Alternative titles; symbols
HGNC Approved Gene Symbol: DPM2
SNOMEDCT: 782772000;
Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38) : 9:127,935,099-127,937,854 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.11 | Congenital disorder of glycosylation, type Iu | 615042 | Autosomal recessive | 3 |
The DPM2 gene encodes dolichyl-phosphate mannosyltransferase-2, a regulatory subunit of the heterotrimeric dolichol-phosphate-mannose synthase complex (summary by Barone et al., 2012). Dolichol-phosphate mannose (Dol-P-Man) acts as a donor for mannosylation reactions occurring on the luminal side of the endoplasmic reticulum (ER). Dol-P-Man is synthesized from GDP-mannose and dolichol-phosphate on the cytosolic side of the ER by the enzyme Dol-P-Man synthase (EC 2.4.1.83) (Maeda et al., 1998).
Mouse Thy1 (188230)-negative lymphoma mutant cells of complementation class E and Chinese hamster ovary (CHO) Lec15 mutant cells are defective in Dol-P-Man synthesis. Consequently, they do not synthesize glycosylphosphatidylinositol (GPI), whose biosynthesis is dependent on Dol-P-Man, resulting in the defective surface expression of GPI-anchored proteins such as Thy1. The human Dol-P-Man synthase-1 (DPM1; 603503) gene is responsible for the defect of class E cells, but it does not complement the defective Dol-P-Man synthesis in Lec15 cells, indicating that DPM1 is not sufficient for Dol-P-Man synthesis. Maeda et al. (1998) used expression cloning to isolate rat cDNAs that restored GPI anchor synthesis in Lec15 cells. The cDNAs corresponded to a gene that the authors designated Dpm2. By searching an EST database for homologs of rat Dpm2, they identified cDNAs encoding human and mouse DPM2. The deduced 84-amino acid human protein shares 88% sequence identity with rat Dpm2. DPM2 is a hydrophobic protein that contains 2 predicted transmembrane domains and a putative ER localization signal near the C terminus. Cell fractionation and immunofluorescence studies indicated that DPM2 is expressed in the ER membrane.
Maeda et al. (1998) found that DPM2 associates with DPM1 in vivo and is required for the ER localization and stable expression of DPM1. A lack of ER localization of DPM1 coincided with lowered DPM1 expression in Lec15 cells, suggesting that DPM2-dependent localization of DPM1 to the ER is important for its stability. DPM2 also enhances the binding of dolichol-phosphate to DPM1. Maeda et al. (1998) concluded that the biosynthesis of Dol-P-Man in mammalian cells is regulated by DPM2.
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 DPM2 associates with the N-terminal domain of DPM3 and that this interaction stabilizes DPM3; DPM3, in turn, stabilizes DPM1. Using DPM2-deficient cells, Maeda et al. (2000) demonstrated that DPM2 is not essential for Dol-P-Man synthase activity; however, the presence of DPM2 significantly increases the specific enzymatic activity.
In 3 patients from 2 unrelated Sicilian families with congenital disorder of glycosylation type Iu (CDG1U; 615042), Barone et al. (2012) identified homozygous or compound heterozygous mutations in the DPM2 gene (603564.0001 and 603564.0002). DPM synthase activity was severely decreased in patient fibroblasts. The patients had a severe neurologic phenotype with lack of psychomotor development and death in the first years of life.
In a 23-year-old man with CDG1U, Radenkovic et al. (2021) identified compound heterozygous mutations in the DPM2 gene (603564.0003 and 603564.0004). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. Each parent was a carrier of one of the mutations. Patient fibroblasts had reduced DPM2 protein expression compared to controls, as well as decreased DPM1 expression, which is dependent on normal DPM2 and DPM3 expression. Radenkovic et al. (2021) also identified a significant decrease of ICAM1 (147840) protein expression, which suggested abnormal N-linked glycosylation. LAMP2 (309060) expression was also reduced, which was consistent with glycosylation abnormalities. Glycomics analysis in patient fibroblasts was consistent with a CDG type I profile.
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 DPM2 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In 2 brothers, born of consanguineous Sicilian parents, with congenital disorder of glycosylation type Iu (CDG1U; 615042), Barone et al. (2012) identified a homozygous 68A-G transition in exon 1 of the DPM2 gene, resulting in a tyr23-to-cys (Y23C) substitution at a highly conserved residue encoding a transmembrane domain. The mutation was not found in more than 1,600 control exomes. An unrelated patient, also of Sicilian origin, with a similar disorder was compound heterozygous for Y23C and a G-to-C transversion in intron 1 of the DPM2 gene (c.4-1G-C; 603564.0002), resulting in the skipping of exon 2. The brothers were originally reported by Messina et al. (2009).
For discussion of the splice site mutation (c.4-1G-C) in the DPM2 gene that was found in compound heterozygous state in a Sicilian patient with congenital disorder of glycosylation type Iu (CDG1U; 615042) by Barone et al. (2012), see 603564.0001.
In a 23-year-old man with congenital disorder of glycosylation type Iu (CDG1U; 615042), Radenkovic et al. (2021) identified compound heterozygous mutations in the DPM2 gene, a c.139C-T transition resulting in an arg47-to-ter (R47X) substitution and a c.173G-A transition resulting in a gly58-to-asp (G58D; 603564.0004) substitution. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The parents were confirmed to be mutation carriers. Neither mutation was reported in available SNP databases. Patient fibroblasts had reduced DPM2 protein expression compared to controls.
For discussion of the c.173G-A transition in the DPM2 gene, resulting in a gly58-to-asp (G58D) substitution, that was found in compound heterozygous state in a patient with congenital disorder of glycosylation type Iu (CDG1U; 615042) by Radenkovic et al. (2021), see 603564.0003.
Barone, R., Aiello, C., Race, V., Morava, E., Foulquier, F., Riemersma, M., Passarelli, C., Concolino, D., Carella, M., Santorelli, F., Vleugels, W., Mercuri, E., and 9 others. DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy. Ann. Neurol. 72: 550-558, 2012. [PubMed: 23109149] [Full Text: https://doi.org/10.1002/ana.23632]
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]
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]
Maeda, Y., Tomita, S., Watanabe, R., Ohishi, K., Kinoshita, T. DPM2 regulates biosynthesis of dolichol phosphate-mannose in mammalian cells: correct subcellular localization and stabilization of DPM1, and binding of dolichol phosphate. EMBO J. 17: 4920-4929, 1998. [PubMed: 9724629] [Full Text: https://doi.org/10.1093/emboj/17.17.4920]
Messina, S., Tortorella, G., Concolino, D., Spano, M., D'Amico, A., Bruno, C., Santorelli, F. M., Mercuri, E., Bertini, E. Congenital muscular dystrophy with defective alpha-dystroglycan, cerebellar hypoplasia, and epilepsy. Neurology 73: 1599-1601, 2009. [PubMed: 19901254] [Full Text: https://doi.org/10.1212/WNL.0b013e3181c0d47a]
Radenkovic, S., Fitzpatrick-Schmidt, T., Byeon S. K., Madugundu, A. K., Saraswat, M., Lichty, A., Wong, S. Y. W., McGee, S., Kubiak, K., Ligezka, A., Ranatunga, W., Zhang, Y., Wood, T., Friez, M. J., Clarkson, K., Pandey, A., Jones, J. R., Morava, E. Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation. Molec. Genet. Metab. 132: 27-37, 2021. [PubMed: 33129689] [Full Text: https://doi.org/10.1016/j.ymgme.2020.10.007]