Alternative titles; symbols
HGNC Approved Gene Symbol: DPM3
SNOMEDCT: 725044000;
Cytogenetic location: 1q22 Genomic coordinates (GRCh38) : 1:155,139,891-155,140,531 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q22 | ?Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 15 | 618992 | Autosomal recessive | 3 |
| Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15 | 612937 | Autosomal recessive | 3 |
Dolichol-phosphate-mannose is a mannosyl donor important for the biosynthesis of various glycoconjugates (see DPM1, 603503).
Using tagged DPM1 protein, Maeda et al. (2000) purified a protein complex with human DPM synthase activity. The complex contained DPM1, DPM2 (603564), and a novel protein, DPM3. Using peptide sequencing and database searches, the authors identified a cDNA encoding DPM3. The predicted 92-amino acid DPM3 protein contains 2 putative N-terminal transmembrane domains and a hydrophilic C-terminal portion. It shares 25%, 31%, and 97% amino acid identity with the C. elegans, S. pombe, and rat Dpm3 proteins, respectively. By fractionation of transfected cells, Maeda et al. (2000) determined that DPM3 is a membrane protein in the endoplasmic reticulum (ER). Using DPM2 mutant cells, they demonstrated that the ER localization of DPM3 is independent of DPM2.
Maeda et al. (2000) identified an STS within the DPM3 gene that maps to 1q12-q21.
Gross (2018) mapped the DPM3 gene to chromosome 1q22 based on an alignment of the DPM3 sequence (GenBank AF312922) with the genomic sequence (GRCh38).
Using coprecipitation experiments with full-length and truncated DPM3, Maeda et al. (2000) found that DPM2 associates with the N-terminal region of DPM3 and that DPM1 associates with the C-terminal domain of DPM3. DPM1 expression increased following transient overexpression of DPM3 in the absence of DPM2, suggesting that DPM3 directly stabilizes DPM1. Using cotransfection experiments, Maeda et al. (2000) showed that the stability of DPM3 is dependent upon DPM2.
Mutation in the DPM3 gene can cause 2 different forms of muscular dystrophy-dystroglycanopathy (MDDG): a congenital form with impaired intellectual development (type B15; MDDGB15; 618992), and a limb-girdle form (type C15; MDDGC15; 612937).
In a Greek female patient with MDDGC15, Lefeber et al. (2009) identified a homozygous mutation in the DPM3 gene (L85S; 605951.0001). The patient had mild myopathic features and cardiomyopathy. Biochemical studies showed defective O-mannosylation.
In a woman with MDDGC15, Van den Bergh et al. (2017) identified a homozygous missense mutation in the DPM3 gene (L44P; 605951.0002). The mutation, which was found by exome sequencing, segregated with the disorder in the family. DPM synthase activity in patient fibroblasts was reduced by 50% compared to controls.
In 2 unrelated male patients with MDDGC15, Svahn et al. (2019) identified compound heterozygous mutations in the DPM3 gene: the previously identified L44P mutation, which they designated L14P, and a deletion affecting the DPM3 gene. The deletion was predicted to contain at least the region between the first intron and the 3-prime UTR. However, the breakpoints were not exactly defined and it was possible that other genes besides DPM3 were affected. The mutation and deletion were found by next-generation sequencing of targeted genes and confirmed by Sanger sequencing or RT-PCR analysis. The L14P mutation was found in the unaffected father of patient 1; DNA from the mother of patient 1 and the parents of patient 2 were not available for study.
In an 8-year-old Chinese girl with MCCGB15, Fu et al. (2019) identified compound heterozygous mutations in the DPM3 gene (P42A, 605951.0003 and L85X, 605951.0004). The mutations, which were found by next-generation sequencing of a targeted gene panel, segregated with the disorder in the family. Immunoblotting of patient muscle showed significantly decreased levels of alpha-dystroglycan. N-glycosylation studies and functional studies of the variants were not performed.
In a Greek woman with limb-girdle muscular dystrophy-dystroglycanopathy type C15 (MDDGC15; 612937), Lefeber et al. (2009) identified a homozygous c.254T-C transition in the DPM3 gene, resulting in a leu85-to-ser (L85S) substitution at a highly conserved residue in the coiled-coil domain. In vitro studies showed that the mutant protein had no functional enzyme activity and had reduced DPM1 (603503)-binding capacity. The authors noted that 4 biosynthetic pathways depend on DPM activity, including O-mannosylation of alpha-dystroglycan (DAG1; 128239), and postulated that the isolated phenotype of muscular dystrophy in this patient most likely resulted from deficient O-mannosylation of DAG1. These findings linked the congenital disorders of glycosylation to the dystroglycanopathies.
In a woman with adult-onset limb-girdle muscular dystrophy-dystroglycanopathy type C15 (MDDGC15; 612937), Van den Bergh et al. (2017) identified a homozygous c.131T-C transition in the DPM3 gene, resulting in a leu44-to-pro (L44P) substitution at a highly conserved residue. The mutation, which was found by exome sequencing, segregated with the disorder in the family. It was found at a low frequency in heterozygous state (0.00084) in the control population. DPM synthase activity in patient fibroblasts was reduced by 50% compared to controls.
In 2 unrelated male patients with MDDGC15, Svahn et al. (2019) identified compound heterozygous mutations in the DPM3 gene: a c.41T-C transition in exon 2, resulting in a leu14-to-pro (L14P) substitution, and a deletion affecting the DPM3 gene. L14P is the same as the L44P mutation described by Van den Bergh et al. (2017). The deletion was predicted to contain at least the region between the first intron and the 3-prime UTR. However, the breakpoints were not exactly defined and it was possible that other genes besides DPM3 were affected. The mutation and deletion were found by next-generation sequencing of targeted genes and confirmed by Sanger sequencing or RT-PCR analysis. The L14P mutation was found in the unaffected father of patient 1; DNA from the mother of patient 1 and the parents of patient 2 were not available for study.
In an 8-year-old Chinese girl with congenital muscular dystrophy-dystroglycanopathy with impaired intellectual development type B15 (MDDGB15; 618992), Fu et al. (2019) identified compound heterozygous mutations in the DPM3 gene: a c.124C-G transversion (c.124C-G, NM_153471), resulting in a pro42-to-ala (P42A) substitution, and a c.254T-A transversion, resulting in a leu85-to-ter (L85X; 605951.0004) substitution. The mutations, which were found by next-generation sequencing of a targeted gene panel, segregated with the disorder in the family. Immunoblotting of patient muscle showed significantly decreased levels of alpha-dystroglycan. N-glycosylation studies and functional studies of the variants were not performed.
For discussion of the c.254T-A transversion (c.254T-A, NM_153471) in the DPM3 gene, resulting in a leu85-to-ter (L85X) substitution, that was found in compound heterozygous state in a patient with congenital muscular dystrophy-dystroglycanopathy with impaired intellectual development type B15 (MDDGB15; 618992) by Fu et al. (2019), see 605951.0003.
Fu, J., Ma, M., Song, J., Pang, M., Yang, L., Li, G., Zhang, J. Novel mutations in DPM3 cause dystroglycanopathy with central nervous system involvement. (Letter) Clin. Genet. 96: 590-591, 2019. [PubMed: 31469168] [Full Text: https://doi.org/10.1111/cge.13634]
Gross, M. B. Personal Communication. Baltimore, Md. 10/9/2018.
Lefeber, D. J., Schonberger, J., Morava, E., Guillard, M., Huyben, K. M., Verrijp, J., Grafakou, O., Evangeliou, A., Preijers, F. W., Manta, P., Yildiz, J., Grunewald, S., and 11 others. Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies. Am. J. Hum. Genet. 85: 76-86, 2009. [PubMed: 19576565] [Full Text: https://doi.org/10.1016/j.ajhg.2009.06.006]
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]
Svahn, J., Laforet, P., Vial, C., Streichenberger, N., Romero, N., Bouchet-Seraphin, C., Bruneel, A., Dupre, T., Seta, N., Menassa, R., Michel-Calemard, L., Stojkovic, T. Dilated cardiomyopathy and limb-girdle muscular dystrophy-dystroglycanopathy due to novel pathogenic variants in the DPM3 gene. Neuromusc. Disord. 29: 497-502, 2019. [PubMed: 31266720] [Full Text: https://doi.org/10.1016/j.nmd.2019.05.004]
Van den Bergh, P. Y. K., Sznajer, Y., Van Parys, V., van Tol, W., Wevers, R. A., Lefeber, D. J., Xu, L., Lek, M., MacArthur, D. G., Johnson, K., Phillips, L., Topf, A., Straub, V. A homozygous DPM3 mutation in a patient with alpha-dystroglycan-related limb girdle muscular dystrophy. Neuromusc. Disord. 27: 1043-1046, 2017. Note: Erratum: Neuromusc. Disord. 28: 101 only, 2018. [PubMed: 28803818] [Full Text: https://doi.org/10.1016/j.nmd.2017.07.006]