Alternative titles; symbols
HGNC Approved Gene Symbol: DPM1
SNOMEDCT: 725078006;
Cytogenetic location: 20q13.13 Genomic coordinates (GRCh38): 20:50,934,855-50,958,564 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.13 | Congenital disorder of glycosylation, type Ie | 608799 | Autosomal recessive | 3 |
The DPM1 gene encodes the cytoplasmic catalytic subunit of dolichol-phosphate-mannose synthase (EC 2.4.1.83), an enzyme complex that synthesizes dolichol-phosphate-mannose (Dol-P-Man) from GDP-mannose and dolichol-phosphate. DPM2 (603564) and DPM3 (605951) are integral endoplasmic reticulum membrane proteins that stabilize the complex. Dol-P-Man serves as a donor of mannosyl residues in various eukaryotic glycosylation processes, including N-glycosylation of asparagine residues and O-mannosylation of alpha-dystroglycan (DAG1; 128239) (summary by Garcia-Silva et al., 2004 and Yang et al., 2013).
The S. cerevisiae dpm1 gene encodes a Dol-P-Man synthase that is a transmembrane protein expressed in the endoplasmic reticulum. By searching an EST database for homologs of yeast dpm1, Tomita et al. (1998) identified human and mouse DPM1 cDNAs. The predicted 260-amino acid human protein shares approximately 30% identity with yeast dpm1. However, DPM1 lacks the C-terminal transmembrane domain found in dpm1 and does not contain a signal sequence.
Independently, Colussi et al. (1997) cloned human, rat, nematode, and S. pombe DPM1 cDNAs. They reported that the predicted human and rat proteins are 93% identical. Sequence analysis indicated that the human, S. pombe, and nematode DPM1 proteins lack the hydrophobic C-terminal domain found in S. cerevisiae dpm1. However, both human and S. cerevisiae DPM1 complemented the lethal S. pombe dpm1+ mutation.
Mouse Thy1 (188230)-negative thymoma mutant cells of complementation class E do not synthesize Dol-P-Man and consequently do not synthesize the glycosylphosphatidylinositol (GPI) core, resulting in the defective surface expression of GPI-anchored proteins, such as Thy1. Tomita et al. (1998) found that expression of DPM1 in class E mutant mouse cells completely restored surface expression of Thy1, and sequence analysis revealed that the mutant cells have an inactivating mutation in the murine Dpm1 gene. However, the mammalian DPM1 cDNAs did not complement another Dol-P-Man synthesis mutant, hamster Lec15 cells, whereas yeast dpm1 restored both class E and Lec15 cells. Tomita et al. (1998) concluded that mammalian cells require DPM1 and an additional protein for synthesis of Dol-P-Man. See DPM2 (603564).
Maeda et al. (2000) purified human Dol-P-Man synthase and demonstrated that the enzyme is a protein complex with 3 subunits, DPM1, DPM2, and DPM3 (605951). They concluded that DPM1 is stabilized by an association with the C-terminal domain of DPM3, which is stabilized by an association with DPM2.
In 2 unrelated patients with congenital disorder of glycosylation Ie (608799), Kim et al. (2000) identified mutations in the DPM1 gene (603503.0001; 603503.0002).
In 2 sibs with CDG Ie, Imbach et al. (2000) identified compound heterozygosity for 2 mutations in the DPM1 gene (603503.0001; 603503.0003).
Garcia-Silva et al. (2004) identified a homozygous missense mutation in the DPM1 gene (603503.0004) in a girl with a relatively mild form of CDG Ie.
In 2 sibs, born of consanguineous Algerian parents, with CDG Ie, Dancourt et al. (2006) identified a homozygous splice site mutation in the DPM1 gene (603503.0005). Each unaffected parent was heterozygous for the mutation. Patient cells showed only 8% residual enzyme activity and a more than 90% reduction in DPM1 transcript levels.
In a boy with CDG type Ie, Yang et al. (2013) identified compound heterozygous mutations in the DPM1 gene (603503.0006-603503.0007).
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human DPM1 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a patient with congenital disorder of glycosylation type Ie (CDG1E; 608799), Kim et al. (2000) identified a homozygous 274C-G transversion in the DPM1 gene, resulting in an arg92-to-gly (R92G) substitution. Another unrelated patient was compound heterozygous for the R92G mutation and a 13-bp deletion (603503.0002).
In a brother and sister, Imbach et al. (2000) described features of a congenital disorder of glycosylation due to compound heterozygosity for the R92G mutation and a 628C deletion (603503.0003).
In an infant with congenital disorder of glycosylation type Ie (CDG1E; 608799), Kim et al. (2000) found compound heterozygosity for the R92G mutation (603503.0001) and a 13-bp deletion in exon 4 resulting in loss of nucleotides 331-343 at the cDNA level. The predicted translated product resulting from the deletion encodes the first 110 amino acids of the 260-amino acid protein followed by 44 random amino acids.
In a brother and sister with congenital disorder of glycosylation type Ie (CDG1E; 608799), Imbach et al. (2000) identified compound heterozygosity for 2 mutations in the DPM1 gene: a 1-bp deletion (628C) and R92G (603503.0001). These mutations were found in heterozygous state in the mother and father, respectively. The deletion resulted in the premature stop of the translation at position 640 (codon 213).
In a 9-year-old girl, born of consanguineous parents, with congenital disorder of glycosylation type Ie (CDG1E; 608799), Garcia-Silva et al. (2004) identified a homozygous c.742T-C transition in exon 9 of the DPM1 gene, resulting in a ser248-to-pro (S248P) substitution at a partially conserved residue. Functional studies of the variant were not performed.
In 2 sibs, born of consanguineous Algerian parents, with congenital disorder of glycosylation type Ie (CDG1E; 608799), Dancourt et al. (2006) identified a homozygous T-to-A transversion in intron 4 of the DPM1 gene, resulting in the skipping of exon 5 and premature termination. Each unaffected parent was heterozygous for the mutation. Patient cells showed only 8% residual enzyme activity and a more than 90% reduction in DPM1 transcript levels, although some normal transcripts were produced, suggesting that the exon skipping is leaky and that patient cells may retain some residual activity. In addition, levels of DPM2 (603564) were decreased by 42%. The sibs had severely delayed psychomotor development, acquired microcephaly, hypotonia, cerebellar ataxia, tremor, and nystagmus; dysmorphic features and severe epilepsy were not present.
In a boy with congenital disorder of glycosylation type Ie (CDG1E; 608799), Yang et al. (2013) identified compound heterozygous mutations in the DPM1 gene: a c.455G-T transversion, resulting in a gly152-to-val (G152V) substitution at a highly conserved residue, and a 100-kb intragenic deletion spanning exons 3 to 7 (603503.0007). The G152V variant was inherited from the unaffected father. Neither variant was found in the dbSNP or Exome Sequencing Project databases. Patient fibroblast membranes showed an 80% deficiency in DPM1 activity compared to wildtype with a decrease in Vmax. Transfection of the mutation into HEK293 cells showed that the mutant protein was unable to associate with DPM3 (605951). The child had a combined defect of N-glycosylation and O-mannosylation, and showed delayed psychomotor development, seizures, and liver abnormalities as well as muscular dystrophy similar to a dystroglycanopathy (see, e.g., 236670).
For discussion of the 100-kb deletion in the DPM1 gene that was found in a patient with congenital disorder of glycosylation type Ie (CDG1E; 608799) by Yang et al. (2013), see 603503.0006. This intragenic deletion would result in a 302-bp deletion in the transcript.
Colussi, P. A., Taron, C. H., Mack, J. C., Orlean, P. Human and Saccharomyces cerevisiae dolichol phosphate mannose synthases represent two classes of the enzyme, but both function in Schizosaccharomyces pombe. Proc. Nat. Acad. Sci. 94: 7873-7878, 1997. [PubMed: 9223280] [Full Text: https://doi.org/10.1073/pnas.94.15.7873]
Dancourt, J., Vuillaumier-Barrot, S., de Baulny, H. O., Sfaello, I., Barnier, A., le Bizec, C., Dupre, T., Durand, G., Seta, N., Moore, S. E. H. A new intronic mutation in the DPM1 gene is associated with a milder form of CDG Ie in two French siblings. Pediat. Res. 59: 835-839, 2006. [PubMed: 16641202] [Full Text: https://doi.org/10.1203/01.pdr.0000219430.52532.8e]
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Garcia-Silva, M. T., Matthijs, G., Schollen, E., Cabrera, J. C., Sanchez del Pozo, J., Marti Herreros, M., Simon, R., Maties, M., Martin Hernandez, E., Hennet, T., Briones, P. Congenital disorder of glycosylation (CDG) type Ie: a new patient. J. Inherit. Metab. Dis. 27: 591-600, 2004. [PubMed: 15669674] [Full Text: https://doi.org/10.1023/b:boli.0000042984.42433.d8]
Imbach, T., Schenk, B., Schollen, E., Burda, P., Stutz, A., Grunewald, S., Bailie, N. M., King, M. D., Jaeken, J., Matthijs, G., Berger, E. G., Aebi, M., Hennet, T. Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie. J. Clin. Invest. 105: 233-239, 2000. [PubMed: 10642602] [Full Text: https://doi.org/10.1172/JCI8691]
Kim, S., Westphal, V., Srikrishna, G., Mehta, D. P., Peterson, S., Filiano, J., Karnes, P. S., Patterson, M. C., Freeze, H. H. Dolichol phosphate mannose synthase (DPM1) mutations define congenital disorder of glycosylation Ie (CDG-Ie). J. Clin. Invest. 105: 191-198, 2000. [PubMed: 10642597] [Full Text: https://doi.org/10.1172/JCI7302]
Maeda, Y., Tanaka, S., Hino, J., Kangawa, K., Kinoshita, T. Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3. EMBO J. 19: 2475-2482, 2000. [PubMed: 10835346] [Full Text: https://doi.org/10.1093/emboj/19.11.2475]
Tomita, S., Inoue, N., Maeda, Y., Ohishi, K., Takeda, J., Kinoshita, T. A homologue of Saccharomyces cerevisiae Dpm1p is not sufficient for synthesis of dolichol-phosphate-mannose in mammalian cells. J. Biol. Chem. 273: 9249-9254, 1998. [PubMed: 9535917] [Full Text: https://doi.org/10.1074/jbc.273.15.9249]
Yang, A. C., Ng, B. G., Moore, S. A., Rush, J., Waechter, C. J., Raymond, K. M., Willer, T., Campbell, K. P., Freeze, H. H., Mehta, L. Congenital disorder of glycosylation due to DPM1 mutations presenting with dystroglycanopathy-type congenital muscular dystrophy. Molec. Genet. Metab. 110: 345-351, 2013. [PubMed: 23856421] [Full Text: https://doi.org/10.1016/j.ymgme.2013.06.016]