Reviewed, UniProtKB/Swiss-Prot O15305 (PMM2_HUMAN)

Names and origin

Protein names

Recommended name:
    Phosphomannomutase 2
      Short name=PMM 2
    EC=5.4.2.8

Gene names

Name:

PMM2

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	246 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions By similarity.
Catalytic activity	Alpha-D-mannose 1-phosphate = D-mannose 6-phosphate.
Pathway	Nucleotide-sugar biosynthesis; GDP-D-mannose biosynthesis; alpha-D-mannose 1-phosphate from D-fructose 6-phosphate: step 2/2.
Subcellular location	Cytoplasm.
Involvement in disease	Defects in PMM2 are the cause of congenital disorder of glycosylation type 1A (CDG1A) [MIM:212065]; also known as carbohydrate-deficient glycoprotein syndrome type Ia (CDGS1A) or Jaeken syndrome. Congenital disorders of glycosylation are metabolic deficiencies in glycoprotein biosynthesis that usually cause severe mental and psychomotor retardation. They are characterized by under-glycosylated serum glycoproteins. CDG1A is an autosomal recessive disorder characterized by a severe encephalopathy with axial hypotonia, abnormal eye movement, and pronounced psychomotor retardation, as well as peripheral neuropathy, cerebellar hypoplasia, and retinitis pigmentosa. Patients show a peculiar distribution of subcutaneous fat, nipple retraction, and hypogonadism. Ref.1 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20
Sequence similarities	Belongs to the eukaryotic PMM family.

Ontologies

Keywords
Cellular component	Cytoplasm
Coding sequence diversity	Polymorphism
Disease	Congenital disorder of glycosylation Disease mutation
Molecular function	Isomerase
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	GDP-mannose biosynthetic process Ref.1 Traceable author statement. Source: ProtInc protein amino acid glycosylation Ref.1 Traceable author statement. Source: ProtInc
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	phosphomannomutase activity Ref.1 Traceable author statement. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 246

246

Phosphomannomutase 2

PRO_0000199694

Natural variations

Natural variant

9

1

C → Y in CDG1A. Ref.14 Ref.15 Ref.19

VAR_022469

Natural variant

11

1

F → C in CDG1A. Ref.14 Ref.15

VAR_022470

Natural variant

15

1

G → E in CDG1A. Ref.18

VAR_022471

Natural variant

20

1

P → S in CDG1A; reduction of activity. Ref.19

VAR_022472

Natural variant

32

1

L → R in CDG1A. Ref.14 Ref.19

VAR_022473

Natural variant

37

1

Q → H in CDG1A; partial loss of activity. Ref.19

VAR_022474

Natural variant

37

1

Q → L: dbSNP rs2304472. Ref.19

VAR_022133

Natural variant

42

1

G → R Ref.18 Ref.19

VAR_022475

Natural variant

44

1

V → A in CDG1A. Ref.14 Ref.19 Ref.20

VAR_006093

Natural variant

44

1

V → L in CDG1A. Ref.14 Ref.19 Ref.20

VAR_022563

Natural variant

64

1

Y → C in CDG1A. Ref.18

VAR_022476

Natural variant

65

1

D → Y in CDG1A. Ref.14 Ref.19

VAR_006094

Natural variant

67

1

V → M in CDG1A. Ref.14 Ref.15

VAR_022477

Natural variant

69

1

P → S in CDG1A. Ref.14 Ref.19

VAR_022478

Natural variant

76

1

Y → C in CDG1A. Ref.14

VAR_022479

Natural variant

93

1

E → A in CDG1A. Ref.18

VAR_022480

Natural variant

101

1

N → K in CDG1A. Ref.14

VAR_006095

Natural variant

103

1

C → F in CDG1A. Ref.14 Ref.19

VAR_022481

Natural variant

104

1

L → V in CDG1A. Ref.17

VAR_012344

Natural variant

106

1

Y → C in CDG1A. Ref.14

VAR_006096

Natural variant

108

1

A → V in CDG1A. Ref.14 Ref.19

VAR_006097

Natural variant

113

1

P → L in CDG1A. Ref.14 Ref.15 Ref.19

VAR_006098

Natural variant

117

1

G → R in CDG1A; loss of activity. Ref.10 Ref.12 Ref.14 Ref.15

VAR_006099

Natural variant

119

1

F → L in CDG1A; partial loss of activity. Ref.12 Ref.14 Ref.15 Ref.16 Ref.19

VAR_006100

Natural variant

120

1

I → T in CDG1A. Ref.14

VAR_022482

Natural variant

123

1

R → Q in CDG1A. Ref.14 Ref.15 Ref.19

VAR_006101

Natural variant

129

1

V → M in CDG1A. Ref.14 Ref.15 Ref.19

VAR_006102

Natural variant

131

1

P → A in CDG1A. Ref.14 Ref.19

VAR_006103

Natural variant

132

1

I → F in CDG1A; slightly reduced activity. Ref.14 Ref.16 Ref.19

VAR_022483

Natural variant

132

1

I → N in CDG1A. Ref.14 Ref.16 Ref.19

VAR_022484

Natural variant

132

1

I → T in CDG1A. Ref.14 Ref.16 Ref.19

VAR_006104

Natural variant

139

1

E → K in CDG1A; this mutation seems to disrupt a splicing enhancer sequence and thus results in most cases in a protein with exon 5 skipped; slightly reduced activity. Ref.13 Ref.14 Ref.19

VAR_009232

Natural variant

141

1

R → C in CDG1A; loss of activity. Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.19

VAR_022485

Natural variant

141

1

R → H in CDG1A; frequent mutation; loss of activity; observed in heterozygous patients; homozygosis of this mutation is incompatible with life. Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.19

VAR_006105

Natural variant

144

1

F → L in CDG1A. Ref.11

VAR_022486

Natural variant

148

1

D → N in CDG1A. Ref.14 Ref.16

VAR_022487

Natural variant

151

1

E → G in CDG1A. Ref.14

VAR_022488

Natural variant

153

1

I → T in CDG1A. Ref.14 Ref.19

VAR_022489

Natural variant

157

1

F → S in CDG1A. Ref.14 Ref.19

VAR_022490

Natural variant

162

1

R → W in CDG1A. Ref.14 Ref.19

VAR_006106

Natural variant

172

1

F → V in CDG1A. Ref.14 Ref.15

VAR_022491

Natural variant

175

1

G → R in CDG1A. Ref.14 Ref.15

VAR_006107

Natural variant

176

1

G → V in CDG1A; loss of activity. Ref.19

VAR_022492

Natural variant

177

1

Q → H in CDG1A; partial loss of activity. Ref.19

VAR_022493

Natural variant

183

1

F → S in CDG1A. Ref.14 Ref.15 Ref.16

VAR_022494

Natural variant

185

1

D → G in CDG1A. Ref.14 Ref.15

VAR_022495

Natural variant

188

1

D → G in CDG1A; severe. Ref.14

VAR_006108

Natural variant

192

1

C → G in CDG1A; normal activity but lower affinity for alpha-D-mannose 1-phosphate. Ref.12 Ref.14 Ref.15

VAR_022496

Natural variant

195

1

H → R in CDG1A. Ref.14

VAR_022497

Natural variant

197

1

E → A in CDG1A. dbSNP rs34258285. Ref.14 Ref.19

VAR_022498

Natural variant

206

1

F → S in CDG1A. Ref.14

VAR_022499

Natural variant

208

1

G → A in CDG1A. Ref.14 Ref.16

VAR_006109

Natural variant

212

1

M → V: dbSNP rs3743808.

VAR_022134

Natural variant

214

1

G → S in CDG1A. Ref.18 Ref.19

VAR_022500

Natural variant

216

1

N → I in CDG1A. Ref.14 Ref.15

VAR_006110

Natural variant

216

1

N → S in CDG1A. Ref.14 Ref.15

VAR_022501

Natural variant

217

1

D → E in CDG1A. Ref.14 Ref.15

VAR_022502

Natural variant

218

1

H → L in CDG1A. Ref.14

VAR_022503

Natural variant

223

1

D → E in CDG1A; normal activity but lower affinity for alpha-D-mannose 1-phosphate. Ref.10 Ref.12 Ref.14 Ref.15 Ref.18

VAR_006111

Natural variant

223

1

D → N in CDG1A. Ref.10 Ref.12 Ref.14 Ref.15 Ref.18

VAR_022504

Natural variant

226

1

T → S in CDG1A. Ref.14 Ref.19

VAR_022505

Natural variant

228

1

G → C in CDG1A. Ref.14 Ref.15

VAR_022506

Natural variant

228

1

G → R in CDG1A. Ref.14 Ref.15

VAR_022507

Natural variant

229

1

Y → S in CDG1A. Ref.11 Ref.14

VAR_006112

Natural variant

231

1

V → M in CDG1A. Ref.14 Ref.15 Ref.16 Ref.19 Ref.20

VAR_006113

Natural variant

233

1

A → T in CDG1A; could be a rare polymorphism. Ref.14

VAR_006114

Natural variant

237

1

T → M in CDG1A. Ref.12 Ref.14 Ref.15 Ref.16 Ref.19

VAR_006115

Natural variant

237

1

T → R in CDG1A; loss of activity. Ref.12 Ref.14 Ref.15 Ref.16 Ref.19

VAR_022508

Natural variant

238

1

R → G in CDG1A. Ref.11 Ref.14

VAR_022509

Natural variant

238

1

R → P in CDG1A. Ref.11 Ref.14

VAR_006116

Natural variant

241

1

C → S in CDG1A. Ref.14 Ref.19

VAR_022510

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

246

Helix Strand Turn

Details...

Beta strand

6 – 14

9

Turn

15 – 17

3

Helix

26 – 35

10

Turn

36 – 38

3

Beta strand

39 – 44

6

Helix

49 – 56

8

Helix

60 – 63

4

Beta strand

65 – 69

5

Helix

70 – 72

3

Beta strand

74 – 77

4

Beta strand

80 – 84

5

Helix

87 – 91

5

Helix

93 – 109

17

Beta strand

119 – 123

5

Beta strand

126 – 129

4

Helix

138 – 151

14

Helix

153 – 164

12

Turn

165 – 167

3

Beta strand

170 – 175

6

Turn

176 – 178

3

Beta strand

179 – 184

6

Helix

189 – 195

7

Turn

196 – 198

3

Beta strand

202 – 208

7

Helix

219 – 222

4

Beta strand

226 – 230

5

Helix

234 – 244

11

Sequences

	Sequence		Length	Mass (Da)
	O15305-1 [UniParc]. Last modified January 1, 1998. Version 1. Checksum: 29F1D5B9539B6221	FASTA	246	28,082
	10 20 30 40 50 60 MAAPGPALCL FDVDGTLTAP RQKITKEMDD FLQKLRQKIK IGVVGGSDFE KVQEQLGNDV 70 80 90 100 110 120 VEKYDYVFPE NGLVAYKDGK LLCRQNIQSH LGEALIQDLI NYCLSYIAKI KLPKKRGTFI 130 140 150 160 170 180 EFRNGMLNVS PIGRSCSQEE RIEFYELDKK ENIRQKFVAD LRKEFAGKGL TFSIGGQISF 190 200 210 220 230 240 DVFPDGWDKR YCLRHVENDG YKTIYFFGDK TMPGGNDHEI FTDPRTMGYS VTAPEDTRRI CELLFS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome)." Matthijs G., Schollen E., Pardon E., Veiga-Da-Cunha M., Jaeken J., Cassiman J.-J., van Schaftingen E. Nat. Genet. 16:88-92(1997) [PubMed: 9140401] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS CDG1A.
[2]	Erratum Matthijs G., Schollen E., Pardon E., Veiga-Da-Cunha M., Jaeken J., Cassiman J.-J., van Schaftingen E. Nat. Genet. 16:316-316(1997)
[3]	"Comparative analysis of the phosphomannomutase genes PMM1, PMM2 and PMM2psi: the sequence variation in the processed pseudogene is a reflection of the mutations found in the functional gene." Schollen E., Pardon E., Heykants L., Renard J., Doggett N.A., Callen D.F., Cassiman J.J., Matthijs G. Hum. Mol. Genet. 7:157-164(1998) [PubMed: 9425221] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Pancreas.
[5]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[6]	"Ensemble refinement of protein crystal structures: validation and application." Levin E.J., Kondrashov D.A., Wesenberg G.E., Phillips G.N. Jr. Structure 15:1040-1052(2007) [PubMed: 17850744] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.09 ANGSTROMS).
[7]	"X-ray structure of human phosphomannomutase 2 (PMM2)." Center for eukaryotic structural genomics (CESG) Submitted (FEB-2009) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.09 ANGSTROMS).
[8]	"Phosphomannomutase deficiency: the molecular basis of the classical Jaeken syndrome (CDGS type Ia)." Matthijs G., Schollen E., Heykants L., Gruenewald S. Mol. Genet. Metab. 68:220-226(1999) [PubMed: 10527672] [Abstract] Cited for: REVIEW ON VARIANTS CDG1A.
[9]	"Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome type 1A." Matthijs G., Schollen E., van Schaftingen E., Cassiman J.-J., Jaeken J. Am. J. Hum. Genet. 62:542-550(1998) [PubMed: 9497260] [Abstract] Cited for: VARIANTS CDG1A.
[10]	"Absence of homozygosity for predominant mutations in PMM2 in Danish patients with carbohydrate-deficient glycoprotein syndrome type 1." Kjaergaard S., Skovby F., Schwartz M. Eur. J. Hum. Genet. 6:331-336(1998) [PubMed: 9781039] [Abstract] Cited for: VARIANTS CDG1A ARG-117 AND GLU-223.
[11]	"Missense mutations in phosphomannomutase 2 gene in two Japanese families with carbohydrate-deficient glycoprotein syndrome type 1." Kondo I., Mizugishi K., Yoneda Y., Hashimoto T., Kuwajima K., Yuasa I., Shigemoto K., Kuroda Y. Clin. Genet. 55:50-54(1999) [PubMed: 10066032] [Abstract] Cited for: VARIANTS CDG1A LEU-144; SER-229 AND PRO-238.
[12]	"Carbohydrate-deficient glycoprotein syndrome type 1A: expression and characterisation of wild type and mutant PMM2 in E. coli." Kjaergaard S., Skovby F., Schwartz M. Eur. J. Hum. Genet. 7:884-888(1999) [PubMed: 10602363] [Abstract] Cited for: VARIANT CDG1A GLY-192, CHARACTERIZATION OF VARIANTS CDG1A ARG-117; LEU-119; HIS-141; GLY-192; GLU-223 AND ARG-237.
[13]	"Characterization of the 415G>A (E139K) PMM2 mutation in carbohydrate-deficient glycoprotein syndrome type Ia disrupting a splicing enhancer resulting in exon 5 skipping." Vuillaumier-Barrot S., Barnier A., Cuer M., Durand G., Grandchamp B., Seta N. Hum. Mutat. 14:543-544(1999) [PubMed: 10571956] [Abstract] Cited for: VARIANTS CDG1A LYS-139 AND HIS-141.
[14]	"Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia)." Matthijs G., Schollen E., Bjursell C., Erlandson A., Freeze H., Imtiaz F., Kjaergaard S., Martinsson T., Schwartz M., Seta N., Vuillaumier-Barrot S., Westphal V., Winchester B. Hum. Mutat. 16:386-394(2000) [PubMed: 11058895] [Abstract] Cited for: VARIANTS CDG1A TYR-9; CYS-11; ARG-32; ALA-44; TYR-65; MET-67; SER-69; CYS-76; LYS-101; PHE-103; CYS-106; VAL-108; LEU-113; ARG-117; LEU-119; THR-120; GLN-123; MET-129; ALA-131; ASN-132; THR-132; LYS-139; HIS-141; ASN-148; GLY-151; THR-153; SER-157; TRP-162; VAL-172; ARG-175; SER-183; GLY-185; GLY-188; GLY-192; ARG-195; ALA-197; SER-206; ALA-208; ILE-216; SER-216; GLU-217; LEU-218; GLU-223; SER-226; ARG-228; CYS-228; SER-229; MET-231; THR-233; ARG-237; MET-237; GLY-238 AND SER-241.
[15]	"PMM2 mutation spectrum, including 10 novel mutations, in a large CDG type 1A family material with a focus on Scandinavian families." Bjursell C., Erlandson A., Nordling M., Nilsson S., Wahlstroem J., Stibler H., Kristiansson B., Martinsson T. Hum. Mutat. 16:395-400(2000) [PubMed: 11058896] [Abstract] Cited for: VARIANTS CDG1A TYR-9; CYS-11; MET-67; LEU-113; ARG-117; LEU-119; GLN-123; MET-129; HIS-141; VAL-172; ARG-175; SER-183; GLY-185; GLY-192; SER-216; GLU-217; GLU-223; ARG-228; MET-231 AND ARG-237.
[16]	"Genotypes and phenotypes of patients in the UK with carbohydrate-deficient glycoprotein syndrome type 1." Imtiaz F., Worthington V., Champion M., Beesley C., Charlwood J., Clayton P., Keir G., Mian N., Winchester B. J. Inherit. Metab. Dis. 23:162-174(2000) [PubMed: 10801058] [Abstract] Cited for: VARIANTS CDG1A LEU-119; ASN-132; HIS-141; ASN-148; SER-183; ALA-208; MET-231 AND MET-237.
[17]	"Functional analysis of novel mutations in a congenital disorder of glycosylation Ia patient with mixed Asian ancestry." Westphal V., Enns G.M., McCracken M.F., Freeze H.H. Mol. Genet. Metab. 73:71-76(2001) [PubMed: 11350185] [Abstract] Cited for: VARIANT CDG1A VAL-104.
[18]	"DHPLC analysis as a platform for molecular diagnosis of congenital disorders of glycosylation (CDG)." Schollen E., Martens K., Geuzens E., Matthijs G. Eur. J. Hum. Genet. 10:643-648(2002) [PubMed: 12357336] [Abstract] Cited for: VARIANTS CDG1A GLU-15; CYS-64; ALA-93; SER-214 AND ASN-223, VARIANT ARG-42.
[19]	"A new insight into PMM2 mutations in the French population." Le Bizec C., Vuillaumier-Barrot S., Barnier A., Dupre T., Durand G., Seta N. Hum. Mutat. 25:504-505(2005) [PubMed: 15844218] [Abstract] Cited for: VARIANTS CDG1A TYR-9; SER-20; ARG-32; HIS-37; LEU-44; TYR-65; SER-69; PHE-103; VAL-108; LEU-113; LEU-119; GLN-123; MET-129; ALA-131; THR-132; PHE-132; LYS-139; CYS-141; HIS-141; THR-153; SER-157; TRP-162; VAL-176; HIS-177; ALA-197; SER-214; SER-226; MET-231; ARG-237; MET-237 AND SER-241, VARIANT ARG-42, CHARACTERIZATION OF VARIANTS CDG1A SER-20; HIS-37; PHE-132; LYS-139; CYS-141; HIS-141; VAL-176 AND HIS-177.
[20]	"Characterization of two unusual truncating PMM2 mutations in two CDG-Ia patients." Schollen E., Keldermans L., Foulquier F., Briones P., Chabas A., Sanchez-Valverde F., Adamowicz M., Pronicka E., Wevers R., Matthijs G. Mol. Genet. Metab. 90:408-413(2007) [PubMed: 17307006] [Abstract] Cited for: VARIANTS CDG1A ALA-44 AND MET-231.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBLGenBankDDBJ

U85773 mRNA. Translation: AAC51368.1.
AF157796 , AF157790, AF157791, AF157792, AF157793, AF157794, AF157795 Genomic DNA. Translation: AAD45895.1.
BC008310 mRNA. Translation: AAH08310.1.

IPI

IPI00006092.

RefSeq

NP_000294.1.

UniGene

Hs.659263
Hs.708805
Hs.713724

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2AMY	X-ray	2.09	A	2-246	[»]
2Q4R	X-ray	2.09	A	2-246	[»]

ModBase

Search...

PTM databases

PhosphoSite

O15305.

Proteomic databases

PeptideAtlas

O15305.

PRIDE

O15305.

Genome annotation databases

Ensembl

ENSG00000140650. Homo sapiens. [Contig view]

GeneID

5373.

KEGG

hsa:5373.

NMPDR

fig|9606.3.peg.11694.

UCSC

uc002czf.2. human.

Organism-specific databases

GeneCards

GC16P008799.

H-InvDB

HIX0012808.

HGNC

HGNC:9115. PMM2.

MIM

212065. phenotype.
601785. gene.

Orphanet

137. CDG syndrome.
79318. CDG syndrome, type Ia.

PharmGKB

PA33441.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

O15305.

HOVERGEN

O15305.

OMA

O15305. LLCKQNI.

Enzyme and pathway databases

BRENDA

5.4.2.8. 247.

Gene expression databases

ArrayExpress

O15305.

Bgee

O15305.

CleanEx

HS_PMM2.

GermOnline

ENSG00000140650. Homo sapiens.

Family and domain databases

InterPro

IPR006379. HAD-SF_hydro_IIB.
IPR005002. PMM.
[Graphical view]

PANTHER

PTHR10466. PMM. 1 hit.

Pfam

PF03332. PMM. 1 hit.
[Graphical view]

TIGRFAMs

TIGR01484. HAD-SF-IIB. 1 hit.

ProtoNet

Search...

Other Resources

NextBio

20846.

SOURCE

Search...

Entry information

Entry name

PMM2_HUMAN

Accession

Primary (citable) accession number: O15305

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1998
Last sequence update:	January 1, 1998
Last modified:	July 7, 2009
This is version 100 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)