormal larynx, and radial ray and tibial abnormalities (RCPS; 268305) by Favaro et al. (2014), see 608546.0003.
Chan, C. C., Dostie, J., Diem, M. D., Feng, W., Mann, M., Rappsilber, J., Dreyfuss, G. eIF4A3 is a novel component of the exon junction complex. RNA 10: 200-209, 2004. [PubMed: 14730019] [Full Text: https://doi.org/10.1261/rna.5230104]
Favaro, F. P., Alvizi, L., Zechi-Ceide, R. M., Bertola, D., Felix, T. M., de Souza, J., Raskin, S., Twigg, S. R. F., Weiner, A. M. J., Armas, P., Margarit, E., Calcaterra, N. B., Andersen, G. R., McGowan, S. J., Wilkie, A. O. M., Richieri-Costa, A., de Almeida, M. L. G., Passos-Bueno, M. R. A noncoding expansion in EIF4A3 causes Richieri-Costa-Pereira syndrome, a craniofacial disorder associated with limb defects. Am. J. Hum. Genet. 94: 120-128, 2014. [PubMed: 24360810] [Full Text: https://doi.org/10.1016/j.ajhg.2013.11.020]
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Holzmann, K., Gerner, C., Poltl, A., Schafer, R., Obrist, P., Ensinger, C., Grimm, R., Sauermann, G. A human common nuclear matrix protein homologous to eukaryotic translation initiation factor 4A. Biochem. Biophys. Res. Commun. 267: 339-344, 2000. [PubMed: 10623621] [Full Text: https://doi.org/10.1006/bbrc.1999.1973]
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Richieri-Costa, A., Pereira, S. C. S. Autosomal recessive short stature, Robin sequence, cleft mandible, pre/postaxial hand anomalies, and clubfeet in male patients. Am. J. Med. Genet. 47: 707-709, 1993. [PubMed: 8267000] [Full Text: https://doi.org/10.1002/ajmg.1320470524]
Richieri-Costa, A., Pereira, S. C. S. Short stature, Robin sequence, cleft mandible, pre/postaxial hand anomalies, and clubfoot: a new autosomal recessive syndrome. Am. J. Med. Genet. 42: 681-687, 1992. [PubMed: 1632438] [Full Text: https://doi.org/10.1002/ajmg.1320420511]
Souza, J., dal Vesco, K., Tonocchi, R., Closs-Ono, M. C., Passos-Bueno, M. R., da Silva-Freitas, R. The Richieri-Costa and Pereira syndrome: report of two Brazilian siblings and review of literature. Am. J. Med. Genet. 155A: 1173-1177, 2011. [PubMed: 21485002] [Full Text: https://doi.org/10.1002/ajmg.a.33975]
Tabith, A., Jr., Bento-Goncalves, C. G. A. Laryngeal malformation in the Richieri-Costa-Pereira acrofacial dysostosis: description of two new patients. Am. J. Med. Genet. 122A: 133-138, 2003. [PubMed: 12955765] [Full Text: https://doi.org/10.1002/ajmg.a.10227]
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