* 603564

DOLICHYL-PHOSPHATE MANNOSYLTRANSFERASE 2, REGULATORY SUBUNIT; DPM2


Alternative titles; symbols

DOLICHOL-PHOSPHATE MANNOSYLTRANSFERASE 2
DOLICHOL-PHOSPHATE MANNOSE SYNTHASE 2


HGNC Approved Gene Symbol: DPM2

Cytogenetic location: 9q34.11     Genomic coordinates (GRCh38): 9:127,935,099-127,937,854 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
9q34.11 Congenital disorder of glycosylation, type Iu 615042 AR 3

TEXT

Description

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).


Cloning and Expression

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.


Gene Function

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.


Molecular Genetics

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.


Animal Model

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).


ALLELIC VARIANTS ( 4 Selected Examples):

.0001 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iu

DPM2, TYR23CYS
  
RCV000032641

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).


.0002 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iu

DPM2, IVS1AS, G-C, -1
  
RCV000032642

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.


.0003 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iu

DPM2, ARG47TER
  
RCV001375849

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.


.0004 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iu

DPM2, GLY58ASP
  
RCV001375850

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.


REFERENCES

  1. 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, related citations] [Full Text]

  2. 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, related citations] [Full Text]

  3. 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, images, related citations] [Full Text]

  4. 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, related citations] [Full Text]

  5. 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, related citations] [Full Text]

  6. 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, related citations] [Full Text]


Hilary J. Vernon - updated : 04/28/2021
Ada Hamosh - updated : 02/16/2017
Cassandra L. Kniffin - updated : 1/29/2013
Dawn Watkins-Chow - updated : 5/18/2001
Creation Date:
Rebekah S. Rasooly : 2/19/1999
carol : 04/29/2021
carol : 04/28/2021
carol : 02/26/2021
carol : 02/01/2018
alopez : 02/16/2017
carol : 09/18/2015
mcolton : 8/18/2015
carol : 9/18/2013
tpirozzi : 9/18/2013
tpirozzi : 9/17/2013
carol : 1/29/2013
ckniffin : 1/29/2013
terry : 7/26/2006
mgross : 5/21/2001
terry : 5/18/2001
psherman : 2/24/1999
psherman : 2/24/1999
psherman : 2/19/1999

* 603564

DOLICHYL-PHOSPHATE MANNOSYLTRANSFERASE 2, REGULATORY SUBUNIT; DPM2


Alternative titles; symbols

DOLICHOL-PHOSPHATE MANNOSYLTRANSFERASE 2
DOLICHOL-PHOSPHATE MANNOSE SYNTHASE 2


HGNC Approved Gene Symbol: DPM2

SNOMEDCT: 782772000;  


Cytogenetic location: 9q34.11     Genomic coordinates (GRCh38): 9:127,935,099-127,937,854 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
9q34.11 Congenital disorder of glycosylation, type Iu 615042 Autosomal recessive 3

TEXT

Description

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).


Cloning and Expression

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.


Gene Function

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.


Molecular Genetics

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.


Animal Model

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).


ALLELIC VARIANTS 4 Selected Examples):

.0001   CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iu

DPM2, TYR23CYS
SNP: rs397514503, gnomAD: rs397514503, ClinVar: RCV000032641

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).


.0002   CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iu

DPM2, IVS1AS, G-C, -1
SNP: rs797044467, ClinVar: RCV000032642

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.


.0003   CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iu

DPM2, ARG47TER
SNP: rs549450795, gnomAD: rs549450795, ClinVar: RCV001375849

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.


.0004   CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iu

DPM2, GLY58ASP
SNP: rs1185338798, gnomAD: rs1185338798, ClinVar: RCV001375850

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.


REFERENCES

  1. 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]

  2. 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]

  3. 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]

  4. 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]

  5. 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]

  6. 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]


Contributors:
Hilary J. Vernon - updated : 04/28/2021
Ada Hamosh - updated : 02/16/2017
Cassandra L. Kniffin - updated : 1/29/2013
Dawn Watkins-Chow - updated : 5/18/2001

Creation Date:
Rebekah S. Rasooly : 2/19/1999

Edit History:
carol : 04/29/2021
carol : 04/28/2021
carol : 02/26/2021
carol : 02/01/2018
alopez : 02/16/2017
carol : 09/18/2015
mcolton : 8/18/2015
carol : 9/18/2013
tpirozzi : 9/18/2013
tpirozzi : 9/17/2013
carol : 1/29/2013
ckniffin : 1/29/2013
terry : 7/26/2006
mgross : 5/21/2001
terry : 5/18/2001
psherman : 2/24/1999
psherman : 2/24/1999
psherman : 2/19/1999