Alternative titles; symbols
HGNC Approved Gene Symbol: EFTUD2
SNOMEDCT: 711543008;
Cytogenetic location: 17q21.31 Genomic coordinates (GRCh38) : 17:44,849,948-44,899,445 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.31 | Mandibulofacial dysostosis, Guion-Almeida type | 610536 | Autosomal dominant | 3 |
The EFTUD2 gene encodes U5-116kD, a highly conserved spliceosomal GTPase (Fabrizio et al., 1997).
The 4 small nuclear ribonucleoprotein (snRNP) particles U1, U2, U4/U6, and U5 are mRNA splicing factors that contain 1 or more of the small nuclear RNA (snRNA) components. The 20S U5 snRNP contains the common proteins present in each particle (see 603541) as well as 9 specific proteins with molecular weights ranging from 15 to 220 kD. By searching sequence databases with the partial protein sequence of U5-116kD, Fabrizio et al. (1997) determined that the KIAA0031 cDNA identified by Nomura et al. (1994) encodes human U5-116kD. The predicted 972-amino acid protein is structurally closely related to the eukaryotic translation elongation factor EF2 (130610), sharing 27 to 50% sequence identity depending on the region examined. U5-116kD contains consensus GTPase motifs, and Fabrizio et al. (1997) showed that this protein bound GTP specifically. Immunofluorescence microscopy revealed that U5-116kD is located in the nucleus of HeLa cells and colocalizes with snRNP-containing nuclear speckles. Antibodies against U5-116kD inhibited pre-mRNA splicing in a HeLa nuclear extract. These authors also identified homologs in S. cerevisiae, C. elegans, and mouse, designating them Snu114p, Caeel-116H, and U5-116kD, respectively. Human U5-116kD shares 32%, 74%, and 99% identity with Snu114p, Caeel-116H, and mouse U5-116kD, respectively.
Gordon et al. (2012) performed in situ hybridization on cryosections of mice at embryonic day 11.5 and observed strong Eftud2 expression in the mesenchyme of limb buds and lung buds. Eftud2 expression was also noted in the trachea and esophagus, mandibular mesenchyme, ventricular zone cells of the forebrain, and the epithelium of the otic vesicle.
By analysis of somatic cell hybrids, Nomura et al. (1994) mapped the EFTUD2 gene to chromosome 17.
Fabrizio et al. (1997) demonstrated that yeast Snu114 is essential for cell viability and pre-mRNA splicing in vivo. A mutation in the putative GTP-binding site of Snu114 was lethal. The authors concluded that the GTP-binding domain of the U5-116kD protein plays an important role in either the splicing process itself or the recycling of spliceosomal snRNPs.
Using cryoelectron microscopy single-particle reconstruction of the S. cerevisiae tri-snRNP at 5.9-angstrom resolution, Nguyen et al. (2015) determined the complete organization of the tri-snRNP RNA and protein components, including Brr2 (SNRNP200; 601664), Snu114, and Prp8 (PRPF8; 607300). The single-stranded region of U4 snRNA (see 620822) between its 3-prime stem-loop and the U4/U6 (see 180692) snRNA stem I was loaded into the Brr2 helicase active site ready for unwinding. Snu114 and the N-terminal domain of Prp8 positioned U5 snRNA (see 180691) to insert its loop I, which aligns exons for splicing, into the Prp8 active-site cavity.
In 12 unrelated patients with mandibulofacial dysostosis with microcephaly (MFDGA; 610536), Lines et al. (2012) identified heterozygous de novo mutations in or deletions involving the EFTUD2 gene (see, e.g., 603892.0001-603892.0005). A range of mutations, including deletions, frameshifts, splice site, nonsense, and missense mutations were identified, consistent with haploinsufficiency as the disease mechanism. The mutations were found by exome capture and high-throughput sequencing of 4 unrelated affected individuals, followed by analysis of EFTUD2 in 8 additional patients. The phenotype was characterized by progressive microcephaly, midface and malar hypoplasia, micrognathia, microtia, dysplastic ears, preauricular skin tags, global developmental delay, and speech delay. A significant number of patients had major sequelae, including choanal atresia resulting in respiratory difficulties, conductive hearing loss, and cleft palate. MFDGA is the first multiple malformation syndrome attributed to a defect of the major spliceosome.
In a patient with features of the Nager type of acrofacial dysostosis (AFD1; 154400) but who also exhibited microcephaly and was negative for mutation in the SF3B4 gene (605593), Bernier et al. (2012) identified a nonsense mutation in the EFTUD2 gene (603892.0006). Bernier et al. (2012) suggested that the correct diagnosis in this patient was MFDGA.
Gordon et al. (2012) analyzed the EFTUD2 gene in 3 groups of patients: 17 cases with isolated esophageal atresia, 19 cases with oculoauriculovertebral spectrum (OAVS; see 164210), and 14 patients with mandibulofacial dysostosis and esophageal atresia and/or microcephaly. No mutations were found in the first 2 groups, but 10 of the last group had pathogenic EFTUD2 mutations (see, e.g., 603892.0007 and 603892.0008) or deletions. Of the 10 patients with pathogenic EFTUD2 mutations, 8 presented with esophageal atresia as a component of the phenotype; Gordon et al. (2012) concluded that esophageal atresia is an additional malformation caused by heterozygous EFTUD2 loss-of-function mutations. The authors noted that microcephaly might not be a consistent feature in this syndrome and proposed designating the entity 'MFD Guion-Almeida type.'
Beauchamp et al. (2021) found that mice homozygous for neural crest cell-specific deletion of Eftud2 had craniofacial malformations and underwent embryonic lethality. Sensory cranial ganglia were formed in mutant embryos, but they were abnormal. Eftud2 mutant neural crest cells migrated to the craniofacial region but failed to survive and expand due to increased apoptosis. RNA sequencing analysis revealed increased exon skipping and altered gene expression in Eftud2 mutants, findings also observed in cells from patients with MFDGA. However, changes in gene expression were not due to the introduction of exons containing premature termination codons. P53 (191170) was among the upregulated genes in Eftud2 mutant neural crest cells. Loss of Eftud2 led to increased skipping of exon 3 of Mdm2 (164785), a master regulator of p53, which in turn resulted in increased accumulation of nuclear p53 and expression of p53 target genes. Moreover, decreasing p53 activity via an inhibitor at least partially rescued a subset of craniofacial defects in Eftud2 mutant mice.
In a patient with mandibulofacial dysostosis with microcephaly (MFDGA; 610536) reported by Wieczorek et al. (2009), Lines et al. (2012) identified a heterozygous de novo c.784C-T transition in the EFTUD2 gene, resulting in an arg262-to-trp (R262W) substitution in a highly conserved residue in the GTP-binding pocket.
In a patient with the Guion-Almeida type of mandibulofacial dysostosis (MFDGA; 610536) reported by Wieczorek et al. (2009), Lines et al. (2012) identified a heterozygous de novo c.2770C-T transition in the EFTUD2 gene, resulting in a gln924-to-ter (Q924X) substitution.
In a patient with the Guion-Almeida type of mandibulofacial dysostosis (MFDGA; 610536) reported by Guion-Almeida et al. (2006), Lines et al. (2012) identified a heterozygous de novo 1-bp deletion at nucleotide 1758 of the EFTUD2 gene, resulting in a frameshift and premature termination.
In a patient with the Guion-Almeida type of mandibulofacial dysostosis (MFDGA; 610536), Lines et al. (2012) identified a heterozygous de novo c.2493C-A transversion in the EFTUD2 gene, resulting in a tyr831-to-ter (Y831X) substitution.
In a patient with the Guion-Almeida type of mandibulofacial dysostosis (MFDGA; 610536), Lines et al. (2012) identified a heterozygous de novo c.1910T-G transversion in the EFTUD2 gene, resulting in a leu637-to-arg (L637R) substitution in a highly conserved residue that forms an internal contact in domain III, predicted to result in substantial derangement of protein function and/or stability.
In a patient with the Guion-Almeida type of mandibulofacial dysostosis (MFDGA; 610536), Bernier et al. (2012) identified heterozygosity for a c.2495C-G transversion in the EFTUD2 gene, resulting in a tyr832-to-ter (Y832X) substitution. The patient had originally been diagnosed with the Nager type of acrofacial dysostosis (AFD1; 154400), but in retrospect was noted to display microcephaly, suggesting that MFDGA rather than Nager syndrome was the appropriate diagnosis.
In a 4-year-old patient with the Guion-Almeida type of mandibulofacial dysostosis (MFDGA; 610536), Gordon et al. (2012) identified a heterozygous de novo c.623A-G transition in the EFTUD2 gene, resulting in a his208-to-arg (H208R) substitution at a conserved residue within the switch II region of the GTP-binding domain, a putative guanine exchange factor interaction site. The mutation was not found in the dbSNP or 1000 Genomes Project databases. The patient presented with choanal atresia, esophageal atresia, facial asymmetry, dysplastic ears, hearing loss, agenesis of the lateral semicircular canals, postnatal microcephaly, and delayed psychomotor development.
In a female fetus for whom pregnancy was terminated at 29 weeks' gestation due to the association of esophageal atresia and delayed gyration and in whom dysplastic ears, microretrognathia, and microcephaly with no brain formation were reported on necropsy (MFDGA; 610536), Gordon et al. (2012) identified heterozygosity for a 1-bp deletion involving the donor splice site of intron 27 (c.2823+1del), predicted to abolish splicing. The mutation, which was inherited from the mother in whom it had arisen de novo, was 'absent from databases.' Features in the mother included microcephaly, mixed hearing loss, mild intellectual disability, and brachydactyly of fingers.
Beauchamp, M. C., Djedid, A., Bareke, E., Merkuri, F., Aber, R., Tam, A. S., Lines, M. A., Boycott, K. M., Stirling, P. C., Fish, J. L., Majewski, J., Jerome-Majewska, L. A. Mutation in Eftud2 causes craniofacial defects in mice via mis-splicing of Mdm2 and increased P53. Hum. Molec. Genet. 30: 739-757, 2021. [PubMed: 33601405] [Full Text: https://doi.org/10.1093/hmg/ddab051]
Bernier, F. P., Caluseriu, O., Ng, S., Schwartzentruber, J., Buckingham, K. J., Innes, A. M., Jabs, E. W., Innis, J. W., Schuette, J. L., Gorski, J. L., Byers, P. H., Andelfinger, G., and 12 others. Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome. Am. J. Hum. Genet. 90: 925-933, 2012. [PubMed: 22541558] [Full Text: https://doi.org/10.1016/j.ajhg.2012.04.004]
Fabrizio, P., Laggerbauer, B., Lauber, J., Lane, W. S., Luhrmann, R. An evolutionarily conserved U5 snRNP-specific protein is a GTP-binding factor closely related to the ribosomal translocase EF-2. EMBO J. 16: 4092-4106, 1997. [PubMed: 9233818] [Full Text: https://doi.org/10.1093/emboj/16.13.4092]
Gordon, C. T., Petit, F., Oufadem, M., Decaestecker, C., Jourdain, A.-S., Andrieux, J., Malan, V., Alessandri, J.-L., Baujat, G., Baumann, C., Boute-Benejean, O., Caumes, R., and 20 others. EFTUD2 haploinsufficiency leads to syndromic oesophageal atresia. J. Med. Genet. 49: 737-746, 2012. [PubMed: 23188108] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101173]
Guion-Almeida, M. L., Zechi-Ceide, R. M., Vendramini, S., Tabith, A., Jr. A new syndrome with growth and mental retardation, mandibulofacial dysostosis, microcephaly, and cleft palate. Clin. Dysmorph. 15: 171-174, 2006. [PubMed: 16760738] [Full Text: https://doi.org/10.1097/01.mcd.0000220603.09661.7e]
Lines, M. A., Huang, L., Schwartzentruber, J., Douglas, S. L., Lynch, D. C., Beaulieu, C., Guion-Almeida, M. L., Zechi-Ceide, R. M., Gener, B., Gillessen-Kaesbach, G., Nava, C., Baujat, G., and 16 others. Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly. Am. J. Hum. Genet. 90: 369-377, 2012. [PubMed: 22305528] [Full Text: https://doi.org/10.1016/j.ajhg.2011.12.023]
Nguyen, T. H. D., Galej, W. P., Bai, X., Savva, C. G., Newman, A. J., Scheres, S. H. W., Nagai, K. The architecture of the spliceosomal U4/U6.U5 tri-snRNP. Nature 523: 47-52, 2015. [PubMed: 26106855] [Full Text: https://doi.org/10.1038/nature14548]
Nomura, N., Miyajima, N., Sazuka, T., Tanaka, A., Kawarabayashi, Y., Sato, S., Nagase, T., Seki, N., Ishikawa, K., Tabata, S. Prediction of the coding sequences of unidentified human genes. I. The coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of randomly sampled cDNA clones from human immature myeloid cell line, KG-1. DNA Res. 1: 27-35, 1994. Note: Erratum: DNA Res. 2: 210 only, 1995. [PubMed: 7584026] [Full Text: https://doi.org/10.1093/dnares/1.1.27]
Wieczorek, D., Gener, B., Gonzalez, M. J. M., Seland, S., Fischer, S., Hehr, U., Kuechler, A., Hoefsloot, L. H., de Leeuw, N., Gillessen-Kaesbach, G., Lohmann, D. R. Microcephaly, microtia, preauricular tags, choanal atresia and developmental delay in three unrelated patients: a mandibulofacial dysostosis distinct from Treacher Collins syndrome. Am. J. Med. Genet. 149A: 837-843, 2009. [PubMed: 19334086] [Full Text: https://doi.org/10.1002/ajmg.a.32747]