RBCC Red Blood Cell Collection

PMM2 [Confidence: low (only semi-automatic identification from reviews)]
Phosphomannomutase 2; PMM 2; 5.4.2.8
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt O15305
ID PMM2_HUMAN Reviewed; 246 AA.
AC O15305; A8K672; D3DUF3;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JAN-1998, sequence version 1.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Phosphomannomutase 2;
DE Short=PMM 2;
DE EC=5.4.2.8;
GN Name=PMM2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS CDG1A.
RX PubMed=9140401; DOI=10.1038/ng0597-88;
RA Matthijs G., Schollen E., Pardon E., Veiga-Da-Cunha M., Jaeken J.,
RA Cassiman J.-J., van Schaftingen E.;
RT "Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in
RT carbohydrate-deficient glycoprotein type I syndrome (Jaeken
RT syndrome).";
RL Nat. Genet. 16:88-92(1997).
RN [2]
RP ERRATUM.
RA Matthijs G., Schollen E., Pardon E., Veiga-Da-Cunha M., Jaeken J.,
RA Cassiman J.-J., van Schaftingen E.;
RL Nat. Genet. 16:316-316(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9425221; DOI=10.1093/hmg/7.2.157;
RA Schollen E., Pardon E., Heykants L., Renard J., Doggett N.A.,
RA Callen D.F., Cassiman J.J., Matthijs G.;
RT "Comparative analysis of the phosphomannomutase genes PMM1, PMM2 and
RT PMM2psi: the sequence variation in the processed pseudogene is a
RT reflection of the mutations found in the functional gene.";
RL Hum. Mol. Genet. 7:157-164(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=16540464; DOI=10.1074/jbc.M601505200;
RA Silvaggi N.R., Zhang C., Lu Z., Dai J., Dunaway-Mariano D.,
RA Allen K.N.;
RT "The X-ray crystal structures of human alpha-phosphomannomutase 1
RT reveal the structural basis of congenital disorder of glycosylation
RT type 1a.";
RL J. Biol. Chem. 281:14918-14926(2006).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [9]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.09 ANGSTROMS).
RX PubMed=17850744; DOI=10.1016/j.str.2007.06.019;
RA Levin E.J., Kondrashov D.A., Wesenberg G.E., Phillips G.N. Jr.;
RT "Ensemble refinement of protein crystal structures: validation and
RT application.";
RL Structure 15:1040-1052(2007).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.09 ANGSTROMS).
RG Center for eukaryotic structural genomics (CESG);
RT "X-ray structure of human phosphomannomutase 2 (PMM2).";
RL Submitted (FEB-2009) to the PDB data bank.
RN [12]
RP REVIEW ON VARIANTS CDG1A.
RX PubMed=10527672; DOI=10.1006/mgme.1999.2914;
RA Matthijs G., Schollen E., Heykants L., Gruenewald S.;
RT "Phosphomannomutase deficiency: the molecular basis of the classical
RT Jaeken syndrome (CDGS type Ia).";
RL Mol. Genet. Metab. 68:220-226(1999).
RN [13]
RP VARIANTS CDG1A.
RX PubMed=9497260; DOI=10.1086/301763;
RA Matthijs G., Schollen E., van Schaftingen E., Cassiman J.-J.,
RA Jaeken J.;
RT "Lack of homozygotes for the most frequent disease allele in
RT carbohydrate-deficient glycoprotein syndrome type 1A.";
RL Am. J. Hum. Genet. 62:542-550(1998).
RN [14]
RP VARIANTS CDG1A ARG-117 AND GLU-223.
RX PubMed=9781039; DOI=10.1038/sj.ejhg.5200194;
RA Kjaergaard S., Skovby F., Schwartz M.;
RT "Absence of homozygosity for predominant mutations in PMM2 in Danish
RT patients with carbohydrate-deficient glycoprotein syndrome type 1.";
RL Eur. J. Hum. Genet. 6:331-336(1998).
RN [15]
RP VARIANTS CDG1A LEU-144; SER-229 AND PRO-238.
RX PubMed=10066032; DOI=10.1034/j.1399-0004.1999.550109.x;
RA Kondo I., Mizugishi K., Yoneda Y., Hashimoto T., Kuwajima K.,
RA Yuasa I., Shigemoto K., Kuroda Y.;
RT "Missense mutations in phosphomannomutase 2 gene in two Japanese
RT families with carbohydrate-deficient glycoprotein syndrome type 1.";
RL Clin. Genet. 55:50-54(1999).
RN [16]
RP VARIANT CDG1A GLY-192, AND CHARACTERIZATION OF VARIANTS CDG1A ARG-117;
RP LEU-119; HIS-141; GLY-192; GLU-223 AND ARG-237.
RX PubMed=10602363; DOI=10.1038/sj.ejhg.5200398;
RA Kjaergaard S., Skovby F., Schwartz M.;
RT "Carbohydrate-deficient glycoprotein syndrome type 1A: expression and
RT characterisation of wild type and mutant PMM2 in E. coli.";
RL Eur. J. Hum. Genet. 7:884-888(1999).
RN [17]
RP VARIANTS CDG1A LYS-139 AND HIS-141.
RX PubMed=10571956;
RX DOI=10.1002/(SICI)1098-1004(199912)14:6<543::AID-HUMU17>3.3.CO;2-J;
RA Vuillaumier-Barrot S., Barnier A., Cuer M., Durand G., Grandchamp B.,
RA Seta N.;
RT "Characterization of the 415G>A (E139K) PMM2 mutation in carbohydrate-
RT deficient glycoprotein syndrome type Ia disrupting a splicing enhancer
RT resulting in exon 5 skipping.";
RL Hum. Mutat. 14:543-544(1999).
RN [18]
RP VARIANTS CDG1A TYR-9; CYS-11; ARG-32; ALA-44; TYR-65; MET-67; SER-69;
RP CYS-76; LYS-101; PHE-103; CYS-106; VAL-108; LEU-113; ARG-117; LEU-119;
RP THR-120; GLN-123; MET-129; ALA-131; ASN-132; THR-132; LYS-139;
RP HIS-141; ASN-148; GLY-151; THR-153; SER-157; TRP-162; VAL-172;
RP ARG-175; SER-183; GLY-185; GLY-188; GLY-192; ARG-195; ALA-197;
RP SER-206; ALA-208; ILE-216; SER-216; GLU-217; LEU-218; GLU-223;
RP SER-226; ARG-228; CYS-228; SER-229; MET-231; THR-233; ARG-237;
RP MET-237; GLY-238 AND SER-241.
RX PubMed=11058895;
RX DOI=10.1002/1098-1004(200011)16:5<386::AID-HUMU2>3.0.CO;2-Y;
RA Matthijs G., Schollen E., Bjursell C., Erlandson A., Freeze H.,
RA Imtiaz F., Kjaergaard S., Martinsson T., Schwartz M., Seta N.,
RA Vuillaumier-Barrot S., Westphal V., Winchester B.;
RT "Mutations in PMM2 that cause congenital disorders of glycosylation,
RT type Ia (CDG-Ia).";
RL Hum. Mutat. 16:386-394(2000).
RN [19]
RP VARIANTS CDG1A TYR-9; CYS-11; MET-67; LEU-113; ARG-117; LEU-119;
RP GLN-123; MET-129; HIS-141; VAL-172; ARG-175; SER-183; GLY-185;
RP GLY-192; SER-216; GLU-217; GLU-223; ARG-228; MET-231 AND ARG-237.
RX PubMed=11058896;
RX DOI=10.1002/1098-1004(200011)16:5<395::AID-HUMU3>3.3.CO;2-K;
RA Bjursell C., Erlandson A., Nordling M., Nilsson S., Wahlstroem J.,
RA Stibler H., Kristiansson B., Martinsson T.;
RT "PMM2 mutation spectrum, including 10 novel mutations, in a large CDG
RT type 1A family material with a focus on Scandinavian families.";
RL Hum. Mutat. 16:395-400(2000).
RN [20]
RP VARIANTS CDG1A LEU-119; ASN-132; HIS-141; ASN-148; SER-183; ALA-208;
RP MET-231 AND MET-237.
RX PubMed=10801058; DOI=10.1023/A:1005669900330;
RA Imtiaz F., Worthington V., Champion M., Beesley C., Charlwood J.,
RA Clayton P., Keir G., Mian N., Winchester B.;
RT "Genotypes and phenotypes of patients in the UK with carbohydrate-
RT deficient glycoprotein syndrome type 1.";
RL J. Inherit. Metab. Dis. 23:162-174(2000).
RN [21]
RP VARIANT CDG1A VAL-104.
RX PubMed=11350185; DOI=10.1006/mgme.2001.3174;
RA Westphal V., Enns G.M., McCracken M.F., Freeze H.H.;
RT "Functional analysis of novel mutations in a congenital disorder of
RT glycosylation Ia patient with mixed Asian ancestry.";
RL Mol. Genet. Metab. 73:71-76(2001).
RN [22]
RP VARIANTS CDG1A GLU-15; CYS-64; ALA-93; SER-214 AND ASN-223, AND
RP VARIANT ARG-42.
RX PubMed=12357336; DOI=10.1038/sj.ejhg.5200858;
RA Schollen E., Martens K., Geuzens E., Matthijs G.;
RT "DHPLC analysis as a platform for molecular diagnosis of congenital
RT disorders of glycosylation (CDG).";
RL Eur. J. Hum. Genet. 10:643-648(2002).
RN [23]
RP VARIANTS CDG1A TYR-9; SER-20; ARG-32; HIS-37; LEU-44; TYR-65; SER-69;
RP PHE-103; VAL-108; LEU-113; LEU-119; GLN-123; MET-129; ALA-131;
RP THR-132; PHE-132; LYS-139; CYS-141; HIS-141; THR-153; SER-157;
RP TRP-162; VAL-176; HIS-177; ALA-197; SER-214; SER-226; MET-231;
RP ARG-237; MET-237 AND SER-241, VARIANT ARG-42, AND CHARACTERIZATION OF
RP VARIANTS CDG1A SER-20; HIS-37; PHE-132; LYS-139; CYS-141; HIS-141;
RP VAL-176 AND HIS-177.
RX PubMed=15844218; DOI=10.1002/humu.9336;
RA Le Bizec C., Vuillaumier-Barrot S., Barnier A., Dupre T., Durand G.,
RA Seta N.;
RT "A new insight into PMM2 mutations in the French population.";
RL Hum. Mutat. 25:504-505(2005).
RN [24]
RP VARIANTS CDG1A ALA-44 AND MET-231.
RX PubMed=17307006; DOI=10.1016/j.ymgme.2007.01.003;
RA Schollen E., Keldermans L., Foulquier F., Briones P., Chabas A.,
RA Sanchez-Valverde F., Adamowicz M., Pronicka E., Wevers R.,
RA Matthijs G.;
RT "Characterization of two unusual truncating PMM2 mutations in two CDG-
RT Ia patients.";
RL Mol. Genet. Metab. 90:408-413(2007).
CC -!- FUNCTION: Involved in the synthesis of the GDP-mannose and
CC dolichol-phosphate-mannose required for a number of critical
CC mannosyl transfer reactions (By similarity).
CC -!- CATALYTIC ACTIVITY: Alpha-D-mannose 1-phosphate = D-mannose 6-
CC phosphate.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=16 uM for alpha-D-mannose 1-phosphate;
CC KM=13.5 uM for alpha-D-glucose 1-phosphate;
CC -!- PATHWAY: Nucleotide-sugar biosynthesis; GDP-alpha-D-mannose
CC biosynthesis; alpha-D-mannose 1-phosphate from D-fructose 6-
CC phosphate: step 2/2.
CC -!- SUBUNIT: Homodimer (By similarity).
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- DISEASE: Congenital disorder of glycosylation 1A (CDG1A)
CC [MIM:212065]: A multisystem disorder caused by a defect in
CC glycoprotein biosynthesis and characterized by under-glycosylated
CC serum glycoproteins. Congenital disorders of glycosylation result
CC in a wide variety of clinical features, such as defects in the
CC nervous system development, psychomotor retardation, dysmorphic
CC features, hypotonia, coagulation disorders, and immunodeficiency.
CC The broad spectrum of features reflects the critical role of N-
CC glycoproteins during embryonic development, differentiation, and
CC maintenance of cell functions. Congenital disorder of
CC glycosylation type 1A is an autosomal recessive disorder
CC characterized by a severe encephalopathy with axial hypotonia,
CC abnormal eye movement, and pronounced psychomotor retardation, as
CC well as peripheral neuropathy, cerebellar hypoplasia, and
CC retinitis pigmentosa. Patients show a peculiar distribution of
CC subcutaneous fat, nipple retraction, and hypogonadism. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the eukaryotic PMM family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PMM2";
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DR EMBL; U85773; AAC51368.1; -; mRNA.
DR EMBL; AF157796; AAD45895.1; -; Genomic_DNA.
DR EMBL; AF157790; AAD45895.1; JOINED; Genomic_DNA.
DR EMBL; AF157791; AAD45895.1; JOINED; Genomic_DNA.
DR EMBL; AF157792; AAD45895.1; JOINED; Genomic_DNA.
DR EMBL; AF157793; AAD45895.1; JOINED; Genomic_DNA.
DR EMBL; AF157794; AAD45895.1; JOINED; Genomic_DNA.
DR EMBL; AF157795; AAD45895.1; JOINED; Genomic_DNA.
DR EMBL; AK291537; BAF84226.1; -; mRNA.
DR EMBL; CH471112; EAW85202.1; -; Genomic_DNA.
DR EMBL; CH471112; EAW85203.1; -; Genomic_DNA.
DR EMBL; BC008310; AAH08310.1; -; mRNA.
DR RefSeq; NP_000294.1; NM_000303.2.
DR UniGene; Hs.625732; -.
DR PDB; 2AMY; X-ray; 2.09 A; A=2-246.
DR PDB; 2Q4R; X-ray; 2.09 A; A=2-246.
DR PDBsum; 2AMY; -.
DR PDBsum; 2Q4R; -.
DR ProteinModelPortal; O15305; -.
DR SMR; O15305; 4-246.
DR STRING; 9606.ENSP00000268261; -.
DR BindingDB; O15305; -.
DR ChEMBL; CHEMBL1741162; -.
DR PhosphoSite; O15305; -.
DR PaxDb; O15305; -.
DR PeptideAtlas; O15305; -.
DR PRIDE; O15305; -.
DR DNASU; 5373; -.
DR Ensembl; ENST00000268261; ENSP00000268261; ENSG00000140650.
DR GeneID; 5373; -.
DR KEGG; hsa:5373; -.
DR UCSC; uc002czf.4; human.
DR CTD; 5373; -.
DR GeneCards; GC16P008799; -.
DR HGNC; HGNC:9115; PMM2.
DR HPA; HPA040852; -.
DR MIM; 212065; phenotype.
DR MIM; 601785; gene.
DR neXtProt; NX_O15305; -.
DR Orphanet; 79318; PMM2-CDG syndrome.
DR PharmGKB; PA33441; -.
DR eggNOG; COG0561; -.
DR HOGENOM; HOG000181843; -.
DR HOVERGEN; HBG009971; -.
DR InParanoid; O15305; -.
DR KO; K17497; -.
DR OMA; TYCLQHV; -.
DR BRENDA; 5.4.2.8; 2681.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_17015; Metabolism of proteins.
DR SABIO-RK; O15305; -.
DR UniPathway; UPA00126; UER00424.
DR ChiTaRS; PMM2; human.
DR EvolutionaryTrace; O15305; -.
DR GeneWiki; PMM2; -.
DR GenomeRNAi; 5373; -.
DR NextBio; 20846; -.
DR PRO; PR:O15305; -.
DR ArrayExpress; O15305; -.
DR Bgee; O15305; -.
DR CleanEx; HS_PMM2; -.
DR Genevestigator; O15305; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0004615; F:phosphomannomutase activity; TAS:ProtInc.
DR GO; GO:0006488; P:dolichol-linked oligosaccharide biosynthetic process; TAS:Reactome.
DR GO; GO:0009298; P:GDP-mannose biosynthetic process; TAS:Reactome.
DR GO; GO:0019307; P:mannose biosynthetic process; IEA:InterPro.
DR GO; GO:0043687; P:post-translational protein modification; TAS:Reactome.
DR GO; GO:0018279; P:protein N-linked glycosylation via asparagine; TAS:Reactome.
DR Gene3D; 3.40.50.1000; -; 2.
DR InterPro; IPR023214; HAD-like_dom.
DR InterPro; IPR006379; HAD-SF_hydro_IIB.
DR InterPro; IPR005002; PMM.
DR PANTHER; PTHR10466; PTHR10466; 1.
DR Pfam; PF03332; PMM; 1.
DR SUPFAM; SSF56784; SSF56784; 1.
DR TIGRFAMs; TIGR01484; HAD-SF-IIB; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome;
KW Congenital disorder of glycosylation; Cytoplasm; Disease mutation;
KW Isomerase; Polymorphism; Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 246 Phosphomannomutase 2.
FT /FTId=PRO_0000199694.
FT ACT_SITE 12 12 Nucleophile (By similarity).
FT ACT_SITE 14 14 Proton donor/acceptor (Potential).
FT BINDING 21 21 Substrate (By similarity).
FT BINDING 123 123 Substrate (By similarity).
FT BINDING 134 134 Substrate (By similarity).
FT BINDING 141 141 Substrate (By similarity).
FT BINDING 179 179 Substrate (By similarity).
FT BINDING 181 181 Substrate (By similarity).
FT MOD_RES 2 2 N-acetylalanine.
FT VARIANT 9 9 C -> Y (in CDG1A).
FT /FTId=VAR_022469.
FT VARIANT 11 11 F -> C (in CDG1A).
FT /FTId=VAR_022470.
FT VARIANT 15 15 G -> E (in CDG1A).
FT /FTId=VAR_022471.
FT VARIANT 20 20 P -> S (in CDG1A; reduction of activity).
FT /FTId=VAR_022472.
FT VARIANT 32 32 L -> R (in CDG1A).
FT /FTId=VAR_022473.
FT VARIANT 37 37 Q -> H (in CDG1A; partial loss of
FT activity).
FT /FTId=VAR_022474.
FT VARIANT 37 37 Q -> L (in dbSNP:rs2304472).
FT /FTId=VAR_022133.
FT VARIANT 42 42 G -> R.
FT /FTId=VAR_022475.
FT VARIANT 44 44 V -> A (in CDG1A).
FT /FTId=VAR_006093.
FT VARIANT 44 44 V -> L (in CDG1A).
FT /FTId=VAR_022563.
FT VARIANT 64 64 Y -> C (in CDG1A).
FT /FTId=VAR_022476.
FT VARIANT 65 65 D -> Y (in CDG1A).
FT /FTId=VAR_006094.
FT VARIANT 67 67 V -> M (in CDG1A).
FT /FTId=VAR_022477.
FT VARIANT 69 69 P -> S (in CDG1A).
FT /FTId=VAR_022478.
FT VARIANT 76 76 Y -> C (in CDG1A).
FT /FTId=VAR_022479.
FT VARIANT 93 93 E -> A (in CDG1A).
FT /FTId=VAR_022480.
FT VARIANT 101 101 N -> K (in CDG1A).
FT /FTId=VAR_006095.
FT VARIANT 103 103 C -> F (in CDG1A).
FT /FTId=VAR_022481.
FT VARIANT 104 104 L -> V (in CDG1A).
FT /FTId=VAR_012344.
FT VARIANT 106 106 Y -> C (in CDG1A).
FT /FTId=VAR_006096.
FT VARIANT 108 108 A -> V (in CDG1A).
FT /FTId=VAR_006097.
FT VARIANT 113 113 P -> L (in CDG1A).
FT /FTId=VAR_006098.
FT VARIANT 117 117 G -> R (in CDG1A; loss of activity).
FT /FTId=VAR_006099.
FT VARIANT 119 119 F -> L (in CDG1A; partial loss of
FT activity).
FT /FTId=VAR_006100.
FT VARIANT 120 120 I -> T (in CDG1A).
FT /FTId=VAR_022482.
FT VARIANT 123 123 R -> Q (in CDG1A).
FT /FTId=VAR_006101.
FT VARIANT 129 129 V -> M (in CDG1A; dbSNP:rs28938475).
FT /FTId=VAR_006102.
FT VARIANT 131 131 P -> A (in CDG1A).
FT /FTId=VAR_006103.
FT VARIANT 132 132 I -> F (in CDG1A; slightly reduced
FT activity).
FT /FTId=VAR_022483.
FT VARIANT 132 132 I -> N (in CDG1A).
FT /FTId=VAR_022484.
FT VARIANT 132 132 I -> T (in CDG1A).
FT /FTId=VAR_006104.
FT VARIANT 139 139 E -> K (in CDG1A; this mutation seems to
FT disrupt a splicing enhancer sequence and
FT thus results in most cases in a protein
FT with exon 5 skipped; slightly reduced
FT activity).
FT /FTId=VAR_009232.
FT VARIANT 141 141 R -> C (in CDG1A; loss of activity).
FT /FTId=VAR_022485.
FT VARIANT 141 141 R -> H (in CDG1A; frequent mutation; loss
FT of activity; observed in heterozygous
FT patients; homozygosis of this mutation is
FT incompatible with life;
FT dbSNP:rs28936415).
FT /FTId=VAR_006105.
FT VARIANT 144 144 F -> L (in CDG1A; dbSNP:rs150719105).
FT /FTId=VAR_022486.
FT VARIANT 148 148 D -> N (in CDG1A).
FT /FTId=VAR_022487.
FT VARIANT 151 151 E -> G (in CDG1A).
FT /FTId=VAR_022488.
FT VARIANT 153 153 I -> T (in CDG1A).
FT /FTId=VAR_022489.
FT VARIANT 157 157 F -> S (in CDG1A; dbSNP:rs190521996).
FT /FTId=VAR_022490.
FT VARIANT 162 162 R -> W (in CDG1A).
FT /FTId=VAR_006106.
FT VARIANT 172 172 F -> V (in CDG1A).
FT /FTId=VAR_022491.
FT VARIANT 175 175 G -> R (in CDG1A).
FT /FTId=VAR_006107.
FT VARIANT 176 176 G -> V (in CDG1A; loss of activity).
FT /FTId=VAR_022492.
FT VARIANT 177 177 Q -> H (in CDG1A; partial loss of
FT activity).
FT /FTId=VAR_022493.
FT VARIANT 183 183 F -> S (in CDG1A).
FT /FTId=VAR_022494.
FT VARIANT 185 185 D -> G (in CDG1A).
FT /FTId=VAR_022495.
FT VARIANT 188 188 D -> G (in CDG1A; severe).
FT /FTId=VAR_006108.
FT VARIANT 192 192 C -> G (in CDG1A; normal activity but
FT lower affinity for alpha-D-mannose 1-
FT phosphate).
FT /FTId=VAR_022496.
FT VARIANT 195 195 H -> R (in CDG1A).
FT /FTId=VAR_022497.
FT VARIANT 197 197 E -> A (in CDG1A; dbSNP:rs34258285).
FT /FTId=VAR_022498.
FT VARIANT 206 206 F -> S (in CDG1A).
FT /FTId=VAR_022499.
FT VARIANT 208 208 G -> A (in CDG1A).
FT /FTId=VAR_006109.
FT VARIANT 212 212 M -> V (in dbSNP:rs3743808).
FT /FTId=VAR_022134.
FT VARIANT 214 214 G -> S (in CDG1A).
FT /FTId=VAR_022500.
FT VARIANT 216 216 N -> I (in CDG1A; dbSNP:rs78290141).
FT /FTId=VAR_006110.
FT VARIANT 216 216 N -> S (in CDG1A; dbSNP:rs78290141).
FT /FTId=VAR_022501.
FT VARIANT 217 217 D -> E (in CDG1A).
FT /FTId=VAR_022502.
FT VARIANT 218 218 H -> L (in CDG1A).
FT /FTId=VAR_022503.
FT VARIANT 223 223 D -> E (in CDG1A; normal activity but
FT lower affinity for alpha-D-mannose 1-
FT phosphate).
FT /FTId=VAR_006111.
FT VARIANT 223 223 D -> N (in CDG1A).
FT /FTId=VAR_022504.
FT VARIANT 226 226 T -> S (in CDG1A).
FT /FTId=VAR_022505.
FT VARIANT 228 228 G -> C (in CDG1A).
FT /FTId=VAR_022506.
FT VARIANT 228 228 G -> R (in CDG1A).
FT /FTId=VAR_022507.
FT VARIANT 229 229 Y -> S (in CDG1A).
FT /FTId=VAR_006112.
FT VARIANT 231 231 V -> M (in CDG1A).
FT /FTId=VAR_006113.
FT VARIANT 233 233 A -> T (in CDG1A; could be a rare
FT polymorphism).
FT /FTId=VAR_006114.
FT VARIANT 237 237 T -> M (in CDG1A; dbSNP:rs80338708).
FT /FTId=VAR_006115.
FT VARIANT 237 237 T -> R (in CDG1A; loss of activity;
FT dbSNP:rs80338708).
FT /FTId=VAR_022508.
FT VARIANT 238 238 R -> G (in CDG1A).
FT /FTId=VAR_022509.
FT VARIANT 238 238 R -> P (in CDG1A).
FT /FTId=VAR_006116.
FT VARIANT 241 241 C -> S (in CDG1A).
FT /FTId=VAR_022510.
FT STRAND 6 14
FT TURN 15 17
FT HELIX 26 35
FT TURN 36 38
FT STRAND 39 44
FT HELIX 49 56
FT HELIX 60 63
FT STRAND 65 69
FT HELIX 70 72
FT STRAND 74 77
FT STRAND 80 84
FT HELIX 87 91
FT HELIX 93 109
FT STRAND 119 123
FT STRAND 126 129
FT HELIX 138 151
FT HELIX 153 164
FT TURN 165 167
FT STRAND 170 175
FT TURN 176 178
FT STRAND 179 184
FT HELIX 189 195
FT TURN 196 198
FT STRAND 202 208
FT HELIX 219 222
FT STRAND 226 230
FT HELIX 234 244
SQ SEQUENCE 246 AA; 28082 MW; 29F1D5B9539B6221 CRC64;
MAAPGPALCL FDVDGTLTAP RQKITKEMDD FLQKLRQKIK IGVVGGSDFE KVQEQLGNDV
VEKYDYVFPE NGLVAYKDGK LLCRQNIQSH LGEALIQDLI NYCLSYIAKI KLPKKRGTFI
EFRNGMLNVS PIGRSCSQEE RIEFYELDKK ENIRQKFVAD LRKEFAGKGL TFSIGGQISF
DVFPDGWDKR YCLRHVENDG YKTIYFFGDK TMPGGNDHEI FTDPRTMGYS VTAPEDTRRI
CELLFS
//

MIM 212065
*RECORD*
*FIELD* NO
212065
*FIELD* TI
#212065 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia; CDG1A
;;CDG Ia; CDGIa;;
JAEKEN SYNDROME;;
read morePHOSPHOMANNOMUTASE 2 DEFICIENCY;;
CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME, TYPE Ia, FORMERLY
*FIELD* TX
A number sign (#) is used with this entry because congenital disorder of
glycosylation type Ia (CDG Ia, CDG1A) is caused by mutation in the gene
encoding phosphomannomutase-2 (PMM2; 601785).

DESCRIPTION

Congenital disorders of glycosylation (CDGs) are a genetically
heterogeneous group of autosomal recessive disorders caused by enzymatic
defects in the synthesis and processing of asparagine (N)-linked glycans
or oligosaccharides on glycoproteins. These glycoconjugates play
critical roles in metabolism, cell recognition and adhesion, cell
migration, protease resistance, host defense, and antigenicity, among
others. CDGs are divided into 2 main groups: type I CDGs comprise
defects in the assembly of the dolichol lipid-linked oligosaccharide
(LLO) chain and its transfer to the nascent protein, whereas type II
CDGs (see, e.g., CDG2A, 212066) refer to defects in the trimming and
processing of the protein-bound glycans either late in the endoplasmic
reticulum or the Golgi compartments. CDG1A is the most common form of
CDG and was the first to be characterized at the molecular level
(reviews by Marquardt and Denecke, 2003; Grunewald et al., 2002).

Matthijs et al. (1997) noted that Jaeken syndrome (CDG1A) is a genetic
multisystem disorder characterized by defective glycosylation of
glycoconjugates. It usually presents as a severe disorder in the
neonatal period. There is 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. There is a 20% lethality in the
first year of life due to severe infections, liver insufficiency, or
cardiomyopathy.

- Genetic Heterogeneity of Congenital Disorder of Glycosylation
Type I

Multiple forms of CDG type I have been identified; see CDG1B (602579)
through CDG1X (615597).

CLINICAL FEATURES

CDG type Ia was first described in an abstract by Jaeken et al. (1980).
In a complete report, Jaeken et al. (1984) described Belgian identical
twin sisters with a disorder characterized by psychomotor retardation
suggestive of a demyelinating disease and multiple serum glycoprotein
abnormalities. Serum and CSF transferrin (TF; 190000) were found to be
deficient in sialic acid.

Jaeken et al. (1987) described 4 girls, including the monozygotic twins
described earlier, from 3 unrelated families who had a neurologic
syndrome characterized by severe psychomotor retardation with
generalized hypotonia, hyporeflexia, and trunk ataxia. Growth was
retarded, but 2 were moderately obese. All 4 had almond-shaped eyes and
alternating internal strabismus. Two had fusiform phalanges of the
fingers, prominent labia majora, and symmetric fat accumulations as well
as lipodystrophy of the buttocks, which seemed to disappear with age.
Biochemical analysis and isoelectric focusing showed a decrease of
several serum glycoproteins, and total serum glycoproteins were
deficient in sialic acid, galactose, and N-acetylglucosamine. Serum
activity of N-acetylglucosaminyltransferase was reduced to 37% of
normal, but Jaeken et al. (1987) suggested that since a mixture of
isoenzymes from various sources was being measured, the 37% reduction
might represent a more profound deficiency of 1 isoenzyme. Among the
parents, only the fathers showed some biochemical abnormalities: partial
thyroxine-binding globulin (TBG; 314200) deficiency,
hypocholesterolemia, and a 10% deficiency of sialic acid, galactose, and
N-acetylglucosamine in total serum glycoproteins. Jaeken et al. (1987)
thus initially considered that the affected girls might be homozygous
for a mutant gene coding for an N-acetylglucosaminyltransferase,
possibly on the X chromosome.

Jaeken and Stibler (1989) described the disorder as a neurologic
syndrome with cerebellar hypoplasia and peripheral demyelination
associated with abnormalities of multiple secretory glycoproteins. All
serum glycoproteins were reported as partially deficient in sialic acid,
galactose, and N-acetylglucosamine, suggesting a deficiency of
N-acetylglucosaminyltransferase.

Kristiansson et al. (1989) reported 7 Swedish children with what the
authors termed 'disialotransferrin developmental deficiency syndrome.'
There were 3 pairs of sibs and 1 sporadic case. All 7 patients had
mental retardation, were prone to acute cerebral dysfunction during
catabolic states, and developed abnormal lower neuron, cerebellar, and
retinal functions in later childhood. They had a characteristic external
appearance with decreased subcutaneous tissue. Biochemical studies
showed abnormal sialic acid transferrin patterns in serum and CSF.

Buist and Powell (1991) reported 2 sisters, aged 14 and 16 years, whom
they had followed for 13 years. Both presented in infancy with
developmental delay, hypotonia, wandering eye movements, strabismus, and
failure to thrive. One child had pseudolipomas over each gluteus medius
and the other had similar fatty tissue causing enlarged labia majora.
The characteristic fat pads disappeared in childhood. Isoelectric
focusing of transferrin showed marked decrease of the tetrasialo
fraction and increase in the di- and asialo fractions. The findings
suggested a generalized defect in sialylation of serum glycoproteins.

Eeg-Olofsson and Wahlstrom (1991) reported that 20 Swedish patients with
the carbohydrate-deficient glycoprotein syndrome came from 13 families,
all from the southern part of the country. The oldest patient with CDG
was a woman born in 1942, and the youngest, a girl born in 1988. Eight
Swedish families had 2 sibs with CDG. Two concordantly affected
monozygotic twin-pairs were known. In 20 CDG families, if correction was
made for the ascertainment bias by exclusion of the index patient in
each family, the number of affected sibs and healthy sibs agreed
satisfactorily with the recessive hypothesis.

Harrison et al. (1992) studied a 24-month-old girl whose clinical
findings of hypotonia, delayed development, cerebellar hypoplasia, and
metabolic crises were consistent with the clinical diagnosis of CDG.
They also studied a brother and sister, aged 21 and 19 years,
respectively, with this disorder. High-resolution 2-dimensional
polyacrylamide gel electrophoresis (2DE) and silver staining yielded a
potentially pathognomonic profile of multiple serum protein anomalies in
CDG. Both parents had normal serum protein 2DE patterns.

Petersen et al. (1993) reported on the first 5 of 8 patients with CDG
diagnosed in Denmark from 1989 until the end of 1991. Three were male
and 2 were a pair of male-female twins. All 5 children were seen during
their first year of life with failure to thrive, feeding difficulties,
psychomotor retardation, hypotonia, esotropia, inverted nipples,
lipodystrophy, pericardial effusion, and hepatic dysfunction. Steatosis
was observed in liver biopsy specimens, and cerebellar hypoplasia was
present on computed tomography.

Ohno et al. (1992) described 3 affected Japanese children from 2
families. The clinical picture was that of a multisystem disorder
characterized by mental retardation, nonprogressive ataxia,
polyneuropathy, hepatopathy during infancy, and growth retardation.
Studies of serum transferrin by isoelectric focusing demonstrated
increases in disialotransferrin and asialotransferrin. Removal of sialic
acid with neuraminidase demonstrated the same transferrin phenotypes as
in the parents. Similarly, carbohydrate-deficient fractions of serum
alpha-1-antitrypsin (PI; 107400) were detected.

Harrison (1993) identified 9 patients with CDG, including 1 from a
nonconsanguineous Puerto Rican family and another from a
nonconsanguineous Chinese family.

In a review, Hagberg et al. (1993) stated that CDG I had been diagnosed
in 45 Scandinavian patients and presented different clinical phenotypic
features of the syndrome according to period of life. During infancy,
internal organ symptoms predominate and some may be life-threatening. In
later childhood and adolescence, static mental deficiency, cerebellar
ataxia, slowly progressive lower limb neuropathy, pigmentary retinal
degeneration, and secondary skeletal deformities are the most prominent
findings. Hagberg et al. (1993) summarized the features of CDG IIa and
compared them with those of CDG I.

Drouin-Garraud et al. (2001) also noted that clinical findings of CDG Ia
tend to change with age. During infancy, patients present with severe
neurologic involvement with hypotonia, failure to thrive, roving eye
movements, and developmental delay. There is often cerebellar and
brainstem atrophy as well as hepatic and cardiac manifestations.
Children with CDG Ia have a relatively static clinical course, with
ataxia as the predominant sign. Musculoskeletal complications, such as
kyphoscoliosis and muscular atrophy, appear in late childhood. Adults
commonly manifest endocrine dysfunctions, such as hypogonadism and
insulin resistance.

De Lonlay et al. (2001) reported the clinical, biologic, and molecular
analysis of 26 patients with CDG I including 20 CDG Ia, 2 CDG Ib, 1 CDG
Ic, and 3 CDG Ix patients detected by Western blotting and isoelectric
focusing of serum transferrin. Based on clinical features, de Lonlay et
al. (2001) concluded that CDG Ia could be split into 2 subtypes: a
neurologic form with psychomotor retardation, strabismus, cerebellar
hypoplasia, and retinitis pigmentosa, and a multivisceral form with
neurologic and extraneurologic manifestations including liver, cardiac,
renal, or gastrointestinal involvement. Inverted nipples, cerebellar
hypoplasia, and abnormal subcutaneous fat distribution were not present
in all cases.

Drouin-Garraud et al. (2001) identified a French family in which 3 sibs
with CDG Ia displayed an unusual presentation remarkable for both the
neurologic presentation and the dissociation between intermediate PMM2
activity in fibroblasts and a decreased PMM2 activity in leukocytes.
Their report showed that the diagnosis of CDG Ia must be considered in
patients with nonregressive early-onset encephalopathy with cerebellar
atrophy, and that intermediate values of PMM2 activity in fibroblasts do
not exclude the diagnosis.

Coman et al. (2008) reviewed the skeletal manifestations of congenital
disorders of glycosylation, which they suggested may be underrecognized.

- Neonatal-Onset CDG Ia

The most severe form of CDG Ia has a neonatal onset. Agamanolis et al.
(1986) reported 2 sibs with olivopontocerebellar degeneration, failure
to thrive, hepatic fatty change and cirrhosis, and a dyslipoproteinemia
characterized by low cholesterol and elevated triglycerides. Cerebellar
degeneration progressed rapidly during the first year of life and both
children died from intercurrent infections and surgical complications.
The authors suggested a metabolic defect. Harding et al. (1988) reported
a similar case of neonatal onset with biochemical abnormalities and
other systemic involvement. Horslen et al. (1991) reported 2 brothers
with neonatal onset of olivopontocerebellare degeneration, failure to
thrive, hypotonia, liver disease, and visual inattention. Microcystic
renal changes were observed at autopsy. The patients also had
abnormalities in serum transferrin, and Horslen et al. (1991) concluded
that the disorder was a severe manifestation of CDG.

Clayton et al. (1992) described their seventh patient with
neonatal-onset CDG in whom the disorder was established by
electrophoresis with immunofixation of serum transferrin, which showed a
reduced amount of tetrasialotransferrin, an increased amount of
disialotransferrin, and the presence of asialotransferrin. A new feature
was severe hypertrophic cardiomyopathy. Respiratory distress and a
murmur with episodes of arterial oxygen desaturation had brought the
neonate to cardiologic assessment. After initial spontaneous improvement
he presented at 9 weeks with severe manifestations of the
cardiomyopathy. Chang et al. (1993) reported the case of an 8-month-old
male infant who presented in the neonatal period with failure to thrive,
bilateral pleural and pericardial effusions, and hepatic insufficiency
and showed at autopsy olivopontocerebellar atrophy, micronodular
cirrhosis, and renal tubular microcysts.

In a neonate with neurologic abnormalities and congenital nephrotic
syndrome of diffuse mesangial sclerosis type, van der Knapp et al.
(1996) found diagnostic evidence of CDG I. However, there was no
evidence of pontocerebellar atrophy by imaging or at autopsy. They
concluded that CDG I should be considered in patients with congenital
nephrotic syndrome and that absence of pontocerebellar atrophy did not
exclude the diagnosis.

OTHER FEATURES

Stromland et al. (1990) found all 10 of the children with this syndrome
who were examined had ocular involvement. Esotropia and deficient
abduction was found in all 10 patients. Seven children had retinitis
pigmentosa, which was verified by an ERG in 3. One patient had retinal
signs suggestive of retinitis pigmentosa.

Andreasson et al. (1991) reported the findings in full-field ERGs in 5
patients with CDG. Only 2 of them showed fundus changes typical for
retinitis pigmentosa, whereas abnormal ERGs were seen in all. There was
no recordable rod response; however, a delay in the cone b-wave implicit
time was noted. All patients had nyctalopia. The observations suggested
that patients with CDG have a progressive tapetoretinal degenerative
disorder of the retinitis pigmentosa type with defined alterations in
the ERG.

Martinsson et al. (1994) pictured a 16-year-old patient who showed short
stature, prominent jaw, mild anterior chest deformity, and muscle
atrophy of the lower limbs. He was unable to stand and walk without
support because of peripheral neuropathy and cerebellar ataxia.

Fiumara et al. (1994, 1996) suggested that a familial Dandy-Walker
variant (220200) may occur as a feature of the CDG.

de Koning et al. (1998) observed 2 sibs with CDG and nonimmune hydrops
fetalis.

Patients with CDG Ia have a thrombotic tendency, whereas a patient with
CDG IIa, described by Van Geet et al. (2001), had an increased bleeding
tendency. This prompted Van Geet et al. (2001) to investigate whether
abnormally glycosylated platelet membrane glycoproteins are involved in
the hemostatic complications of both CDG groups. Van Geet et al. (2001)
observed abnormal glycosylation of platelet glycoproteins in CDG Ia
causing enhanced onset of platelet interactions, leading to thrombotic
tendency. Reduced GP Ib (231200)-mediated platelet reactivity with
vessel wall components in the CDG IIa patient under flow conditions
provided a basis for his bleeding tendency.

Bohles et al. (2001) reported a male infant who presented with
persistent hyperinsulinemic hypoglycemia responding to diazoxide
treatment. However, this therapy was discontinued because of seizures as
a consequence of disturbed water and electrolyte balance. Glucose
homeostasis could only be maintained by subtotal pancreatectomy, which
was performed at 3.75 years of age. The patient subsequently developed a
severe thrombosis, whereupon a congenital disorder of glycosylation was
suspected. An abnormal isoelectric focusing pattern of transferring was
found and a diagnosis of CDG Ia was confirmed by enzymatic and molecular
genetic analysis. The patient had internal strabismus and inverted
nipples with an MRI scan demonstrating hypoplasia of the cerebellar
vermis and of both cerebral hemispheres. Molecular analysis identified
compound heterozygosity for 2 mutations in the PMM2 gene (601785.0001;
601785.0018). Fibroblast phosphomannomutase activity was less than 5% of
normal.

Silengo et al. (2003) described hair abnormalities in 3 patients with
CDG type I, 1 with CDG Ia and 2 with an unclassified form of the
disorder. The hair was sparse and coarse textured, lacked luster, and
was slow growing. It showed enhanced fragility with the microscopic
findings of trichorrhexis nodosa and pili torti. Silengo et al. (2003)
postulated that the underlying cause of the hair anomaly in CDG I was an
abnormality of membrane glycoprotein expression during differentiation
of epidermis and adnexes.

Coman et al. (2008) described a female infant with mutation-positive
CDG1A who died at 3 weeks of age due to cardiac tamponade and who had a
skeletal phenotype reminiscent of a type II collagenopathy. Skeletal
survey revealed short long bones with 'dumbbell' metaphyseal expansions,
generalized epiphyseal ossification delay, ovoid and anteriorly beaked
vertebral bodies, hypoplastic cervical vertebrae, 13 rib pairs,
hypoplastic pubic bones, and bullet-shaped short tubular bones. Coman et
al. (2008) stated that the radiographic skeletal appearance was
consistent with a primary skeletal dysplasia, most similar to Kniest
dysplasia (156550) or spondyloepiphyseal dysplasia congenita (183900).
In addition, MRI of the cervical spine showed elevation of the posterior
arch of C1 with the occipital bone and significant spinal canal stenosis
at the craniocervical junction due to a bone spur.

BIOCHEMICAL FEATURES

The characteristic biochemical abnormality of CDG was discovered
serendipitously by Stibler and Jaeken (1990) in the isoelectric focusing
of serum transferrin, a test originally devised to screen for alcohol
abuse in normal adults (Stibler et al., 1978). Serum transferrin from
affected individuals showed a consistent increase of isotransferrins
with higher isoelectric points than normal. Carbohydrate determinations
in purified transferrin showed deficiencies of sialic acid, galactose,
and N-acetylglucosamine. The results suggested that either 2 or all of
the normally 4 terminal trisaccharides in transferrin were missing,
suggesting a defect in synthesis or catabolism.

Wada et al. (1992) determined the structure of serum transferrin in CDG
type I and showed that it was disialylated, missing either of 2 N-linked
sugar chains, suggestive of a metabolic error in the early steps of
protein glycosylation.

Because coagulation factors and inhibitors are glycoproteins, Van Geet
and Jaeken (1993) performed a systematic study of these factors and
inhibitors in 9 patients with CDG. All showed a decreased activity of
factor XI (F11; 264900) and of the coagulation inhibitors antithrombin
III (AT3; 107300) and protein C (PROC; 612283). In 5 of 7 patients older
than 1 year, there was also a less pronounced decrease of protein S
(PROS1; 176880) and of heparin cofactor II (HCF2; 142360). The authors
suggested that this combined coagulation inhibitor deficiency may
explain the stroke-like episodes occurring in children with this
disorder.

Van Schaftingen and Jaeken (1995) reported that the activity of
phosphomannomutase, the enzyme that converts mannose 6-phosphate to
mannose 1-phosphate, was markedly deficient (10% or less of control
activity) in fibroblasts, liver, and/or leukocytes of 6 patients with
CDG I. This was the first report of phosphomannomutase deficiency in
higher organisms. Other enzymes involved in the conversion of glucose to
mannose 1-phosphate had normal activities. Phosphomannomutase activity
was normal in fibroblasts of 2 patients with CDG IIa (212066). Since
this enzyme provides the mannose 1-phosphate required for the initial
step of protein glycosylation, Van Schaftingen and Jaeken (1995)
concluded that phosphomannomutase deficiency is a major cause of CDG I.

Sala et al. (2002) investigated the possible relationship between lipid
and protein glycosylation to determine if a compensatory mechanism was
present. CDG Ia fibroblasts had higher levels of glycosphingolipids
(GSLs) compared to normal fibroblasts and a diminished biosynthesis of
cellular glycoproteins in metabolic studies with radioactive precursor
sugars including galactose and N-acetylmannosamine. CDG Ia fibroblasts
also had increased GSL biosynthesis with radiolabeled sphingosine and
lactosylceramide and slowed degradation of GSLs. Using normal and CHO
fibroblasts labeled with radioactive galactose in the presence or
absence of dMM (an inhibitor of N-glycan maturation), Sala et al. (2002)
found an inverse relationship between glycoprotein expression and GSL
content. The authors concluded that the increase in GSLs may help to
preserve the overall equilibrium of the outer layer of the plasma
membrane.

DIAGNOSIS

Heyne and Weidinger (1992) reported 3 cases. Analyses of the
glycoprotein alpha-1-antitrypsin showed an abnormal cathodic isoform
which represented almost half of the total amount of
alpha-1-antitrypsin. The authors suggested the use of this marker
glycoprotein as a diagnostic tool and suggested that diseases due to
inborn errors of N-glycan synthesis be referred to as 'glycanoses.'

Skovby (1993) emphasized the diagnostic usefulness of the finding of
inverted nipples at birth in CDG Ia. This sign in floppy infants with
poor weight gain, strabismus, abnormal distribution of subcutaneous fat,
and cerebellar hypoplasia can suggest the diagnosis which is confirmed
by demonstration of carbohydrate-deficient transferrin in serum.

Schollen et al. (2004) concluded that the recurrence risk for CDG Ia is
close to 1 in 3 rather than 1 in 4 as expected of an autosomal
recessive, indicating transmission ratio distortion. In 92 independent
pregnancies among couples at risk for CDG Ia, genotyping in the context
of prenatal diagnosis demonstrated that the percentage of affected
fetuses (34%; 31/92, p = 0.039) was higher than expected based on
Mendel's second law. The transmission ratio distortion might explain the
relatively high carrier frequency of the R141H mutation in the PMM2 gene
(601785.0001). The authors suggested that the drive of the mutated
alleles may relate to a reproductive advantage at the stage of
gametogenesis, fertilization, implantation, or embryogenesis, rather
than to resistance to environmental factors during infant or adult life.

- Prenatal Diagnosis

Bjursell et al. (1998) proposed the combined use of mutation analysis
and linkage analysis with polymorphic markers as diagnostic tools for
Scandinavian CDG I families requesting prenatal diagnosis. Using this
strategy, they had successfully performed 15 prenatal diagnoses for CDG
Ia to the time of report.

PATHOGENESIS

The typical side chains (or 'antennae') of complex-type N-linked
oligosaccharides on most normal human serum glycoproteins arise from the
processing and remodeling of mannose-containing structures and are
therefore the net product of multiple exoglycosidases and
glycosyltransferases. Based on a partial decrease in total GlcNAc
transferase activity in serum, abnormalities were postulated of one or
more of the specific GlcNAc transferases responsible for the initial
extension of the antennae of N-linked oligosaccharides. Powell et al.
(1994) studied both serum glycoproteins and oligosaccharides derived
from fibroblasts of individuals with CDG type I. Several experiments
failed to show a specific defect in the processing of N-linked
oligosaccharides, but instead suggested a defect in the synthesis and
transfer of the dolichol lipid-linked precursor itself, with reduced
levels of mannose incorporation into both the precursor and nascent
glycoproteins. As protein synthesis itself was not affected, the net
result was a relative underglycosylation of glycoproteins in the CDG
samples relative to controls. In some CDG patients, the lipid-linked
oligosaccharide was abnormally small. Powell et al. (1994) concluded
that at least in some patients, CDG is not due to a defect in processing
of N-linked oligosaccharides, but rather to defective synthesis and
transfer of nascent dolichol-linked oligosaccharide precursors.

Panneerselvam and Freeze (1996) showed that 4 CDG fibroblast cell lines
had 2 glycosylation abnormalities: incorporation of labeled mannose into
proteins was reduced 3- to 10-fold below normal and the size of the
lipid-linked oligosaccharide precursor was much smaller than in
controls. Addition of exogenous mannose, but not glucose, to these CDG
cells corrected both abnormalities. The correction was not permanent,
and the defects immediately reappeared when mannose was removed.
Although they did not identify the primary defect in CDG, Panneerselvam
and Freeze (1996) suggested that their studies showed that intracellular
mannose is limited and that some patients may benefit from including
mannose in their regular diets.

Barone et al. (2008) reported 2 adult Sicilian brothers with CDGIa
confirmed by genetic analysis (601785.0001; 601785.0003). Clinical
features in both patients included early-onset cerebellar atrophy,
mental impairment, pigmentary retinopathy, and dysmorphic features. The
younger brother, patient 2, was more severely affected and had
additional features, including abnormal subcutaneous fat distribution,
inverted nipples, genu valgum and flat and inverted feet. He also had
more severely affected motor-adaptive functions and communication
ability and lower full-scale IQ compared to his older brother. MALDI-TOF
mass spectrometry of serum transferrin and alpha-1-antitrypsin showed
more pronounced glycosylation defects in the younger brother. Barone et
al. (2008) concluded that there is a correlation between absence of
N-glycosylation and clinical expression, and that glycoproteomic
analysis may reveal differences in CDGIa patients with different disease
severity.

MAPPING

Martinsson et al. (1994) performed linkage analysis in 25 CDG I
pedigrees using highly polymorphic microsatellite markers and detected
linkage with markers on chromosome 16p. The lod score was above 8 (theta
= 0.00) for several markers in that region. Recombination events in some
pedigrees indicated that the CDG1 locus was located in a 13-cM interval
between D16S406 and D16S500. No heterogeneity could be detected in the
European families studied. The positions of the cytogenetically
localized flanking markers suggested that the CDG1 locus was on
16p13.3-p13.12.

Matthijs et al. (1996) analyzed a series of polymorphic markers on 16p13
in 17 families with CDG1 and confirmed linkage to the region between
D16S406 and D16S500. The telomeric border of the candidate region was
placed proximal to D16S406 by crossovers observed in 2 families. In 1
family with 2 affected sibs, the disease was not linked to 16p. Matthijs
et al. (1996) stated that genetic heterogeneity had not previously been
reported for CDG I and they noted implications for prenatal diagnosis.
Allelic associations suggested to them that the disease locus was close
to D16S414/D16S497.

Bjursell et al. (1997) studied 44 CDG I families from 9 countries using
markers from the 16p13 region. One specific haplotype was found to be
markedly overrepresented in CDG I patients from a geographically
distinct region in Scandinavia: western parts of Sweden, southern parts
of Norway, and eastern Denmark. Their analyses of the extent of the
common haplotype in these families indicated a refined region for the
CDG1 gene and indicated strong linkage disequilibrium with selected
markers, thus narrowing the assignment to less than 1 Mb of DNA and less
than 1 cM in the very distal part of the CDG1 region previously defined
by Martinsson et al. (1994).

MOLECULAR GENETICS

In 16 CDG I patients from different geographic origins and with a
documented phosphomannomutase deficiency, Matthijs et al. (1997) found
11 different missense mutations in the PMM2 gene (see, e.g.,
601785.0001-601785.0004). Additional mutations, including point
mutations, deletions, intronic mutations and exon-skipping mutations
were reported by others, including Carchon et al. (1999), Matthijs et
al. (1999), and Vuillaumier-Barrot et al. (1999).

Imtiaz et al. (2000) reported the U.K. experience with CDG type Ia.
Eighteen patients from 14 families had been diagnosed with CDG type I on
the basis of their clinical symptoms and/or abnormal electrophoretic
patterns of serum transferrin. Eleven of the 16 infants died before the
age of 2 years. Patients from 12 families had a typical type I
transferrin profile, but one had a variant profile and another, who had
many clinical features of CDG type I, had a normal profile. Eleven of
the patients from 10 families with a typical type I profile had
deficiency of PMM, but there was no correlation between residual enzyme
activity and severity of disease. All these patients were compound
heterozygotes for mutations in the PMM2 gene, with 7 of 10 families
having the common arg141-to-his (601785.0001) mutation. Imtiaz et al.
(2000) identified 8 different mutations in the PMM2 gene, including 3
novel ones. There was no correlation between genotype and phenotype,
although the sibs had similar phenotypes. Three patients, including the
one with the normal transferrin profile, did not have a deficiency of
phosphomannomutase or phosphomannose isomerase.

Neumann et al. (2003) identified homozygosity for an N216I mutation
(601785.0002) in the PMM2 gene in a 16-month-old boy with postnatal
macrosomia, unusual eyebrows, and typical biochemical findings on
isoelectric focusing of serum transferrin and reduced phosphomannomutase
activity in leukocytes and cultured fibroblasts. The child did not have
inverted nipples or abnormal fat pads. Neumann et al. (2003) suggested
that the homozygous mutation could have a specific CDG Ia phenotype
correlation.

Van de Kamp et al. (2007) reported 2 unrelated male and female infants
who presented with nonimmune hydrops fetalis and were later diagnosed
with CDG Ia. Both patients were compound heterozygotes for the common,
relatively mild F119L mutation (601785.0006), as well as a more severe
mutation (a frameshift and another missense mutation, respectively). Van
de Kamp et al. (2007) suggested that the presence of 1 severe mutation
may be required for the development of hydrops fetalis, and that CDG Ia
should be considered in the differential diagnosis of nonimmune hydrops
fetalis.

Najmabadi et al. (2011) performed homozygosity mapping followed by exon
enrichment and next-generation sequencing in 136 consanguineous families
(over 90% Iranian and less than 10% Turkish or Arabic) segregating
syndromic or nonsyndromic forms of autosomal recessive intellectual
disability. In family 8307998, they identified a homozygous missense
mutation in the PMM2 gene (601785.0023) in 3 sibs with mild intellectual
disability, thin upper lip, flat nasal bridge, and strabismus, who were
diagnosed with glycosylation disorder CDG Ia (212065). The parents, who
were first cousins, were carriers, and they had 5 healthy children.

POPULATION GENETICS

Skovby (1993) stated that cases of CDG Ia had been observed in many
parts of the world, including Iran and Japan, but that about half of the
cases known worldwide were Scandinavian.

Bjursell et al. (1998) showed that the specific haplotype in CDG I
patients from western Scandinavia is associated with the 357C-A mutation
in the PMM2 gene (601785.0010).

Briones et al. (2002) presented their experience with a diagnosis of CDG
Ia in 26 Spanish patients from 19 families. Patients in all but 1 of the
families were compound heterozygous for mutations in the PMM2 gene.
Eighteen different mutations were detected. In contrast to other series
in which the R141H (601785.0001) mutation represents 43 to 53% of the
alleles, only 9 of 36 (25%) of the alleles had this mutation. The common
European F119L (601785.0006) mutation was not identified in any of the
Spanish patients, but the V44A (601785.0020) and D65Y (601785.0005)
mutations probably originated in the Iberian peninsula, as they have
only been reported in Portuguese and Latin-American patients. Probably
because of this genetic heterogeneity, Spanish patients showed very
diverse phenotypes that are, in general, milder than in other series.

NOMENCLATURE

CDGs were formerly referred to as 'carbohydrate-deficient glycoprotein
syndromes' (Marquardt and Denecke, 2003; Grunewald et al., 2002).
Conventionally, untyped and unclassified cases of CDG are labeled CDG-x
(see 212067) until they are characterized at the molecular level. Orlean
(2000) discussed the revised nomenclature for CDGs proposed by the
participants at the First International Workshop on CDGs in Leuven,
Belgium, in November 1999.

HISTORY

Jaeken (1990) favored autosomal recessive inheritance, although he had
not completely abandoned the possibility of X-linked inheritance. Some
have referred to the condition as the 'desialotransferrin developmental
deficiency syndrome' (Kristiansson et al., 1989), but this is a misnomer
since the serum protein abnormality is not limited to sialic acid or to
transferrin (Jaeken, 1990).

ANIMAL MODEL

Schneider et al. (2012) generated transgenic mice with homozygous or
compound heterozygous hypomorphic Pmm2 alleles: R137H, which is
analogous to human R141H (601785.0001), and F118L, which is predicted to
lead to mild loss of enzyme activity. Homozygous R137H and compound
heterozygous R137H/F118L mice were embryonic lethal. Homozygosity for
R137H was associated with no residual enzymatic activity, whereas
R137H/F118L mice had about 11% residual activity. Homozygous F118L mice
were clinically similar to wildtype, with 38 to 42% residual PMM2
activity, which was sufficient to prevent pathologic consequences.
Compound heterozygous R137H/F118L embryos showed very poor intrauterine
growth with extensive degradation of multiple organs and evidence of
hypoglycosylation of glycoproteins. Treatment of heterozygous F118L
females with oral mannose in water beginning 1 week prior to mating
resulted in a 2-fold increase of serum mannose concentrations and
rescued the embryonic lethality of compound heterozygous R137H/F118L
offspring, who survived beyond weaning. Compound heterozygous offspring
under treatment showed organ development and glycosylation comparable to
wildtype mice, indicating mannose-mediated normalization of
glycosylation. The phenotypic rescue remained apparent even after
4-month maintenance of the offspring on normal water. The results
revealed an essential role for proper glycosylation during embryogenesis
and suggested that mannose administration to at-risk mothers may reduce
the phenotype of offspring.

*FIELD* SA
Jaeken et al. (1993); Jaeken et al. (1991)
*FIELD* RF
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*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Weight];
Failure to thrive

HEAD AND NECK:
[Head];
Microcephaly (50% of patients);
[Face];
Prominent forehead;
[Ears];
Large ears;
[Eyes];
Abnormal eye movements;
Internal strabismus;
Retinitis pigmentosa;
Nystagmus;
[Nose];
Flat nasal bridge;
[Mouth];
Thin upper lip

CARDIOVASCULAR:
[Heart];
Pericardial effusion;
Cardiomyopathy

CHEST:
[Breasts];
Inverted nipples

ABDOMEN:
[Liver];
Hepatomegaly;
Liver fibrosis;
Steatosis;
[Gastrointestinal];
Feeding problems;
Diarrhea;
Vomiting

GENITOURINARY:
[Internal genitalia, female];
Primary ovarian failure;
[Kidneys];
Renal cysts;
Nephrotic syndrome;
Proximal tubulopathy

SKELETAL:
Osteopenia;
[Spine];
Kyphosis;
[Limbs];
Joint contractures

SKIN, NAILS, HAIR:
[Skin];
Abnormal subcutaneous fat tissue distribution;
Fat pads;
'Orange peel' skin

MUSCLE, SOFT TISSUE:
Abnormal subcutaneous fat tissue distribution;
Weakness

NEUROLOGIC:
[Central nervous system];
Hypotonia;
Psychomotor retardation;
Ataxia;
Hyporeflexia;
Stroke-like episodes;
Seizures;
Most patients are wheelchair-bound;
Olivopontocerebellar hypoplasia;
[Peripheral nervous system];
Peripheral neuropathy

ENDOCRINE FEATURES:
Hypothyroidism;
Decreased thyroxine;
Decreased thyroxine-binding globulin;
Hypergonadotropic hypogonadism

HEMATOLOGY:
Prolonged prothrombin time;
Factor XI deficiency;
Antithrombin III deficiency;
Thrombocytosis

IMMUNOLOGY:
Decreased immunoglobulin A (IgA);
Decreased immunoglobulin G (IgG)

PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Nonimmune hydrops fetalis

LABORATORY ABNORMALITIES:
Abnormal isoelectric focusing of serum transferrin (type 1 pattern);
Abnormal serum glycoproteins;
Elevated transaminases;
Proteinuria;
Decreased copper, iron, zinc;
Hypocholesterolemia;
Hypoalbuminemia;
Phosphomannomutase deficiency in leukocytes, fibroblasts, or liver

MISCELLANEOUS:
Two clinical presentations - solely neurologic form and a neurologic-multivisceral
form;
Mortality approximately 20% in first 2 years

MOLECULAR BASIS:
Caused by mutation in the phosphomannomutase 2 gene (PMM2, 601785.0001)

*FIELD* CN
Marla J. F. O'Neill - updated: 7/2/2007
Cassandra L. Kniffin - updated: 6/22/2007
Kelly A. Przylepa - updated: 2/27/2002
Kelly A. Przylepa - revised: 2/20/2002

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 03/19/2008
joanna: 7/2/2007
ckniffin: 6/22/2007
ckniffin: 7/8/2004
joanna: 2/27/2002
joanna: 2/20/2002

*FIELD* CN
Cassandra L. Kniffin - updated: 2/15/2012
Ada Hamosh - updated: 1/6/2012
Cassandra L. Kniffin - updated: 4/16/2009
Cassandra L. Kniffin - updated: 10/20/2008
Marla J. F. O'Neill - updated: 4/24/2008
Cassandra L. Kniffin - reorganized: 6/26/2007
Cassandra L. Kniffin - updated: 6/22/2007
Marla J. F. O'Neill - updated: 6/5/2007
Victor A. McKusick - updated: 12/16/2004
Natalie E. Krasikov - updated: 3/12/2004
Natalie E. Krasikov - updated: 2/9/2004
Ada Hamosh - updated: 10/9/2003
Ada Hamosh - updated: 10/2/2003
Ada Hamosh - updated: 1/16/2002
Victor A. McKusick - updated: 5/16/2001
Michael J. Wright - updated: 2/5/2001
Ada Hamosh - updated: 5/22/2000
Hudson H. Freeze - updated: 2/17/2000
Hudson H. Freeze - reviewed: 2/17/2000
Victor A. McKusick - updated: 2/10/2000
Victor A. McKusick - updated: 1/7/2000
Victor A. McKusick - updated: 3/17/1999
Victor A. McKusick - updated: 10/13/1998
Victor A. McKusick - updated: 4/16/1998
Beat Steinmann - updated: 1/23/1998
Victor A. McKusick - updated: 4/30/1997
Victor A. McKusick - updated: 2/20/1997
Victor A. McKusick - updated: 4/1/1997

*FIELD* CD
Victor A. McKusick: 5/29/1991

*FIELD* ED
carol: 01/13/2014
tpirozzi: 9/18/2013
carol: 6/12/2013
carol: 1/29/2013
ckniffin: 1/29/2013
ckniffin: 11/8/2012
carol: 5/10/2012
carol: 3/2/2012
ckniffin: 3/1/2012
carol: 2/23/2012
ckniffin: 2/15/2012
carol: 1/9/2012
terry: 1/6/2012
carol: 1/14/2011
terry: 10/13/2010
carol: 7/22/2010
carol: 9/4/2009
wwang: 4/17/2009
ckniffin: 4/16/2009
terry: 4/9/2009
carol: 2/2/2009
wwang: 10/22/2008
ckniffin: 10/20/2008
carol: 9/12/2008
wwang: 4/25/2008
terry: 4/24/2008
carol: 6/27/2007
ckniffin: 6/26/2007
carol: 6/26/2007
ckniffin: 6/22/2007
wwang: 6/8/2007
terry: 6/5/2007
carol: 12/28/2004
terry: 12/16/2004
terry: 7/6/2004
carol: 3/23/2004
terry: 3/12/2004
carol: 2/9/2004
cwells: 10/9/2003
cwells: 10/2/2003
alopez: 1/18/2002
terry: 1/16/2002
mcapotos: 5/23/2001
mcapotos: 5/22/2001
terry: 5/16/2001
alopez: 2/5/2001
alopez: 6/1/2000
terry: 5/22/2000
carol: 3/1/2000
carol: 2/17/2000
terry: 2/10/2000
carol: 1/28/2000
terry: 1/7/2000
carol: 3/30/1999
terry: 3/17/1999
carol: 12/7/1998
carol: 10/19/1998
terry: 10/13/1998
carol: 9/18/1998
terry: 9/15/1998
carol: 4/28/1998
terry: 4/16/1998
joanna: 1/23/1998
mark: 4/30/1997
terry: 4/30/1997
jenny: 4/1/1997
terry: 3/21/1997
mark: 2/20/1997
terry: 2/12/1997
terry: 9/10/1996
terry: 8/22/1996
terry: 7/2/1996
terry: 6/28/1996
terry: 6/20/1996
mark: 4/29/1996
terry: 4/24/1996
terry: 12/21/1994
carol: 12/2/1994
pfoster: 4/25/1994
mimadm: 4/18/1994
warfield: 4/15/1994
carol: 11/3/1993

MIM 601785
*RECORD*
*FIELD* NO
601785
*FIELD* TI
*601785 PHOSPHOMANNOMUTASE 2; PMM2
*FIELD* TX

DESCRIPTION

The PMM2 gene encodes phosphomannomutase (EC 5.4.2.8), an enzyme
read morenecessary for the synthesis of GDP-mannose.

CLONING

Matthijs et al. (1997) identified phosphomannomutase-1 (PMM1; 601786) by
database searching for human cDNAs with similarity to Candida or yeast
phosphomannomutase. Biochemical studies of PMM1 and phosphomannomutases
from rat and human liver provided evidence for the existence in mammals
of a second phosphomannomutase with different kinetic and antigenic
properties. By database searching for sequences similar to that of PMM1,
Matthijs et al. (1997) identified identified and subsequently cloned a
PMM2 cDNA. The deduced 246-amino acid PMM2 protein shares 66% and 57%
sequence identity with PMM1 and yeast phosphomannomutase, respectively.

MAPPING

Matthijs et al. (1997) mapped the PMM2 gene to 16p13 by Southern blot
analysis of a genomic mapping panel and by hybridization to DNA from
YACs previously assigned to that chromosomal region (D16S406 to
D16S404). Bjursell et al. (1998) achieved refined mapping of the PMM2
gene by analysis of radiation hybrids.

GENE STRUCTURE

Schollen et al. (1998) determined the PMM2 intron/exon structure and
identified 8 exons.

MOLECULAR GENETICS

Van Schaftingen and Jaeken (1995) identified a deficiency of
phosphomannomutase activity in patients with carbohydrate-deficient
glycoprotein syndrome type Ia (CDG1A; 212065).

In 16 patients with CDG1A from different geographic origins and with a
documented phosphomannomutase deficiency, Matthijs et al. (1997)
identified 11 different missense mutations in PMM2 (see, e.g.,
601785.0001-601785.0004).

Matthijs et al. (1998) described the results of an exhaustive mutation
analysis of the PMM2 gene in 56 patients with documented PMM deficiency
from different geographic origins. By SSCP analysis and by sequencing,
they identified 23 different missense mutations and a single-basepair
deletion in 99% of the disease chromosomes. The R141H mutation
(601785.0001) was found in 43 of 112 disease alleles. However, this
mutation was never observed in the homozygous state, suggesting that
homozygosity is incompatible with live birth. Homozygous mutations were
found in other patients (D65Y, 601785.0005 and F119L, 601785.0006). One
particular genotype, R141H/D188G (601785.0007), which was prevalent in
Belgium and the Netherlands, was associated with a severe phenotype and
a high mortality. Apart from this, there was only a limited relation
between the genotype and the clinical phenotype.

Kjaergaard et al. (1998) identified 34 mutations on 36 disease
chromosomes in 18 unrelated Danish patients with CDG1. All patients had
less than 15% residual activity of phosphomannomutase. Two mutations
accounted for 88% of all mutations: F119L (601785.0006) and R141H
(601785.0001) were each found in 16 of 36 CDG1 alleles. These 2 new
mutations were found to be in linkage disequilibrium with 2 different
alleles of the marker D16S3020, suggesting that there is 1 ancestral
origin for each mutation. Two new mutations, G117R and D223E, were
identified also. As reported by others, no patient was homozygous for
either of the 2 common mutations. This could be interpreted as
indicating that homozygosity for these mutations is lethal or, on the
other hand, so benign that such patients are not detected.

Kondo et al. (1999) identified 3 missense mutations in the PMM2 gene in
2 unrelated Japanese families with CDG1. The mutations occurred in exons
5 and 8, as have most of the mutations identified in the Caucasian
population.

Kjaergaard et al. (1999) determined the PMM2 genotypes of 22 unrelated
Danish patients with CDG Ia. The largest proportion (18) had the
genotype R141H/F119L. R141H was present in heterozygous state in 1
patient, while F119L was homozygous in 1 patient and heterozygous with
G117R in another. The lack of patients homozygous for R141H was
statistically highly significant. To investigate the effect of PMM2
mutations on phosphomannomutase activity, Kjaergaard et al. (1999)
cloned the cDNA into a vector. Following the introduction of mutations
into the PMM2 cDNA by site-specific mutagenesis, wildtype and mutant
PMM2 cDNAs were expressed in E. coli, and the activity of PMM2 was
determined by an enzymatic assay. Recombinant R141H, G117R, and T237R
(601785.0011) PMM2 had no detectable catalytic activity. F119L PMM2 had
25% of the activity of wildtype. Each of the 22 patients had at least 1
mutation that retained residual PMM2 activity. The results supported the
hypotheses that a genotype conveying residual PMM2 catalytic activity is
required for survival, and that homozygosity for R141H impairs PMM2 to a
degree incompatible with life.

Matthijs et al. (1999) reviewed the molecular basis of CDG Ia. Matthijs
et al. (2000) collated data from 6 research and diagnostic laboratories
involved in searching for PMM2 mutations. In total, they listed 58
different mutations found in 249 patients from 23 countries. Bjursell et
al. (2000) performed a mutation screen on 61 CDG Ia patients, 37 of whom
were from Scandinavian countries. They succeeded in detecting more than
95% of the mutations, all of them missense mutations. Seven were found
only in Scandinavian families. Of the 20 mutations found, 10 had not
previously been reported. The R141H (601785.0001) and F119L
(601785.0006) mutations accounted for 58% of the mutations detected. The
most common genotype was compound heterozygosity for these 2 mutations
(36%). Although 2 patients were homozygous for F119L, no patient was
homozygous for the most common mutation, R141H. Most mutations were
located in exon 5 or exon 8, while no mutation was detected in exon 2.
When the frequency of each mutation was considered, exon 5 comprised 61%
of the mutations. Thus, analysis of exon 5 in these patients enabled
reliable and time-saving first screening in prenatal diagnostic cases.

Grunewald et al. (2001) reported that 9 of 54 patients with CDG Ia had a
rather high residual PMM activity in fibroblasts included in the normal
range (means of controls +/- 2 SD), amounting to 35 to 70% of the mean
control value. The clinical diagnosis of CDG Ia was difficult because 6
of the 9 patients belonged to a subgroup characterized by a phenotype
that is milder than classic CDG Ia. These patients lacked some of the
symptoms that are suggestive for the diagnosis, such as inverted nipples
and abnormal fat deposition, and, as a mean, had higher residual PMM
activity in fibroblasts compared with patients with moderate or severe
manifestations. However, they all showed mild mental retardation,
hypotonia, cerebellar hypoplasia, and strabismus. All of them had an
abnormal serum transferrin pattern and a significantly reduced PMM
activity in leukocytes. Of the 9 patients with mild presentation, 6 were
compound heterozygotes for the C241S mutation (601785.0012), which is
known to reduce PMM activity by only approximately 2-fold. Grunewald et
al. (2001) suggested that intermediate PMM values in fibroblasts may
mask the diagnosis of CDG Ia, which is better accomplished by
measurement of PMM activity in leukocytes and mutation search in the
PMM2 gene.

Vuillaumier-Barrot et al. (2000) studied the activity of mutant proteins
encoded by arg141 to his (R141H; 601785.0001), cys241 to ser (C241S;
601785.0012), cys9 to tyr (C9Y; 601785.0015), leu32 to arg (L32R;
601785.0016), and thr226 to ser (T226S; 601785.0017). They found that
the protein encoded by R141H had no detectable activity, while the
others had increased specific activity (23 to 41% of normal levels). The
authors speculated that this is the reason R141H is not seen in
homozygous state since, in this form, it would most likely be lethal.

Among a total of 55 patients with CDG1A, Westphal et al. (2002) found
that a 911T-C (F304S) polymorphism in the ALG6 gene (604566) was almost
twice as frequent in severely affected patients (0.41) compared to
moderate or mildly affected patients (0.21). Functional expression
studies showed that the F304S allele had a reduced ability to rescue
defective glycosylation of an alg6-deficient strain of S. cerevisiae
during rapid growth. The authors concluded that the presence of the
F304S allele may act as a genetic modifier to exacerbate the clinical
outcome in severely affected CDG1A patients.

Briones et al. (2002) presented their experience with a diagnosis of 26
Spanish patients from 19 families with CDG Ia due to PMM deficiency.
Patients in all but 1 of the families were compound heterozygous for
PMM2 mutations. Eighteen different mutations were detected. In contrast
to other series in which the R141H mutation represents 43 to 53% of the
alleles, only 9 of 36 (25%) of the alleles had this mutation. The common
European F119L mutation was not identified in any of the Spanish
patients but the V44A (601785.0020) and D65Y (601785.0005) mutations
probably originated in the Iberian peninsula, as they have only been
reported in Portuguese and Latin-American patients. Probably because of
this genetic heterogeneity, Spanish patients showed very diverse
phenotypes that are, in general, milder than in other series.

Schollen et al. (2007) described 2 unusual truncating mutations in 2 CDG
Ia patients. One was a deep intronic point mutation (601785.0019), and
the other was an Alu retrotransposition-mediated complex deletion
(601785.0021). Schollen et al. (2007) cautioned that detection of these
mutations stresses the importance of combining PMM2 mutation screening
on genomic DNA with analysis of the transcripts and/or with the
enzymatic analysis of the phosphomannomutase activity, as these types of
mutations would not be easily identified by PCR-based mutation analysis
at the genomic level. Vega et al. (2009) found that the deep intronic
mutation identified by Schollen et al. (2007) activated a pseudoexon
sequence in intron 7. Antisense morpholino oligonucleotides targeted to
the 3- and 5-prime cryptic splice sites rescued the defect and allowed
correctly spliced mRNA to be translated into a functional protein.

Najmabadi et al. (2011) performed homozygosity mapping followed by exon
enrichment and next-generation sequencing in 136 consanguineous families
(over 90% Iranian and less than 10% Turkish or Arabic) segregating
syndromic or nonsyndromic forms of autosomal recessive intellectual
disability. In family 8307998, they identified a homozygous missense
mutation in the PMM2 gene (601785.0023) in 3 sibs with mild intellectual
disability, thin upper lip, flat nasal bridge, and strabismus, who were
diagnosed with glycosylation disorder CDG Ia (212065). The parents, who
were first cousins, were carriers, and they had 5 healthy children.

ANIMAL MODEL

Schneider et al. (2012) generated transgenic mice with homozygous or
compound heterozygous hypomorphic Pmm2 alleles: R137H, which is
analogous to human R141H (601785.0001), and F118L, which is predicted to
lead to mild loss of enzyme activity. Homozygous R137H and compound
heterozygous R137H/F118L mice were embryonic lethal. Homozygosity for
R137H was associated with no residual enzymatic activity, whereas
R137H/F118L mice had about 11% residual activity. Homozygous F118L mice
were clinically similar to wildtype, with 38 to 42% residual PMM2
activity, which was sufficient to prevent pathologic consequences.
Compound heterozygous R137H/F118L embryos showed very poor intrauterine
growth with extensive degradation of multiple organs and evidence of
hypoglycosylation of glycoproteins. Treatment of heterozygous F118L
females with oral mannose in water beginning 1 week prior to mating
resulted in a 2-fold increase of serum mannose concentrations and
rescued the embryonic lethality of compound heterozygous R137H/F118L
offspring, who survived beyond weaning. Compound heterozygous offspring
under treatment showed organ development and glycosylation comparable to
wildtype mice, indicating mannose-mediated normalization of
glycosylation. The phenotypic rescue remained apparent even after
4-month maintenance of the offspring on normal water. The results
revealed an essential role for proper glycosylation during embryogenesis
and suggested that mannose administration to at-risk mothers may reduce
the phenotype of offspring.

*FIELD* AV
.0001
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, ARG141HIS

In a family in Sicily in which linkage studies indicated mapping of CDG
Ia (212065) to 16p13, Matthijs et al. (1997) found that affected
individuals were compound heterozygous for a 425G-A transition (R141H)
and a 647A-T transversion (N216I; 601785.0002) in the PMM2 gene. Among
18 unrelated Danish patients with CDG Ia, Kjaergaard et al. (1998) found
that this and the F119L mutation (601785.0006) accounted for 88% of all
mutations. Each was found in 16 of 36 PMM2 alleles.

Matthijs et al. (1999) commented on the intriguing observation of the
total lack of patients homozygous for the common R141H mutation. The
residual activity of the in vitro expressed R141H recombinant protein is
almost zero, supporting the inference that homozygosity for this
mutation is lethal early in development. Patients homozygous for the
relatively frequent F119L mutation have been found, and 1 patient
homozygous for the D65Y mutation (601785.0005) has been identified. In
these patients, the residual activity of the deficient enzyme was, in
the words of Matthijs et al. (1999), 'relatively pronounced.'

Schollen et al. (2000) determined the frequency of the R141H mutation in
2 normal populations: in neonates of Dutch origin, 1 in 79 were
carriers, whereas in the Danish population, a carrier frequency of 1 in
60 was found. These figures were clearly in disequilibrium with the
frequency of CDG Ia that had been estimated at 1 in 80,000 and 1 in
40,000 in these populations. Haplotype analysis of 43 patients with the
R141H mutation of different geographic origins indicated that it is an
old mutation in the Caucasian population. Based on the new data, the
disease frequency was calculated at 1 in 20,000 in these populations.
The authors concluded that the disease was probably underdiagnosed.

Vuillaumier-Barrot et al. (2000) identified the R141H mutation in 9 of
22 (41%) chromosomes in French patients with CDG Ia.

In a male infant diagnosed with CDG Ia, Bohles et al. (2001) showed a
pro113-to-leu (P113L) mutation in compound heterozygosity with the
arg141-to-his mutation.

Quelhas et al. (2006) found that the R141H substitution was the most
common mutation among 15 Portuguese patients with CDG1A, accounting for
7 of 26 mutations (26%). The second most common mutation was D65Y
(601785.0005), which accounted for 6 of 26 mutations (23%). Haplotype
analysis indicated a founder effect for the R141H substitution.

.0002
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, ASN216ILE

See 601785.0001 and Matthijs et al. (1997).

Neumann et al. (2003) identified homozygosity for the N216I mutation in
a 16-month-old boy with CDG Ia. In contrast to previously reported
patients, he had postnatal macrosomia and did not have inverted nipples
or abnormal fat pads. His parents, who were consanguineous, were
heterozygous for the mutation. The authors suggested that homozygosity
for this mutation could have a specific phenotype correlation.

.0003
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, VAL129MET

In a family from Sicily in which CDG Ia (212065) showed linkage to
16p13, Matthijs et al. (1997) found that members with CDG Ia were
compound heterozygous for a 385G-A transition (V129M) and a 484C-T
transition (R162W; 601785.0004) in the PMM2 gene.

.0004
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, ARG162TRP

See 601785.0003 and Matthijs et al. (1997).

.0005
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, ASP65TYR

In a mutation screening of 56 patients with CDG Ia (see 212065),
Matthijs et al. (1998) identified 3 alleles (one homozygous and one
compound heterozygous patient) with a G-to-T transversion at nucleotide
193, resulting in an asp65-to-tyr (D65Y) mutation. The compound
heterozygous patient, who died at the age of 4 months due to hepatic
insufficiency, had the R141H mutation (601785.0001) on the other allele.

Quelhas et al. (2006) found that the R141H substitution was the most
common mutation among 15 Portuguese patients with CDG1A, accounting for
7 of 26 mutations (26%). The second most common mutation was D65Y, which
accounted for 6 of 26 mutations (23%). Haplotype analysis indicated a
founder effect of Iberian origin for the D65Y substitution.

.0006
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, PHE119LEU

In a mutation screening of 56 patients with CDG I (see 212065), Matthijs
et al. (1998) identified 18 occurrences of a phe119-to-leu (F119L)
mutation, which resulted from a C-to-A transversion at nucleotide 357.
Among 18 unrelated Danish patients with CDG1, Kjaergaard et al. (1998)
found that this and the R141H mutation (601785.0001) accounted for 88%
of all mutations. Each was found in 16 of 36 CDG1 alleles.

.0007
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, ASP188GLY

In a mutation screening of 56 patients with CDG I (see 212065), Matthijs
et al. (1998) identified 5 occurrences of an asp188-to-gly (D188G)
mutation, all of which were in compound heterozygous state with the
R141H mutation (601785.0001). An A-to-G transition at nucleotide 563
resulted in the D188G substitution.

.0008
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, GLY117ARG

In Danish cases of CDG Ia (212065), Kjaergaard et al. (1998) identified
a G-to-C transversion at nucleotide 349, resulting in a gly117-to-arg
(G117R) substitution. The mutation was present in compound heterozygous
state with the common F119L mutation (601785.0006).

.0009
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, ASP223GLU

In Danish cases of CDG Ia (212065), Kjaergaard et al. (1998) identified
a C-to-G transversion at nucleotide 669, resulting in an asp223-to-glu
(D223E) substitution. The patient was a compound heterozygote, but the
second mutation was not identified.

.0010
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, 357C-A

Bjursell et al. (1998) identified a 357C-A transversion in exon 5 of the
PMM2 gene as the change associated with the frequent 'haplotype A' found
in CDG Ia (212065) patients from western Scandinavia. The mutation
created a restriction site not present in the normal allele which could
be recognized by the restriction enzyme Tru9I.

.0011
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, THR237ARG

In a patient with CDG Ia (212065), Kjaergaard et al. (1999) identified a
thr237-to-arg substitution (T237R) in the PMM2 gene. The patient was a
compound heterozygote for the asp223-to-glu substitution (601785.0009).

.0012
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, CYS241SER

In a review of PMM2 mutations causing CDG Ia (212065), Matthijs et al.
(1999) noted that 4 patients had a 722G-C change in exon 8, resulting in
a cys241-to-ser (C241S) mutation in a nonconserved region in the
C-terminal part of the PMM2 protein. Vuillaumier-Barrot et al. (2000)
determined that this mutation decreases the activity of PMM2 by only
50%. Grunewald et al. (2001) found that the C241S mutation was present
in compound heterozygous state in 6 of 9 patients with a mild form of
CDG Ia.

Vuillaumier-Barrot et al. (2000) identified the C241S mutation in
compound heterozygosity with R141H (601785.0001) in a French patient
with CDG Ia.

.0013
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, ILE132THR

In 3 of 22 chromosomes in French patients with CDG Ia (212065),
Vuillaumier-Barrot et al. (2000) identified a 395T-C transition in exon
5 of the PMM2 gene, resulting in an ile132-to-thr (I132T) substitution.
Two of the patients were compound heterozygous for I132T and R141H
(601785.0001), and the other was compound heterozygous for I132T and
another pathogenic PMM2 mutation.

.0014
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, VAL231MET

In 3 of 22 chromosomes in French patients with CDG Ia (212065),
Vuillaumier-Barrot et al. (2000) identified a 691G-A transition in exon
8 in the PMM2 gene, resulting in a val231-to-met (V231M) substitution.
All patients were compound heterozygous for V231M and R141H
(601785.0001).

.0015
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, CYS9TYR

In a French patient with CDG1A (212065), Vuillaumier-Barrot et al.
(2000) identified compound heterozygosity for 2 mutations in the PMM2
gene: a 26G-A transition in exon 1 resulting in a cys9-to-tyr (C9Y)
substitution and R141H (601785.0001).

.0016
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, LEU32ARG

In a French patient with CDG Ia (212065), Vuillaumier-Barrot et al.
(2000) identified a 95TA-GC change in exon 2 of the PMM2 gene, resulting
in a leu32-to-arg (L32R) substitution. The second mutant allele was not
identified.

.0017
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, THR226SER

In a French patient with CDG Ia (212065), Vuillaumier-Barrot et al.
(2000) identified compound heterozygosity for 2 mutations in the PMM2
gene: a 677C-G transversion in exon 8, resulting in a thr226-to-ser
(T226S) substitution, and R141H (601785.0001).

.0018
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, PRO113LEU

In a male infant diagnosed with CDG Ia (212065), Bohles et al. (2001)
identified compound heterozygosity for a pro113-to-leu (P113L) and an
arg141-to-his (R141H; 601785.0001) substitution.

.0019
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, IVS7, C-T

In a patient with CDG Ia (212065), Schollen et al. (2007) detected
compound heterozygosity for a V231M mutation in PMM2 (601785.0014) and a
deep intronic point mutation, notated as 639-15479C-T in the cDNA. The
latter variant activated a cryptic splice site which resulted in
in-frame insertion of a pseudoexon of 123 bp between exons 7 and 8.

Vega et al. (2009) referred to this mutation as 640-15479C-T or
IVS7-15479C-T. In vitro functional expression assays showed that the
mutation activated a pseudoexon sequence in intron 7. Antisense
morpholino oligonucleotides targeted to the 3- and 5-prime cryptic
splice sites rescued the defect and allowed correctly spliced mRNA to be
translated into a functional protein.

.0020
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, VAL44ALA

In a patient with CDG Ia (212065), Schollen et al. (2007) detected
compound heterozygosity for a val44-to-ala (V44A) mutation in PMM2
arising from a 131T-C transition in exon 2, and a large deletion
(601785.0021).

.0021
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, 28-KB DEL

In a patient with CDG Ia (212065), Schollen et al. (2007) found compound
heterozygosity for a missense mutation in the PMM2 gene (601785.0020)
and an Alu retrotransposition-mediated complex deletion of approximately
28 kb encompassing exon 8.

.0022
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, IVS3AS, G-C, -1

In a patient with CDG Ia (212065), Vega et al. (2009) identified
compound heterozygosity for 2 mutations in the PMM2 gene: a G-to-C
transversion in intron 3 (IVS3-1G-C), resulting in the skipping of exons
3 and 4, and the L32R (601785.0016) mutation. Western blot analysis
showed 28% residual protein.

.0023
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
PMM2, TYR106PHE

In family 8307998, Najmabadi et al. (2011) identified a homozygous
A-to-T transversion in the PMM2 gene at genomic coordinate
Chr:16:8807735 (NCBI36), resulting in a tyr106-to-phe (Y106F)
substitution, in 3 sibs with mild intellectual disability, thin upper
lip, flat nasal bridge, and strabismus, who were diagnosed with
glycosylation disorder CDG Ia (212065). The parents, who were first
cousins, were carriers, and they had 5 healthy children.

*FIELD* RF
1. Bjursell, C.; Erlandson, A.; Nordling, M.; Nilsson, S.; Wahlstrom,
J.; Stibler, H.; Kristiansson, B.; Martinsson, T.: PMM2 mutation
spectrum, including 10 novel mutations, in a large CDG type 1A family
material with a focus on Scandinavian families. Hum. Mutat. 16:
395-400, 2000.

2. Bjursell, C.; Wahlstrom, J.; Berg, K.; Stibler, H.; Kristiansson,
B.; Matthijs, G.; Martinsson, T.: Detailed mapping of the phosphomannomutase
2 (PMM2) gene and mutation detection enable improved analysis for
Scandinavian CDG type I families. Europ. J. Hum. Genet. 6: 603-611,
1998.

3. Bohles, H.; Sewell, A. C.; Gebhardt, B.; Reinecke-Luthge, A.; Kloppel,
G.; Marquardt, T.: Hyperinsulinaemic hypogycaemia: leading symptom
in a patient with congenital disorder of glycosylation Ia (phosphomannomutase
deficiency). J. Inherit. Metab. Dis. 24: 858-862, 2001.

4. Briones, P.; Vilaseca, M. A.; Schollen, E.; Ferrer, I.; Maties,
M.; Busquets, C.; Artuch, R.; Gort, L.; Marco, M.; van Schaftingen,
E.; Matthijs, G.; Jaeken, J.; Chabas, A.: Biochemical and molecular
studies in 26 Spanish patients with congenital disorder of glycosylation
type Ia. J. Inherit. Metab. Dis. 25: 635-646, 2002.

5. Grunewald, S.; Schollen, E.; Van Schaftingen, E.; Jaeken, J.; Matthijs,
G.: High residual activity of PMM2 in patients' fibroblasts: possible
pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency). Am.
J. Hum. Genet. 68: 347-354, 2001.

6. Kjaergaard, S.; Skovby, F.; Schwartz, M.: Absence of homozygosity
for predominant mutations in PMM2 in Danish patients with carbohydrate-deficient
glycoprotein syndrome type 1. Europ. J. Hum. Genet. 6: 331-336,
1998.

7. Kjaergaard, S.; Skovby, F.; Schwartz, M.: Carbohydrate-deficient
glycoprotein syndrome type 1A: expression and characterisation of
wild type and mutant PMM2 in E. coli. Europ. J. Hum. Genet. 7: 884-888,
1999.

8. Kondo, I.; Mizugishi, K.; Yoneda, Y.; Hashimoto, T.; Kuwajima,
K.; Yuasa, L.; Shigemoto, K.; Kuroda, Y.: Missense mutations in phosphomannomutase
2 gene in two Japanese families with carbohydrate-deficient glycoprotein
syndrome type 1. Clin. Genet. 55: 50-54, 1999.

9. 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.: Mutations
in PMM2 that cause congenital disorders of glycosylation, type Ia
(CDG-Ia). Hum. Mutat. 16: 386-394, 2000.

10. Matthijs, G.; Schollen, E.; Heykants, L.; Grunewald, S.: Phosphomannomutase
deficiency: the molecular basis of the classical Jaeken syndrome (CDGS
type Ia). Molec. Genet. Metab. 68: 220-226, 1999.

11. Matthijs, G.; Schollen, E.; Pardon, E.; Veiga-Da-Cunha, M.; Jaeken,
J.; Cassiman, J.-J.; Van Schaftingen, E.: Mutations in PMM2, a phosphomannomutase
gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type
I syndrome (Jaeken syndrome). Nature Genet. 16: 88-92, 1997. Note:
Erratum: 16: 316 only, 1997.

12. Matthijs, G.; Schollen, E.; Pirard, M.; Budarf, M. L.; Van Schaftingen,
E.; Cassiman, J.-J.: PMM (PMM1), the human homologue of SEC53 or
yeast phosphomannomutase, is localized on chromosome 22q13. Genomics 40:
41-47, 1997.

13. Matthijs, G.; Schollen, E.; Van Schaftingen, E.; Cassiman, J.-J.;
Jaeken, J.: Lack of homozygotes for the most frequent disease allele
in carbohydrate-deficient glycoprotein syndrome type 1A. Am. J. Hum.
Genet. 62: 542-550, 1998.

14. Najmabadi, H.; Hu, H.; Garshasbi, M.; Zemojtel, T.; Abedini, S.
S.; Chen, W.; Hosseini, M.; Behjati, F.; Haas, S.; Jamali, P.; Zecha,
A.; Mohseni, M.; and 33 others: Deep sequencing reveals 50 novel
genes for recessive cognitive disorders. Nature 478: 57-63, 2011.

15. Neumann, L. M.; von Moers, A.; Kunze, J.; Blankenstein, O.; Marquardt,
T.: Congenital disorder of glycosylation type 1a in a macrosomic
16-month-old boy with an atypical phenotype and homozygosity of the
N216I mutation. Europ. J. Pediat. 162: 710-713, 2003.

16. Quelhas, D.; Quental, R.; Vilarinho, L.; Amorim, A.; Azevedo,
L.: Congenital disorder of glycosylation type Ia: searching for the
origin of common mutations in PMM2. Ann. Hum. Genet. 71: 348-353,
2006.

17. Schneider, A.; Thiel, C.; Rindermann, J.; DeRossi, C.; Popovici,
D.; Hoffmann, G. F.; Grone, H.-J.; Korner, C.: Successful prenatal
mannose treatment for congenital disorder of glycosylation-Ia in mice. Nature
Med. 18: 71-73, 2012.

18. Schollen, E.; Keldermans, L.; Foulquier, F.; Briones, P.; Chabas,
A.; Sanchez-Valverde, F.; Adamowicz, M.; Pronicka, E.; Wevers, R.;
Matthijs, G.: Characterization of two unusual truncating PMM2 mutations
in two CDG-Ia patients. Molec. Genet. Metab. 90: 408-413, 2007.

19. Schollen, E.; Kjaergaard, S.; Legius, E.; Schwartz, M.; Matthijs,
G.: Lack of Hardy-Weinberg equilibrium for the most prevalent PMM2
mutation in CDG-Ia (congenital disorders of glycosylation type Ia). Europ.
J. Hum. Genet. 8: 367-371, 2000.

20. Schollen, E.; Pardon, E.; Heykants, L.; Renard, J.; Doggett, N.
A.; Callen, D. F.; Cassiman, J. J.; Matthijs, G.: Comparative analysis
of the phosphomannomutase genes PMM1, PMM2 and PMM2-psi: the sequence
variation in the processed pseudogene is a reflection of the mutations
found in the functional gene. Hum. Molec. Genet. 7: 157-164, 1998.

21. Van Schaftingen, E.; Jaeken, J.: Phosphomannomutase deficiency
is a cause of carbohydrate-deficient glycoprotein syndrome type I. FEBS
Lett. 377: 318-320, 1995.

22. Vega, A. I.; Perez-Cerda, C.; Desviat, L. R.; Matthijs, G.; Ugarte,
M.; Perez, B.: Functional analysis of three splicing mutations identified
in the PMM2 gene: toward a new therapy for congenital disorder of
glycosylation type IA. Hum. Mutat. 30: 795-803, 2009.

23. Vuillaumier-Barrot, S.; Hetet, G.; Barnier, A.; Dupre, T.; Cuer,
M.; de Lonlay, P.; Cormier-Daire, V.; Durand, G.; Grandchamp, B.;
Seta, N.: Identification of four novel PMM2 mutations in congenital
disorders of glycosylation (CDG) Ia French patients. J. Med. Genet. 37:
579-580, 2000.

24. Westphal, V.; Kjaergaard, S.; Schollen, E.; Martens, K.; Grunewald,
S.; Schwartz, M.; Matthijs, G.; Freeze, H. H.: A frequent mild mutation
in ALG6 may exacerbate the clinical severity of patients with congenital
disorder of glycosylation Ia (CDG-Ia) caused by phosphomannomutase
deficiency. Hum. Molec. Genet. 11: 599-604, 2002.

*FIELD* CN
Cassandra L. Kniffin - updated: 2/15/2012
Ada Hamosh - updated: 1/6/2012
Cassandra L. Kniffin - updated: 8/18/2009
Cassandra L. Kniffin - updated: 6/22/2007
Ada Hamosh - updated: 6/14/2007
Natalie E. Krasikov - updated: 3/12/2004
Ada Hamosh - updated: 10/2/2003
George E. Tiller - updated: 10/9/2002
Michael J. Wright - updated: 8/7/2001
Victor A. McKusick - updated: 3/8/2001
Victor A. McKusick - updated: 11/29/2000
Victor A. McKusick - updated: 11/2/2000
Victor A. McKusick - updated: 2/9/2000
Victor A. McKusick - updated: 1/7/2000
Wilson H. Y. Lo - updated: 8/19/1999
Victor A. McKusick - updated: 3/17/1999
Victor A. McKusick - updated: 10/2/1998
Victor A. McKusick - updated: 5/7/1998
Victor A. McKusick - updated: 5/30/1997

*FIELD* CD
Victor A. McKusick: 4/30/1997

*FIELD* ED
carol: 02/23/2012
ckniffin: 2/15/2012
carol: 1/9/2012
terry: 1/6/2012
carol: 10/26/2010
wwang: 9/8/2009
ckniffin: 8/18/2009
carol: 6/26/2007
ckniffin: 6/26/2007
carol: 6/26/2007
ckniffin: 6/22/2007
alopez: 6/22/2007
terry: 6/14/2007
carol: 4/18/2007
carol: 3/23/2004
terry: 3/12/2004
cwells: 10/2/2003
cwells: 10/9/2002
cwells: 8/16/2001
cwells: 8/9/2001
terry: 8/7/2001
mcapotos: 3/20/2001
mcapotos: 3/14/2001
terry: 3/8/2001
mcapotos: 12/19/2000
mcapotos: 12/14/2000
terry: 11/29/2000
mcapotos: 11/16/2000
mcapotos: 11/10/2000
terry: 11/2/2000
mgross: 2/29/2000
carol: 2/17/2000
terry: 2/9/2000
carol: 1/24/2000
terry: 1/7/2000
carol: 8/19/1999
carol: 3/30/1999
terry: 3/17/1999
carol: 10/7/1998
terry: 10/2/1998
dholmes: 7/2/1998
alopez: 5/13/1998
carol: 5/8/1998
terry: 5/7/1998
dholmes: 1/16/1998
mark: 6/4/1997
mark: 6/3/1997
terry: 5/30/1997
mark: 5/16/1997
mark: 4/30/1997