Alternative titles; symbols
HGNC Approved Gene Symbol: DPH1
SNOMEDCT: 1217229007;
Cytogenetic location: 17p13.3 Genomic coordinates (GRCh38) : 17:2,030,112-2,043,898 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.3 | Developmental delay with short stature, dysmorphic facial features, and sparse hair | 616901 | Autosomal recessive | 3 |
Diphthamide is a unique posttranslationally modified histidine found only in translation elongation factor-2 (EEF2; 130610). This modification is conserved from archaebacteria to humans and serves as the target for ADP-ribosylation and inactivation of EEF2 by diphtheria toxin (DT) and Pseudomonas exotoxin A. DPH1 is one of several enzymes involved in synthesis of diphthamide in EEF2 (Liu et al., 2004).
A region of chromosome 17p13.3 bounded by loci D17S28 and D17S30 is deleted in 80% of all ovarian epithelial malignancies (167000). By exon trapping, Phillips et al. (1996) isolated a cDNA from the common region of deletion. The predicted 363-amino acid protein was designated DPH2L (DPH2-like) because it shares 20% amino acid identity with the S. cerevisiae Dph2 (diphthamide biosynthesis-2) gene. The authors noted that DPH2L is more closely related to Yik3, a predicted yeast protein of unknown function.
Independently, Schultz et al. (1996) identified cDNAs encoding DPH2L, which they called OVCA1. They reported that the predicted OVCA1 protein contains 443 amino acids. The authors also isolated cDNAs corresponding to a second transcript, OVCA2 (607896), that contains the 3-prime region of OVCA1 and an additional exon. Northern blot analysis indicated that OVCA1 and OVCA2 are expressed ubiquitously as 2.3- and 1.1-kb mRNAs, respectively. However, the expression of both transcripts was significantly reduced or was undetectable in the majority of ovarian tumors and tumor cell lines evaluated.
Liu et al. (2004) cloned mouse Dph1. The deduced 438-amino acid protein shares 86% identity with human DPH1.
Liu et al. (2004) showed that mouse Dph1 could complement the DT-resistant phenotype of a diphthamide-deficient mutant Chinese hamster ovary cell line. Immunoprecipitation analysis revealed that yeast and mouse Dph1 and Dph2 (603456) interacted, suggesting that these enzymes may function in diphthamide biosynthesis as a dimer or multimer.
Carette et al. (2009) used insertional mutagenesis to develop a screening method to generate null alleles in a human cell line haploid for all chromosomes except chromosome 8. Using this approach, they identified genes encoding important elements of the biosynthetic pathway of diphthamide, which are required for the cytotoxic effects of diphtheria toxin and exotoxin A. Mutants of the DPH1, DPH2, and DPH5 (611075) genes, involved in diphthamide biosynthesis, were identified as resistant to both anthrax toxin and diphtheria toxin.
Schultz et al. (1996) determined that the OVCA1 gene contains 13 exons and spans approximately 20 kb.
By genomic sequence analysis, Phillips et al. (1996) and Schultz et al. (1996) mapped the DPH1 gene to chromosome 17p13.3.
In 4 affected individuals from a consanguineous Saudi family with developmental delay with short stature, dysmorphic facial features, and sparse hair-1 (DEDSSH1; 616901), Alazami et al. (2015) identified a homozygous missense mutation in the DPH1 gene (L234P; 603527.0001). The family was part of a large cohort of 143 multiplex consanguineous families with various neurodevelopmental disorders who underwent whole-exome sequencing. Functional studies of the variant were not performed.
In 4 patients from a North American genetic isolate with DEDSSH1, Loucks et al. (2015) identified a homozygous missense mutation in the DPH1 gene (M6K; 603527.0002). The mutation was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing. The carrier frequency of the variant was 0.46% in this population, consistent with a founder effect. Functional studies of the variant and studies of patient cells were not performed.
In a Japanese child with DEDSSH1, Nakajima et al. (2018) identified compound heterozygous mutations in the DPH1 gene (L164P, 603527.0003 and c.289delG, 603527.0004). The mutations were identified by whole-exome sequencing.
In 2 Maltese sibs and 2 Bedouin Yemeni sibs with DEDSSH1, Urreizti et al. (2020) identified homozygous mutations in the DPH1 gene (L125P, 603527.0005, and Y112C, 603527.0006, respectively). Urreizti et al. (2020) transfected plasmids containing DPH1 with the L125P or Y112C mutation into MCF7 cells, and showed that ADP-ribosylation of EEF2 (130610) was defective. Urreizti et al. (2020) tested ADP-ribosylation of EEF2 with plasmids containing previously reported DPH1 mutations, including L234P (603527.0001), M6K (603527.0002), P382S, S221P, Ala411ArgfsTer91, and L164P. Reduced ADP-ribosylation compared to wildtype was observed for all but 2 of the mutations, M6K and P382S. Urreizti et al. (2020) noted that the M6K and P382S mutations may correspond to milder patient phenotypes, but could not rule out the possibility that these variants are not pathogenic.
In 4 affected individuals from a consanguineous Saudi family (family 10DG0934) with developmental delay with short stature, dysmorphic facial features, and sparse hair-1 (DEDSSH1; 616901), Alazami et al. (2015) identified a homozygous c.701T-C transition (c.701T-C, NM_001383.3) in the DPH1 gene, resulting in a leu234-to-pro (L234P) substitution. The family was part of a large cohort of 143 multiplex consanguineous families with various neurodevelopmental disorders who underwent whole-exome sequencing. Functional studies of the variant were not performed.
Urreizti et al. (2020) tested ADP-ribosylation of EEF2 with plasmids containing the L234P mutation and found reduced ADP-ribosylation compared to wildtype.
In 4 patients from a North American genetic isolate with developmental delay with short stature, dysmorphic facial features, and sparse hair-1 (DEDSSH1; 616901), Loucks et al. (2015) identified a homozygous c.17T-A transversion (c.17T-A, NM_001383.3) in the DPH1 gene, resulting in a met6-to-lys (M6K) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, was absent from the dbSNP, 1000 Genomes Project, Exome Variant Server, and ExAC databases. The carrier frequency of the variant was 0.46% in the genetic isolate, consistent with a founder effect. Functional studies of the variant and studies of patient cells were not performed.
Urreizti et al. (2020) tested ADP-ribosylation of EEF2 with plasmids containing the M6K mutation and found that ADP-ribosylation was similar to that of wildtype. The authors suggested that the M6K mutation may correspond to a milder phenotype, but could not rule out the possibility that the variant is not pathogenic.
In a Japanese patient with developmental delay with short stature, dysmorphic facial features, and sparse hair-1 (DEDSSH1; 616901), Nakajima et al. (2018) identified compound heterozygous mutations in the DPH1 gene: a c.491T-C transition (c.491T-C, NM_001383.3) in exon 5, resulting in a leu164-to-pro (L164P) substitution at a conserved residue in the diphthamide synthesis domain, and a 1-bp deletion (c.289delG; 603527.0004) in exon 3, predicted to result in a frameshift and premature termination (Glu97LysfsTer8). The c.289delG mutation was predicted to result in nonsense mediated decay. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The parents were confirmed to be mutation carriers.
For description of the 1-bp deletion (c.289delG, NM_001383.3) in the DPH1 gene that was found in compound heterozygous state in a patient with developmental delay with short stature, dysmorphic facial features, and sparse hair-1 (DEDSSH1; 616901) by Nakajima et al. (2018), see 603527.0003.
In 2 Maltese sibs with developmental delay with short stature, dysmorphic facial features, and sparse hair-1 (DEDSSH1; 616901), Urreizti et al. (2020) identified a homozygous c.374T-C transition (c.374T-C, NM_001383.4) in the DPH1 gene, resulting in a leu125-to-pro (L125P) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing, was present in heterozygous state in the parents. Urreizti et al. (2020) transfected a plasmid containing DPH1 with the L125P mutation into MCF7 cells, and showed that ADP-ribosylation of EEF2 was defective. Molecular modeling suggested that the L125P mutation might affect DPH1-DPH2 interactions.
In 2 Bedouin Yemeni sibs, born of consanguineous parents, with developmental delay with short stature, dysmorphic facial features, and sparse hair-1 (DEDSSH1; 616901), Urreizti et al. (2020) identified a homozygous c.335A-G transition (c.335A-G, NM_001383.4) in the DPH1 gene, resulting in a tyr112-to-cys (Y112C) substitution at a conserved residue. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The father was a carrier of the mutation; the status of the mother was not reported. Urreizti et al. (2020) transfected a plasmid containing DPH1 with the Y112C mutation into MCF7 cells, and showed that ADP-ribosylation of EEF2 was defective. Molecular modeling suggested that the mutation could affect the insertion of the iron-sulfur cluster into the proper location in the protein.
Alazami, A. M., Patel, N., Shamseldin, H. E., Anazi, S., Al-Dosari, M. S., Alzahrani, F., Hijazi, H., Alshammari, M., Aldahmesh, M. A., Salih, M. A., Faqeih, E., Alhashem, A., and 41 others. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 10: 148-161, 2015. [PubMed: 25558065] [Full Text: https://doi.org/10.1016/j.celrep.2014.12.015]
Carette, J. E., Guimaraes, C. P., Varadarajan, M., Park, A. S., Wuethrich, I., Godarova, A., Kotecki, M., Cochran, B. H., Spooner, E., Ploegh, H. L., Brummelkamp, T. R. Haploid genetic screens in human cells identify host factors used by pathogens. Science 326: 1231-1235, 2009. [PubMed: 19965467] [Full Text: https://doi.org/10.1126/science.1178955]
Liu, S., Milne, G. T., Kuremsky, J. G., Fink, G. R., Leppla, S. H. Identification of the proteins required for biosynthesis of diphthamide, the target of bacterial ADP-ribosylating toxins on translation elongation factor 2. Molec. Cell. Biol. 24: 9487-9497, 2004. [PubMed: 15485916] [Full Text: https://doi.org/10.1128/MCB.24.21.9487-9497.2004]
Loucks, C. M., Parboosingh, J. S., Shaheen, R., Bernier, F. P., McLeod, D. R., Seidahmed, M. Z., Puffenberger, E. G., Ober, C., Hegele, R. A., Boycott, K. M., Alkuraya, F. S., Innes, A. M. Matching two independent cohorts validates DPH1 as a gene responsible for autosomal recessive intellectual disability with short stature, craniofacial, and ectodermal anomalies. Hum. Mutat. 36: 1015-1019, 2015. [PubMed: 26220823] [Full Text: https://doi.org/10.1002/humu.22843]
Nakajima, J., Oana, S., Sakaguchi, T., Nakashima, M., Numabe, H., Kawashima, H., Matsumoto, N., Miyake, N. Novel compound heterozygous DPH1 mutations in a patient with the unique clinical features of airway obstruction and external genital abnormalities. J. Hum. Genet. 63: 529-532, 2018. [PubMed: 29362492] [Full Text: https://doi.org/10.1038/s10038-017-0399-2]
Phillips, N. J., Zeigler, M. R., Deaven, L. L. A cDNA from the ovarian cancer critical region of deletion on chromosome 17p13.3. Cancer Lett. 102: 85-90, 1996. [PubMed: 8603384] [Full Text: https://doi.org/10.1016/0304-3835(96)04169-9]
Schultz, D. C., Vanderveer, L., Berman, D. B., Hamilton, T. C., Wong, A. J., Godwin, A. K. Identification of two candidate tumor suppressor genes on chromosome 17p13.3. Cancer Res. 56: 1997-2002, 1996. [PubMed: 8616839]
Urreizti, R., Mayer, K., Evrony, G. D., Said, E., Castilla-Vallmanya, L., Cody, N. A. L., Plascencia, G., Gelb, B. D., Grinberg, D., Brinkmann, U., Webb, B. D., Balcells, S. DPH1 syndrome: two novel variants and structural and functional analyses of seven missense variants identified in syndromic patients. Europ. J. Hum. Genet. 28: 64-75, 2020. Note: Erratum: Europ. J. Hum. Genet. 28: 138 only, 2020. [PubMed: 30877278] [Full Text: https://doi.org/10.1038/s41431-019-0374-9]