Full text data of GMPPB
GMPPB
[Confidence: low (only semi-automatic identification from reviews)]
Mannose-1-phosphate guanyltransferase beta; 2.7.7.13 (GDP-mannose pyrophosphorylase B; GTP-mannose-1-phosphate guanylyltransferase beta)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Mannose-1-phosphate guanyltransferase beta; 2.7.7.13 (GDP-mannose pyrophosphorylase B; GTP-mannose-1-phosphate guanylyltransferase beta)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q9Y5P6
ID GMPPB_HUMAN Reviewed; 360 AA.
AC Q9Y5P6; A8K6N5; Q9H7U3;
DT 23-OCT-2007, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-OCT-2007, sequence version 2.
DT 22-JAN-2014, entry version 109.
DE RecName: Full=Mannose-1-phosphate guanyltransferase beta;
DE EC=2.7.7.13;
DE AltName: Full=GDP-mannose pyrophosphorylase B;
DE AltName: Full=GTP-mannose-1-phosphate guanylyltransferase beta;
GN Name=GMPPB;
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] (ISOFORM 1), AND VARIANT ARG-184.
RA Matthijs G., Schollen E., Dierickx D.;
RT "Human homolog of GDP-mannose pyrophosphorylase.";
RL Submitted (MAR-1999) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP ARG-184.
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP ARG-184.
RC TISSUE=Brain, and Eye;
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 [5]
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 [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [7]
RP SUBCELLULAR LOCATION, VARIANT MDDGA14 ASN-334, VARIANTS MDDGB14
RP LEU-32; CYS-185 AND GLN-287, VARIANTS MDDGC14 SER-22; HIS-27 AND
RP ILE-330, CHARACTERIZATION OF VARIANT MDDGA14 ASN-334, CHARACTERIZATION
RP OF VARIANTS MDDGB14 LEU-32; CYS-185 AND GLN-287, AND CHARACTERIZATION
RP OF VARIANTS MDDGC14 SER-22; HIS-27 AND ILE-330.
RX PubMed=23768512; DOI=10.1016/j.ajhg.2013.05.009;
RG UK10K Consortium;
RA Carss K.J., Stevens E., Foley A.R., Cirak S., Riemersma M.,
RA Torelli S., Hoischen A., Willer T., van Scherpenzeel M., Moore S.A.,
RA Messina S., Bertini E., Boennemann C.G., Abdenur J.E., Grosmann C.M.,
RA Kesari A., Punetha J., Quinlivan R., Waddell L.B., Young H.K.,
RA Wraige E., Yau S., Brodd L., Feng L., Sewry C., MacArthur D.G.,
RA North K.N., Hoffman E., Stemple D.L., Hurles M.E., van Bokhoven H.,
RA Campbell K.P., Lefeber D.J., Lin Y.Y., Muntoni F.;
RT "Mutations in GDP-mannose pyrophosphorylase B cause congenital and
RT limb-girdle muscular dystrophies associated with hypoglycosylation of
RT alpha-dystroglycan.";
RL Am. J. Hum. Genet. 93:29-41(2013).
CC -!- CATALYTIC ACTIVITY: GTP + alpha-D-mannose 1-phosphate =
CC diphosphate + GDP-mannose.
CC -!- PATHWAY: Nucleotide-sugar biosynthesis; GDP-alpha-D-mannose
CC biosynthesis; GDP-alpha-D-mannose from alpha-D-mannose 1-phosphate
CC (GTP route): step 1/1.
CC -!- SUBUNIT: Associates with GMPPA (By similarity).
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9Y5P6-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9Y5P6-2; Sequence=VSP_028619;
CC -!- DISEASE: Muscular dystrophy-dystroglycanopathy congenital with
CC brain and eye anomalies A14 (MDDGA14) [MIM:615350]: An autosomal
CC recessive disorder characterized by congenital muscular dystrophy
CC associated with brain anomalies, eye malformations, and profound
CC mental retardation. The disorder includes a severe form designated
CC as Walker-Warburg syndrome and a less severe phenotype known as
CC muscle-eye-brain disease. MDDGA14 features include increased
CC muscle tone, microcephaly, cleft palate, feeding difficulties,
CC severe muscle weakness, sensorineural hearing loss, cerebellar
CC hypoplasia, ataxia, and retinal dysfunction. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Muscular dystrophy-dystroglycanopathy congenital with
CC mental retardation B14 (MDDGB14) [MIM:615351]: A congenital
CC muscular dystrophy characterized by severe muscle weakness
CC apparent in infancy and mental retardation. Some patients may have
CC additional features, such as microcephaly, cardiac dysfunction,
CC seizures, or cerebellar hypoplasia. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Muscular dystrophy-dystroglycanopathy limb-girdle C14
CC (MDDGC14) [MIM:615352]: An autosomal recessive form of muscular
CC dystrophy characterized by mild proximal muscle weakness with
CC onset in early childhood. Some patients may have additional
CC features, such as mild intellectual disability or seizures.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the transferase hexapeptide repeat family.
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DR EMBL; AF135421; AAD38516.1; -; mRNA.
DR EMBL; AK024319; BAB14882.1; -; mRNA.
DR EMBL; AK291700; BAF84389.1; -; mRNA.
DR EMBL; AC099668; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC001141; AAH01141.1; -; mRNA.
DR EMBL; BC008033; AAH08033.1; -; mRNA.
DR RefSeq; NP_037466.2; NM_013334.3.
DR RefSeq; NP_068806.1; NM_021971.2.
DR RefSeq; XP_005265153.1; XM_005265096.1.
DR UniGene; Hs.567488; -.
DR ProteinModelPortal; Q9Y5P6; -.
DR SMR; Q9Y5P6; 1-333.
DR IntAct; Q9Y5P6; 1.
DR MINT; MINT-1461031; -.
DR STRING; 9606.ENSP00000309092; -.
DR PhosphoSite; Q9Y5P6; -.
DR DMDM; 160013885; -.
DR PaxDb; Q9Y5P6; -.
DR PRIDE; Q9Y5P6; -.
DR Ensembl; ENST00000308375; ENSP00000309092; ENSG00000173540.
DR Ensembl; ENST00000308388; ENSP00000311130; ENSG00000173540.
DR Ensembl; ENST00000480687; ENSP00000418565; ENSG00000173540.
DR GeneID; 29925; -.
DR KEGG; hsa:29925; -.
DR UCSC; uc003cxk.1; human.
DR CTD; 29925; -.
DR GeneCards; GC03M049733; -.
DR HGNC; HGNC:22932; GMPPB.
DR HPA; HPA014657; -.
DR MIM; 615320; gene.
DR MIM; 615350; phenotype.
DR MIM; 615351; phenotype.
DR MIM; 615352; phenotype.
DR neXtProt; NX_Q9Y5P6; -.
DR Orphanet; 588; Muscle-eye-brain disease.
DR PharmGKB; PA134875590; -.
DR eggNOG; COG1208; -.
DR HOGENOM; HOG000283479; -.
DR HOVERGEN; HBG107955; -.
DR KO; K00966; -.
DR OMA; CHIKDIS; -.
DR OrthoDB; EOG7CRTPW; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_17015; Metabolism of proteins.
DR UniPathway; UPA00126; UER00930.
DR GeneWiki; GMPPB; -.
DR GenomeRNAi; 29925; -.
DR NextBio; 52539; -.
DR PRO; PR:Q9Y5P6; -.
DR Bgee; Q9Y5P6; -.
DR CleanEx; HS_GMPPB; -.
DR Genevestigator; Q9Y5P6; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0004475; F:mannose-1-phosphate guanylyltransferase activity; IEA:UniProtKB-EC.
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:0043687; P:post-translational protein modification; TAS:Reactome.
DR GO; GO:0018279; P:protein N-linked glycosylation via asparagine; TAS:Reactome.
DR InterPro; IPR001451; Hexapep_transf.
DR InterPro; IPR018357; Hexapep_transf_CS.
DR InterPro; IPR005835; NTP_transferase.
DR Pfam; PF00132; Hexapep; 1.
DR Pfam; PF00483; NTP_transferase; 1.
DR PROSITE; PS00101; HEXAPEP_TRANSFERASES; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome;
KW Congenital muscular dystrophy; Cytoplasm; Disease mutation;
KW Dystroglycanopathy; GTP-binding; Limb-girdle muscular dystrophy;
KW Nucleotide-binding; Nucleotidyltransferase; Polymorphism;
KW Reference proteome; Transferase.
FT CHAIN 1 360 Mannose-1-phosphate guanyltransferase
FT beta.
FT /FTId=PRO_0000307162.
FT VAR_SEQ 317 317 W -> WVSLWAGLGGERGGECACLPDKAYPLLE (in
FT isoform 2).
FT /FTId=VSP_028619.
FT VARIANT 22 22 P -> S (in MDDGC14; causes protein
FT aggregation).
FT /FTId=VAR_070142.
FT VARIANT 27 27 D -> H (in MDDGC14; the protein remains
FT distributed in the cytoplasm and has no
FT discernable changes compared to wild-
FT type).
FT /FTId=VAR_070143.
FT VARIANT 32 32 P -> L (in MDDGB14; causes protein
FT aggregation).
FT /FTId=VAR_070144.
FT VARIANT 126 126 H -> D (in dbSNP:rs34345884).
FT /FTId=VAR_035372.
FT VARIANT 184 184 Q -> R (in dbSNP:rs1466685).
FT /FTId=VAR_035373.
FT VARIANT 185 185 R -> C (in MDDGB14; the protein remains
FT distributed in the cytoplasm and has no
FT discernable changes compared to wild-
FT type).
FT /FTId=VAR_070145.
FT VARIANT 287 287 R -> Q (in MDDGB14).
FT /FTId=VAR_070146.
FT VARIANT 330 330 V -> I (in MDDGC14; causes protein
FT aggregation).
FT /FTId=VAR_070147.
FT VARIANT 334 334 D -> N (in MDDGA14; causes protein
FT aggregation).
FT /FTId=VAR_070148.
SQ SEQUENCE 360 AA; 39834 MW; 8212C77BBB2EF960 CRC64;
MKALILVGGY GTRLRPLTLS TPKPLVDFCN KPILLHQVEA LAAAGVDHVI LAVSYMSQVL
EKEMKAQEQR LGIRISMSHE EEPLGTAGPL ALARDLLSET ADPFFVLNSD VICDFPFQAM
VQFHRHHGQE GSILVTKVEE PSKYGVVVCE ADTGRIHRFV EKPQVFVSNK INAGMYILSP
AVLQRIQLQP TSIEKEVFPI MAKEGQLYAM ELQGFWMDIG QPKDFLTGMC LFLQSLRQKQ
PERLCSGPGI VGNVLVDPSA RIGQNCSIGP NVSLGPGVVV EDGVCIRRCT VLRDARIRSH
SWLESCIVGW RCRVGQWVRM ENVTVLGEDV IVNDELYLNG ASVLPHKSIG ESVPEPRIIM
//
ID GMPPB_HUMAN Reviewed; 360 AA.
AC Q9Y5P6; A8K6N5; Q9H7U3;
DT 23-OCT-2007, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-OCT-2007, sequence version 2.
DT 22-JAN-2014, entry version 109.
DE RecName: Full=Mannose-1-phosphate guanyltransferase beta;
DE EC=2.7.7.13;
DE AltName: Full=GDP-mannose pyrophosphorylase B;
DE AltName: Full=GTP-mannose-1-phosphate guanylyltransferase beta;
GN Name=GMPPB;
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] (ISOFORM 1), AND VARIANT ARG-184.
RA Matthijs G., Schollen E., Dierickx D.;
RT "Human homolog of GDP-mannose pyrophosphorylase.";
RL Submitted (MAR-1999) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP ARG-184.
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP ARG-184.
RC TISSUE=Brain, and Eye;
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 [5]
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 [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [7]
RP SUBCELLULAR LOCATION, VARIANT MDDGA14 ASN-334, VARIANTS MDDGB14
RP LEU-32; CYS-185 AND GLN-287, VARIANTS MDDGC14 SER-22; HIS-27 AND
RP ILE-330, CHARACTERIZATION OF VARIANT MDDGA14 ASN-334, CHARACTERIZATION
RP OF VARIANTS MDDGB14 LEU-32; CYS-185 AND GLN-287, AND CHARACTERIZATION
RP OF VARIANTS MDDGC14 SER-22; HIS-27 AND ILE-330.
RX PubMed=23768512; DOI=10.1016/j.ajhg.2013.05.009;
RG UK10K Consortium;
RA Carss K.J., Stevens E., Foley A.R., Cirak S., Riemersma M.,
RA Torelli S., Hoischen A., Willer T., van Scherpenzeel M., Moore S.A.,
RA Messina S., Bertini E., Boennemann C.G., Abdenur J.E., Grosmann C.M.,
RA Kesari A., Punetha J., Quinlivan R., Waddell L.B., Young H.K.,
RA Wraige E., Yau S., Brodd L., Feng L., Sewry C., MacArthur D.G.,
RA North K.N., Hoffman E., Stemple D.L., Hurles M.E., van Bokhoven H.,
RA Campbell K.P., Lefeber D.J., Lin Y.Y., Muntoni F.;
RT "Mutations in GDP-mannose pyrophosphorylase B cause congenital and
RT limb-girdle muscular dystrophies associated with hypoglycosylation of
RT alpha-dystroglycan.";
RL Am. J. Hum. Genet. 93:29-41(2013).
CC -!- CATALYTIC ACTIVITY: GTP + alpha-D-mannose 1-phosphate =
CC diphosphate + GDP-mannose.
CC -!- PATHWAY: Nucleotide-sugar biosynthesis; GDP-alpha-D-mannose
CC biosynthesis; GDP-alpha-D-mannose from alpha-D-mannose 1-phosphate
CC (GTP route): step 1/1.
CC -!- SUBUNIT: Associates with GMPPA (By similarity).
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9Y5P6-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9Y5P6-2; Sequence=VSP_028619;
CC -!- DISEASE: Muscular dystrophy-dystroglycanopathy congenital with
CC brain and eye anomalies A14 (MDDGA14) [MIM:615350]: An autosomal
CC recessive disorder characterized by congenital muscular dystrophy
CC associated with brain anomalies, eye malformations, and profound
CC mental retardation. The disorder includes a severe form designated
CC as Walker-Warburg syndrome and a less severe phenotype known as
CC muscle-eye-brain disease. MDDGA14 features include increased
CC muscle tone, microcephaly, cleft palate, feeding difficulties,
CC severe muscle weakness, sensorineural hearing loss, cerebellar
CC hypoplasia, ataxia, and retinal dysfunction. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Muscular dystrophy-dystroglycanopathy congenital with
CC mental retardation B14 (MDDGB14) [MIM:615351]: A congenital
CC muscular dystrophy characterized by severe muscle weakness
CC apparent in infancy and mental retardation. Some patients may have
CC additional features, such as microcephaly, cardiac dysfunction,
CC seizures, or cerebellar hypoplasia. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Muscular dystrophy-dystroglycanopathy limb-girdle C14
CC (MDDGC14) [MIM:615352]: An autosomal recessive form of muscular
CC dystrophy characterized by mild proximal muscle weakness with
CC onset in early childhood. Some patients may have additional
CC features, such as mild intellectual disability or seizures.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the transferase hexapeptide repeat family.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF135421; AAD38516.1; -; mRNA.
DR EMBL; AK024319; BAB14882.1; -; mRNA.
DR EMBL; AK291700; BAF84389.1; -; mRNA.
DR EMBL; AC099668; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC001141; AAH01141.1; -; mRNA.
DR EMBL; BC008033; AAH08033.1; -; mRNA.
DR RefSeq; NP_037466.2; NM_013334.3.
DR RefSeq; NP_068806.1; NM_021971.2.
DR RefSeq; XP_005265153.1; XM_005265096.1.
DR UniGene; Hs.567488; -.
DR ProteinModelPortal; Q9Y5P6; -.
DR SMR; Q9Y5P6; 1-333.
DR IntAct; Q9Y5P6; 1.
DR MINT; MINT-1461031; -.
DR STRING; 9606.ENSP00000309092; -.
DR PhosphoSite; Q9Y5P6; -.
DR DMDM; 160013885; -.
DR PaxDb; Q9Y5P6; -.
DR PRIDE; Q9Y5P6; -.
DR Ensembl; ENST00000308375; ENSP00000309092; ENSG00000173540.
DR Ensembl; ENST00000308388; ENSP00000311130; ENSG00000173540.
DR Ensembl; ENST00000480687; ENSP00000418565; ENSG00000173540.
DR GeneID; 29925; -.
DR KEGG; hsa:29925; -.
DR UCSC; uc003cxk.1; human.
DR CTD; 29925; -.
DR GeneCards; GC03M049733; -.
DR HGNC; HGNC:22932; GMPPB.
DR HPA; HPA014657; -.
DR MIM; 615320; gene.
DR MIM; 615350; phenotype.
DR MIM; 615351; phenotype.
DR MIM; 615352; phenotype.
DR neXtProt; NX_Q9Y5P6; -.
DR Orphanet; 588; Muscle-eye-brain disease.
DR PharmGKB; PA134875590; -.
DR eggNOG; COG1208; -.
DR HOGENOM; HOG000283479; -.
DR HOVERGEN; HBG107955; -.
DR KO; K00966; -.
DR OMA; CHIKDIS; -.
DR OrthoDB; EOG7CRTPW; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_17015; Metabolism of proteins.
DR UniPathway; UPA00126; UER00930.
DR GeneWiki; GMPPB; -.
DR GenomeRNAi; 29925; -.
DR NextBio; 52539; -.
DR PRO; PR:Q9Y5P6; -.
DR Bgee; Q9Y5P6; -.
DR CleanEx; HS_GMPPB; -.
DR Genevestigator; Q9Y5P6; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0004475; F:mannose-1-phosphate guanylyltransferase activity; IEA:UniProtKB-EC.
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:0043687; P:post-translational protein modification; TAS:Reactome.
DR GO; GO:0018279; P:protein N-linked glycosylation via asparagine; TAS:Reactome.
DR InterPro; IPR001451; Hexapep_transf.
DR InterPro; IPR018357; Hexapep_transf_CS.
DR InterPro; IPR005835; NTP_transferase.
DR Pfam; PF00132; Hexapep; 1.
DR Pfam; PF00483; NTP_transferase; 1.
DR PROSITE; PS00101; HEXAPEP_TRANSFERASES; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome;
KW Congenital muscular dystrophy; Cytoplasm; Disease mutation;
KW Dystroglycanopathy; GTP-binding; Limb-girdle muscular dystrophy;
KW Nucleotide-binding; Nucleotidyltransferase; Polymorphism;
KW Reference proteome; Transferase.
FT CHAIN 1 360 Mannose-1-phosphate guanyltransferase
FT beta.
FT /FTId=PRO_0000307162.
FT VAR_SEQ 317 317 W -> WVSLWAGLGGERGGECACLPDKAYPLLE (in
FT isoform 2).
FT /FTId=VSP_028619.
FT VARIANT 22 22 P -> S (in MDDGC14; causes protein
FT aggregation).
FT /FTId=VAR_070142.
FT VARIANT 27 27 D -> H (in MDDGC14; the protein remains
FT distributed in the cytoplasm and has no
FT discernable changes compared to wild-
FT type).
FT /FTId=VAR_070143.
FT VARIANT 32 32 P -> L (in MDDGB14; causes protein
FT aggregation).
FT /FTId=VAR_070144.
FT VARIANT 126 126 H -> D (in dbSNP:rs34345884).
FT /FTId=VAR_035372.
FT VARIANT 184 184 Q -> R (in dbSNP:rs1466685).
FT /FTId=VAR_035373.
FT VARIANT 185 185 R -> C (in MDDGB14; the protein remains
FT distributed in the cytoplasm and has no
FT discernable changes compared to wild-
FT type).
FT /FTId=VAR_070145.
FT VARIANT 287 287 R -> Q (in MDDGB14).
FT /FTId=VAR_070146.
FT VARIANT 330 330 V -> I (in MDDGC14; causes protein
FT aggregation).
FT /FTId=VAR_070147.
FT VARIANT 334 334 D -> N (in MDDGA14; causes protein
FT aggregation).
FT /FTId=VAR_070148.
SQ SEQUENCE 360 AA; 39834 MW; 8212C77BBB2EF960 CRC64;
MKALILVGGY GTRLRPLTLS TPKPLVDFCN KPILLHQVEA LAAAGVDHVI LAVSYMSQVL
EKEMKAQEQR LGIRISMSHE EEPLGTAGPL ALARDLLSET ADPFFVLNSD VICDFPFQAM
VQFHRHHGQE GSILVTKVEE PSKYGVVVCE ADTGRIHRFV EKPQVFVSNK INAGMYILSP
AVLQRIQLQP TSIEKEVFPI MAKEGQLYAM ELQGFWMDIG QPKDFLTGMC LFLQSLRQKQ
PERLCSGPGI VGNVLVDPSA RIGQNCSIGP NVSLGPGVVV EDGVCIRRCT VLRDARIRSH
SWLESCIVGW RCRVGQWVRM ENVTVLGEDV IVNDELYLNG ASVLPHKSIG ESVPEPRIIM
//
MIM
615320
*RECORD*
*FIELD* NO
615320
*FIELD* TI
*615320 GDP-MANNOSE PYROPHOSPHORYLASE B; GMPPB
;;GDP-MANNOSE PYROPHOSPHORYLASE, BETA SUBUNIT;;
read moreGMPP-BETA;;
KIAA1851
*FIELD* TX
DESCRIPTION
The GMPPB gene encodes the beta subunit of an essential enzyme,
GDP-mannose pyrophosphorylase (EC 2.7.7.13), that catalyzes the
conversion of mannose-1-phosphate and GTP to inorganic diphosphate and
GDP-mannose, a major mannosyl donor for mannose-containing polymers
(Ning and Elbein, 2000). GDP-mannose is required in 4 glycosylation
pathways, including O-mannosylation of membrane and secretory
glycoproteins, such as alpha-dystroglycan (DAG1; 128239) (summary by
Carss et al., 2013).
CLONING
By sequencing clones obtained from a size-fractionated adult brain cDNA
library, Nagase et al. (2001) obtained a GMPPB clone, which they
designated KIAA1851. RT-PCR ELISA detected uniform GMPPB expression in
all adult and fetal tissues and specific adult brain regions examined.
By searching databases for sequences similar to porcine Gmpp-beta, Ning
and Elbein (2000) identified human GMPPB, as well as GMPPB orthologs in
several lower species, including nematode, yeast, and plants. The
360-amino acid human protein shares 96% identity with porcine Gmpp-beta.
The GMPPB protein contains 2 main functional domains: a nucleotidyl
transferase domain and a bacterial transferase hexapeptide domain. Carss
et al. (2013) determined that the GMPPB gene is transcribed as 2
isoforms in human tissues. The longer isoform (GenBank GENBANK
NM_021971.1) was strongly expressed in all fetal and adult tissues
tested, including brain and skeletal muscle, whereas the shorter isoform
(GenBank GENBANK NM_013334.2) was weakly expressed in the tissues
tested. There appeared to be no developmental difference in the
expression of the 2 isoforms.
GENE STRUCTURE
The coding DNA sequence of one isoform of the GMPPB gene (GenBank
GENBANK NM_021971.1) contains 10 exons, whereas that of another isoform
(GenBank GENBANK NM_013334.2) contains 8 exons (Carss et al., 2013).
GENE FUNCTION
Ning and Elbein (2000) found that recombinant porcine Gmpp-beta
catalyzed bidirectional conversion of mannose-1-phosphate and GTP to
inorganic diphosphate and GDP-mannose. Compared with purified pig liver
Gmpp, which was a dimer of alpha and beta subunits, recombinant
Gmpp-beta showed much lower activity as a GDP-glucose pyrophosphorylase
(EC 2.7.7.34). Divalent cations, particularly Mn(2+), enhanced the
Gmpp-beta reaction, whereas Mg(2+) was the preferred cofactor for the
endogenous dimeric enzyme.
MAPPING
Hartz (2013) mapped the GMPPB gene to chromosome 3p21.31 based on an
alignment of the GMPPB sequence (GenBank GENBANK AB058754) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
By exome sequencing combined with Sanger sequencing of 8 unrelated
patients with various forms of congenital muscular dystrophy, Carss et
al. (2013) identified 8 different mutations in the GMPPB gene (GenBank
GENBANK NM_02197.1) (615320.0001-615320.0008). All mutations occurred in
the homozygous or compound heterozygous state and segregated with the
disorder in the families in whom parental DNA was available. All
affected individuals had at least 1 mutation affecting the highly
conserved nucleotidyl transferase domain. The phenotype was highly
variable. The most severely affected patient had muscle weakness at
birth with severely delayed psychomotor development, retinal
dysfunction, and pontocerebellar hypoplasia, reminiscent of
muscle-eye-brain disease and consistent with congenital muscular
dystrophy-dystroglycanopathy with brain and eye anomalies type A14
(MDDGA14; 615350). Four patients presented with a slightly milder
phenotype with onset of muscle weakness in the first months of life with
milder intellectual disability with or without cerebellar hypoplasia,
consistent with congenital muscular dystrophy-dystroglycanopathy with
mental retardation type B14 (MDDGB14; 615351). The least severe
phenotype, limb-girdle muscular dystrophy-dystroglycanopathy type C14
(MDDGC14; 615352) was present in 3 unrelated patients, 1 of whom had
onset at age 4 and normal intellectual function. Variable features seen
in some patients included microcephaly, seizures, cataracts, and cardiac
dysfunction. All patients had dystrophic features on muscle biopsy, and
immunohistochemical and flow cytometric analysis of patient cells showed
reduced glycosylation of alpha-dystroglycan. Overexpression of wildtype
GMPPB in fibroblasts from an affected individual partially restored
glycosylation of DAG1. Whereas wildtype GMPPB localized to the
cytoplasm, 5 of the identified missense mutations caused formation of
aggregates in the cytoplasm or near membrane protrusions. Knockdown of
the GMPPB ortholog in zebrafish caused structural muscle defects with
decreased motility, eye abnormalities, and reduced glycosylation of
DAG1. None of the patients had evidence of abnormal serum transferrin
glycoforms.
ANIMAL MODEL
Carss et al. (2013) found that zebrafish Gmppb is expressed throughout
development. Morpholino knockdown of Gmppb in zebrafish resulted in
smaller embryos with multiple anomalies, including bent tails,
hypopigmentation, microphthalmia, hydrocephalus, and reduced motility.
Muscle fibers in mutant zebrafish were sparse and disorganized, and the
myosepta were damaged or incompletely developed. There was also evidence
of sarcolemmal damage. Immunostaining showed defective glycosylation of
DAG1 associated with abnormal structure of the basement membrane. These
findings were reminiscent of the muscular dystrophy phenotype found in
humans with GMPPB mutations.
*FIELD* AV
.0001
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE
ANOMALIES), TYPE A, 14
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 14, INCLUDED
GMPPB, ASP334ASN
In a patient (P1) with congenital muscular dystrophy-dystroglycanopathy
with brain and eye anomalies type A14 (MDDGA14; 615350), Carss et al.
(2013) identified compound heterozygous mutations in the GMPPB gene: a
c.1000G-A transition resulting in an asp334-to-asn (D334N) substitution
at a highly conserved residue at the C terminus, and a c.220C-T
transition resulting in an arg74-to-ter (R74X; 615320.0002)
substitution. The mutation were identified by exome sequencing and
confirmed by Sanger sequencing. Each unaffected parent was heterozygous
for 1 of the mutations. Transfection of the D334N mutation into
myoblasts caused the protein to form cytoplasmic aggregates. The R74X
mutation, which occurs in the nucleotidyl transferase domain, is
predicted to cause a severely truncated protein and nonsense-mediated
mRNA. The patient had severely delayed psychomotor development,
sensorineural hearing loss, retinal dysfunction, and pontine and
cerebellar hypoplasia on brain MRI. Studies of the patient's skeletal
muscle and fibroblasts showed decreased glycosylation of
alpha-dystroglycan (DAG1; 128239), which was partially restored by
transfection of wildtype GMPPB. An unrelated patient (P2) with a
somewhat less severe phenotype, limb-girdle muscular
dystrophy-dystroglycanopathy type C14 (MDDGC14; 615352) with mental
retardation, was found to be compound heterozygous for D334N and a
c.64C-T transition resulting in a pro22-to-ser (P22S; 615320.0003)
substitution at a highly conserved residue in the nucleotidyl
transferase domain. Transfection of the P22S mutation into myoblasts
caused the protein to aggregate near membrane protrusions into the
cytoplasm.
.0002
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE
ANOMALIES), TYPE A, 14
GMPPB, ARG74TER
See 615320.0001 and Carss et al. (2013).
.0003
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 14
GMPPB, PRO22SER
See 615320.0001 and Carss et al. (2013).
.0004
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION),
TYPE B, 14
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 14, INCLUDED
GMPPB, ARG185CYS
In 2 unrelated Mexican patients (P3 and P4) with congenital muscular
dystrophy-dystroglycanopathy with mental retardation type B14 (MDDGB14;
615351), Carss et al. (2013) identified a homozygous c.553C-T transition
in the GMPPB gene, resulting in an arg185-to-cys (R185C) substitution at
a highly conserved residue in the nucleotidyl transferase domain. The
mutation was found in 1 of the patients by exome sequencing and
confirmed in both patients by Sanger sequencing. The unaffected mother
of 1 of the patients was heterozygous for the mutation. Exome sequencing
of an Egyptian patient (P8) with a somewhat less severe phenotype,
limb-girdle muscular dystrophy-dystroglycanopathy type C14 (MDDGC14;
615352) with mental retardation and cardiorespiratory dysfunction, also
yielded a homozygous R185C mutation. The unaffected parents of this
patient were heterozygous for the mutation. Transfection of the R185C
mutation into myoblasts caused the protein to remain evenly distributed
in the cytoplasm and had no discernible changes compared to wildtype.
.0005
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION),
TYPE B, 14
GMPPB, PRO32LEU
In 2 unrelated Italian girls (P5, P6) with MDDGB14 with mental
retardation (615351), previously reported by Messina et al. (2009),
Carss et al. (2013) identified compound heterozygosity for 2 mutations
in the GMPPB gene: c.95C-T transition resulting in a pro32-to-leu (P32L)
substitution at a highly conserved residue in the nucleotidyl
transferase domain, and a c.860G-A transition resulting in an
arg287-to-gln (R287Q; 615320.0006) substitution. The mutations, which
were found by exome sequencing and confirmed by Sanger sequencing,
segregated with the disorder in both families. P32L had not been
reported, and R287Q is rare and has a minor allele frequency of less
than or equal to 0.001 in database controls. Transfection of both
mutations into myoblasts caused the protein to form aggregates within
the cytoplasm.
.0006
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION),
TYPE B, 14
GMPPB, ARG287GLN
See 615320.0005 and Carss et al. (2013).
.0007
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 14
GMPPB, ASP27HIS
In a 6-year-old English boy (P7) with MDDGC14 (615351) without mental
retardation, Carss et al. (2013) identified compound heterozygous
mutations in the GMPPB gene: a c.79G-C transversion, resulting in an
asp27-to-his (D27H) substitution at a highly conserved residue in the
nucleotidyl transferase domain, and a c.988G-A transition, resulting in
a val330-to-ile (V330I; 615320.0008) substitution at a highly conserved
residue in the C terminus. Each unaffected parent was heterozygous for 1
of the mutations. Both variants are rare, with minor allele frequencies
of less than or equal to 0.001 in database controls. Transfection of the
D27H mutation into myoblasts caused the protein to remain evenly
distributed in the cytoplasm and had no discernible changes compared to
wildtype, whereas transfection of V330I caused the protein to form
aggregates within the cytoplasm. The patient had a mild form of the
disorder, presenting only with exercise intolerance at age 4 years.
.0008
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 14
GMPPB, VAL330ILE
See 615320.0007 and Carss et al. (2013).
*FIELD* RF
1. Carss, K. J.; Stevens, E.; Foley, A. R.; Cirak, S.; Riemersma,
M.; Torelli, S.; Hoischen, A.; Willer, T.; van Scherpenzeel, M.; Moore,
S. A.; Messina, S.; Bertini, E.; and 24 others: Mutations in GDP-mannose
pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies
associated with hypoglycosylation of alpha-dystroglycan. Am. J. Hum.
Genet. 93: 29-41, 2013.
2. Hartz, P. A.: Personal Communication. Baltimore, Md. 7/19/2013.
3. Messina, S.; Tortorella, G.; Concolino, D.; Spano, M.; D'Amico,
A.; Bruno, C.; Santorelli, F. M.; Mercuri, E.; Bertini, E.: Congenital
muscular dystrophy with defective alpha-dystroglycan, cerebellar hypoplasia,
and epilepsy. Neurology 73: 1599-1601, 2009.
4. Nagase, T.; Nakayama, M.; Nakajima, D.; Kikuno, R.; Ohara, O.:
Prediction of the coding sequences of unidentified human genes. XX.
The complete sequences of 100 new cDNA clones from brain which code
for large proteins in vitro. DNA Res. 8: 85-95, 2001.
5. Ning, B.; Elbein, A. D.: Cloning, expression and characterization
of the pig liver GDP-mannose pyrophosphorylase: evidence that GDP-mannose
and GDP-Glc pyrophosphorylases are different proteins. Europ. J.
Biochem. 267: 6866-6874, 2000.
*FIELD* CN
Cassandra L. Kniffin - updated: 7/31/2013
*FIELD* CD
Patricia A. Hartz: 7/19/2013
*FIELD* ED
carol: 10/07/2013
carol: 8/8/2013
carol: 8/6/2013
ckniffin: 7/31/2013
mgross: 7/19/2013
*RECORD*
*FIELD* NO
615320
*FIELD* TI
*615320 GDP-MANNOSE PYROPHOSPHORYLASE B; GMPPB
;;GDP-MANNOSE PYROPHOSPHORYLASE, BETA SUBUNIT;;
read moreGMPP-BETA;;
KIAA1851
*FIELD* TX
DESCRIPTION
The GMPPB gene encodes the beta subunit of an essential enzyme,
GDP-mannose pyrophosphorylase (EC 2.7.7.13), that catalyzes the
conversion of mannose-1-phosphate and GTP to inorganic diphosphate and
GDP-mannose, a major mannosyl donor for mannose-containing polymers
(Ning and Elbein, 2000). GDP-mannose is required in 4 glycosylation
pathways, including O-mannosylation of membrane and secretory
glycoproteins, such as alpha-dystroglycan (DAG1; 128239) (summary by
Carss et al., 2013).
CLONING
By sequencing clones obtained from a size-fractionated adult brain cDNA
library, Nagase et al. (2001) obtained a GMPPB clone, which they
designated KIAA1851. RT-PCR ELISA detected uniform GMPPB expression in
all adult and fetal tissues and specific adult brain regions examined.
By searching databases for sequences similar to porcine Gmpp-beta, Ning
and Elbein (2000) identified human GMPPB, as well as GMPPB orthologs in
several lower species, including nematode, yeast, and plants. The
360-amino acid human protein shares 96% identity with porcine Gmpp-beta.
The GMPPB protein contains 2 main functional domains: a nucleotidyl
transferase domain and a bacterial transferase hexapeptide domain. Carss
et al. (2013) determined that the GMPPB gene is transcribed as 2
isoforms in human tissues. The longer isoform (GenBank GENBANK
NM_021971.1) was strongly expressed in all fetal and adult tissues
tested, including brain and skeletal muscle, whereas the shorter isoform
(GenBank GENBANK NM_013334.2) was weakly expressed in the tissues
tested. There appeared to be no developmental difference in the
expression of the 2 isoforms.
GENE STRUCTURE
The coding DNA sequence of one isoform of the GMPPB gene (GenBank
GENBANK NM_021971.1) contains 10 exons, whereas that of another isoform
(GenBank GENBANK NM_013334.2) contains 8 exons (Carss et al., 2013).
GENE FUNCTION
Ning and Elbein (2000) found that recombinant porcine Gmpp-beta
catalyzed bidirectional conversion of mannose-1-phosphate and GTP to
inorganic diphosphate and GDP-mannose. Compared with purified pig liver
Gmpp, which was a dimer of alpha and beta subunits, recombinant
Gmpp-beta showed much lower activity as a GDP-glucose pyrophosphorylase
(EC 2.7.7.34). Divalent cations, particularly Mn(2+), enhanced the
Gmpp-beta reaction, whereas Mg(2+) was the preferred cofactor for the
endogenous dimeric enzyme.
MAPPING
Hartz (2013) mapped the GMPPB gene to chromosome 3p21.31 based on an
alignment of the GMPPB sequence (GenBank GENBANK AB058754) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
By exome sequencing combined with Sanger sequencing of 8 unrelated
patients with various forms of congenital muscular dystrophy, Carss et
al. (2013) identified 8 different mutations in the GMPPB gene (GenBank
GENBANK NM_02197.1) (615320.0001-615320.0008). All mutations occurred in
the homozygous or compound heterozygous state and segregated with the
disorder in the families in whom parental DNA was available. All
affected individuals had at least 1 mutation affecting the highly
conserved nucleotidyl transferase domain. The phenotype was highly
variable. The most severely affected patient had muscle weakness at
birth with severely delayed psychomotor development, retinal
dysfunction, and pontocerebellar hypoplasia, reminiscent of
muscle-eye-brain disease and consistent with congenital muscular
dystrophy-dystroglycanopathy with brain and eye anomalies type A14
(MDDGA14; 615350). Four patients presented with a slightly milder
phenotype with onset of muscle weakness in the first months of life with
milder intellectual disability with or without cerebellar hypoplasia,
consistent with congenital muscular dystrophy-dystroglycanopathy with
mental retardation type B14 (MDDGB14; 615351). The least severe
phenotype, limb-girdle muscular dystrophy-dystroglycanopathy type C14
(MDDGC14; 615352) was present in 3 unrelated patients, 1 of whom had
onset at age 4 and normal intellectual function. Variable features seen
in some patients included microcephaly, seizures, cataracts, and cardiac
dysfunction. All patients had dystrophic features on muscle biopsy, and
immunohistochemical and flow cytometric analysis of patient cells showed
reduced glycosylation of alpha-dystroglycan. Overexpression of wildtype
GMPPB in fibroblasts from an affected individual partially restored
glycosylation of DAG1. Whereas wildtype GMPPB localized to the
cytoplasm, 5 of the identified missense mutations caused formation of
aggregates in the cytoplasm or near membrane protrusions. Knockdown of
the GMPPB ortholog in zebrafish caused structural muscle defects with
decreased motility, eye abnormalities, and reduced glycosylation of
DAG1. None of the patients had evidence of abnormal serum transferrin
glycoforms.
ANIMAL MODEL
Carss et al. (2013) found that zebrafish Gmppb is expressed throughout
development. Morpholino knockdown of Gmppb in zebrafish resulted in
smaller embryos with multiple anomalies, including bent tails,
hypopigmentation, microphthalmia, hydrocephalus, and reduced motility.
Muscle fibers in mutant zebrafish were sparse and disorganized, and the
myosepta were damaged or incompletely developed. There was also evidence
of sarcolemmal damage. Immunostaining showed defective glycosylation of
DAG1 associated with abnormal structure of the basement membrane. These
findings were reminiscent of the muscular dystrophy phenotype found in
humans with GMPPB mutations.
*FIELD* AV
.0001
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE
ANOMALIES), TYPE A, 14
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 14, INCLUDED
GMPPB, ASP334ASN
In a patient (P1) with congenital muscular dystrophy-dystroglycanopathy
with brain and eye anomalies type A14 (MDDGA14; 615350), Carss et al.
(2013) identified compound heterozygous mutations in the GMPPB gene: a
c.1000G-A transition resulting in an asp334-to-asn (D334N) substitution
at a highly conserved residue at the C terminus, and a c.220C-T
transition resulting in an arg74-to-ter (R74X; 615320.0002)
substitution. The mutation were identified by exome sequencing and
confirmed by Sanger sequencing. Each unaffected parent was heterozygous
for 1 of the mutations. Transfection of the D334N mutation into
myoblasts caused the protein to form cytoplasmic aggregates. The R74X
mutation, which occurs in the nucleotidyl transferase domain, is
predicted to cause a severely truncated protein and nonsense-mediated
mRNA. The patient had severely delayed psychomotor development,
sensorineural hearing loss, retinal dysfunction, and pontine and
cerebellar hypoplasia on brain MRI. Studies of the patient's skeletal
muscle and fibroblasts showed decreased glycosylation of
alpha-dystroglycan (DAG1; 128239), which was partially restored by
transfection of wildtype GMPPB. An unrelated patient (P2) with a
somewhat less severe phenotype, limb-girdle muscular
dystrophy-dystroglycanopathy type C14 (MDDGC14; 615352) with mental
retardation, was found to be compound heterozygous for D334N and a
c.64C-T transition resulting in a pro22-to-ser (P22S; 615320.0003)
substitution at a highly conserved residue in the nucleotidyl
transferase domain. Transfection of the P22S mutation into myoblasts
caused the protein to aggregate near membrane protrusions into the
cytoplasm.
.0002
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE
ANOMALIES), TYPE A, 14
GMPPB, ARG74TER
See 615320.0001 and Carss et al. (2013).
.0003
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 14
GMPPB, PRO22SER
See 615320.0001 and Carss et al. (2013).
.0004
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION),
TYPE B, 14
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 14, INCLUDED
GMPPB, ARG185CYS
In 2 unrelated Mexican patients (P3 and P4) with congenital muscular
dystrophy-dystroglycanopathy with mental retardation type B14 (MDDGB14;
615351), Carss et al. (2013) identified a homozygous c.553C-T transition
in the GMPPB gene, resulting in an arg185-to-cys (R185C) substitution at
a highly conserved residue in the nucleotidyl transferase domain. The
mutation was found in 1 of the patients by exome sequencing and
confirmed in both patients by Sanger sequencing. The unaffected mother
of 1 of the patients was heterozygous for the mutation. Exome sequencing
of an Egyptian patient (P8) with a somewhat less severe phenotype,
limb-girdle muscular dystrophy-dystroglycanopathy type C14 (MDDGC14;
615352) with mental retardation and cardiorespiratory dysfunction, also
yielded a homozygous R185C mutation. The unaffected parents of this
patient were heterozygous for the mutation. Transfection of the R185C
mutation into myoblasts caused the protein to remain evenly distributed
in the cytoplasm and had no discernible changes compared to wildtype.
.0005
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION),
TYPE B, 14
GMPPB, PRO32LEU
In 2 unrelated Italian girls (P5, P6) with MDDGB14 with mental
retardation (615351), previously reported by Messina et al. (2009),
Carss et al. (2013) identified compound heterozygosity for 2 mutations
in the GMPPB gene: c.95C-T transition resulting in a pro32-to-leu (P32L)
substitution at a highly conserved residue in the nucleotidyl
transferase domain, and a c.860G-A transition resulting in an
arg287-to-gln (R287Q; 615320.0006) substitution. The mutations, which
were found by exome sequencing and confirmed by Sanger sequencing,
segregated with the disorder in both families. P32L had not been
reported, and R287Q is rare and has a minor allele frequency of less
than or equal to 0.001 in database controls. Transfection of both
mutations into myoblasts caused the protein to form aggregates within
the cytoplasm.
.0006
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION),
TYPE B, 14
GMPPB, ARG287GLN
See 615320.0005 and Carss et al. (2013).
.0007
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 14
GMPPB, ASP27HIS
In a 6-year-old English boy (P7) with MDDGC14 (615351) without mental
retardation, Carss et al. (2013) identified compound heterozygous
mutations in the GMPPB gene: a c.79G-C transversion, resulting in an
asp27-to-his (D27H) substitution at a highly conserved residue in the
nucleotidyl transferase domain, and a c.988G-A transition, resulting in
a val330-to-ile (V330I; 615320.0008) substitution at a highly conserved
residue in the C terminus. Each unaffected parent was heterozygous for 1
of the mutations. Both variants are rare, with minor allele frequencies
of less than or equal to 0.001 in database controls. Transfection of the
D27H mutation into myoblasts caused the protein to remain evenly
distributed in the cytoplasm and had no discernible changes compared to
wildtype, whereas transfection of V330I caused the protein to form
aggregates within the cytoplasm. The patient had a mild form of the
disorder, presenting only with exercise intolerance at age 4 years.
.0008
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 14
GMPPB, VAL330ILE
See 615320.0007 and Carss et al. (2013).
*FIELD* RF
1. Carss, K. J.; Stevens, E.; Foley, A. R.; Cirak, S.; Riemersma,
M.; Torelli, S.; Hoischen, A.; Willer, T.; van Scherpenzeel, M.; Moore,
S. A.; Messina, S.; Bertini, E.; and 24 others: Mutations in GDP-mannose
pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies
associated with hypoglycosylation of alpha-dystroglycan. Am. J. Hum.
Genet. 93: 29-41, 2013.
2. Hartz, P. A.: Personal Communication. Baltimore, Md. 7/19/2013.
3. Messina, S.; Tortorella, G.; Concolino, D.; Spano, M.; D'Amico,
A.; Bruno, C.; Santorelli, F. M.; Mercuri, E.; Bertini, E.: Congenital
muscular dystrophy with defective alpha-dystroglycan, cerebellar hypoplasia,
and epilepsy. Neurology 73: 1599-1601, 2009.
4. Nagase, T.; Nakayama, M.; Nakajima, D.; Kikuno, R.; Ohara, O.:
Prediction of the coding sequences of unidentified human genes. XX.
The complete sequences of 100 new cDNA clones from brain which code
for large proteins in vitro. DNA Res. 8: 85-95, 2001.
5. Ning, B.; Elbein, A. D.: Cloning, expression and characterization
of the pig liver GDP-mannose pyrophosphorylase: evidence that GDP-mannose
and GDP-Glc pyrophosphorylases are different proteins. Europ. J.
Biochem. 267: 6866-6874, 2000.
*FIELD* CN
Cassandra L. Kniffin - updated: 7/31/2013
*FIELD* CD
Patricia A. Hartz: 7/19/2013
*FIELD* ED
carol: 10/07/2013
carol: 8/8/2013
carol: 8/6/2013
ckniffin: 7/31/2013
mgross: 7/19/2013
MIM
615350
*RECORD*
*FIELD* NO
615350
*FIELD* TI
#615350 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE
ANOMALIES), TYPE A, 14; MDDGA14
read more;;WALKER-WARBURG SYNDROME OR MUSCLE-EYE-BRAIN DISEASE, GMPPB-RELATED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that this
form of congenital muscular dystrophy-dystroglycanopathy with brain and
eye anomalies (type A14; MDDGA14) is caused by compound heterozygous
mutation in the GMPPB (615320) on chromosome 3p21.
Mutation in the GMPPB gene can also cause a less severe congenital
muscular dystrophy-dystroglycanopathy with mental retardation (type B14;
MDDGB14; 615351) and a limb-girdle muscular dystrophy-dystroglycanopathy
(type C14; MDDGC14; 615352).
For a general phenotypic description and a discussion of genetic
heterogeneity of muscular dystrophy-dystroglycanopathy type A, see
MDDGA1 (236670).
CLINICAL FEATURES
Carss et al. (2013) reported an 8-year-old Pakistani boy who presented
at birth with increased muscle tone, microcephaly, cleft palate, and
feeding difficulties. He later showed severe muscle weakness, delayed
walking (only with support at age 3 years), and severe intellectual
development with lack of speech. Other features included sensorineural
hearing loss, ataxia, and retinal dysfunction. Serum creatine kinase was
increased, and muscle biopsy showed dystrophic features with
hypoglycosylation of alpha-dystroglycan (DAG1; 128239). Brain MRI
revealed pontine and cerebellar hypoplasia. Isoelectric focusing of
transferrin was normal. The diagnosis was a muscle-eye-brain- and/or an
FCMD (253800)-like disorder.
INHERITANCE
The transmission pattern in the family with MDDGA14 reported by Carss et
al. (2013) was consistent with autosomal recessive inheritance.
MOLECULAR GENETICS
In a Pakistani boy with MDDGA14, Carss et al. (2013) identified compound
heterozygous mutations in the GMPPB gene (615320.0001 and 615320.0002).
The mutations were identified by exome sequencing, confirmed by Sanger
sequencing, and not found in large control databases. Each unaffected
parent was heterozygous for 1 of the mutations.
*FIELD* RF
1. Carss, K. J.; Stevens, E.; Foley, A. R.; Cirak, S.; Riemersma,
M.; Torelli, S.; Hoischen, A.; Willer, T.; van Scherpenzeel, M.; Moore,
S. A.; Messina, S.; Bertini, E.; and 24 others: Mutations in GDP-mannose
pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies
associated with hypoglycosylation of alpha-dystroglycan. Am. J. Hum.
Genet. 93: 29-41, 2013.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Retinal dysfunction;
[Mouth];
Cleft palate
ABDOMEN:
[Gastrointestinal];
Feeding difficulties
MUSCLE, SOFT TISSUE:
Muscular dystrophy;
Increased muscle tone at birth;
Muscle weakness;
Hypoglycosylation of alpha-dystroglycan seen on muscle biopsy
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation, severe;
Absent speech;
Ataxia;
Inability to walk unsupported;
Pontine hypoplasia;
Cerebellar hypoplasia
PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Oligohydramnios
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Onset at birth;
One patient has been reported (last curated July 2013)
MOLECULAR BASIS:
Caused by mutation in the GDP-mannose pyrophosphorylase B gene (GMPPB,
615320.0001)
*FIELD* CD
Cassandra L. Kniffin: 7/31/2013
*FIELD* ED
joanna: 10/02/2013
ckniffin: 7/31/2013
*FIELD* CD
Cassandra L. Kniffin: 7/31/2013
*FIELD* ED
carol: 08/06/2013
ckniffin: 7/31/2013
*RECORD*
*FIELD* NO
615350
*FIELD* TI
#615350 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE
ANOMALIES), TYPE A, 14; MDDGA14
read more;;WALKER-WARBURG SYNDROME OR MUSCLE-EYE-BRAIN DISEASE, GMPPB-RELATED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that this
form of congenital muscular dystrophy-dystroglycanopathy with brain and
eye anomalies (type A14; MDDGA14) is caused by compound heterozygous
mutation in the GMPPB (615320) on chromosome 3p21.
Mutation in the GMPPB gene can also cause a less severe congenital
muscular dystrophy-dystroglycanopathy with mental retardation (type B14;
MDDGB14; 615351) and a limb-girdle muscular dystrophy-dystroglycanopathy
(type C14; MDDGC14; 615352).
For a general phenotypic description and a discussion of genetic
heterogeneity of muscular dystrophy-dystroglycanopathy type A, see
MDDGA1 (236670).
CLINICAL FEATURES
Carss et al. (2013) reported an 8-year-old Pakistani boy who presented
at birth with increased muscle tone, microcephaly, cleft palate, and
feeding difficulties. He later showed severe muscle weakness, delayed
walking (only with support at age 3 years), and severe intellectual
development with lack of speech. Other features included sensorineural
hearing loss, ataxia, and retinal dysfunction. Serum creatine kinase was
increased, and muscle biopsy showed dystrophic features with
hypoglycosylation of alpha-dystroglycan (DAG1; 128239). Brain MRI
revealed pontine and cerebellar hypoplasia. Isoelectric focusing of
transferrin was normal. The diagnosis was a muscle-eye-brain- and/or an
FCMD (253800)-like disorder.
INHERITANCE
The transmission pattern in the family with MDDGA14 reported by Carss et
al. (2013) was consistent with autosomal recessive inheritance.
MOLECULAR GENETICS
In a Pakistani boy with MDDGA14, Carss et al. (2013) identified compound
heterozygous mutations in the GMPPB gene (615320.0001 and 615320.0002).
The mutations were identified by exome sequencing, confirmed by Sanger
sequencing, and not found in large control databases. Each unaffected
parent was heterozygous for 1 of the mutations.
*FIELD* RF
1. Carss, K. J.; Stevens, E.; Foley, A. R.; Cirak, S.; Riemersma,
M.; Torelli, S.; Hoischen, A.; Willer, T.; van Scherpenzeel, M.; Moore,
S. A.; Messina, S.; Bertini, E.; and 24 others: Mutations in GDP-mannose
pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies
associated with hypoglycosylation of alpha-dystroglycan. Am. J. Hum.
Genet. 93: 29-41, 2013.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly;
[Ears];
Hearing loss, sensorineural;
[Eyes];
Retinal dysfunction;
[Mouth];
Cleft palate
ABDOMEN:
[Gastrointestinal];
Feeding difficulties
MUSCLE, SOFT TISSUE:
Muscular dystrophy;
Increased muscle tone at birth;
Muscle weakness;
Hypoglycosylation of alpha-dystroglycan seen on muscle biopsy
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation, severe;
Absent speech;
Ataxia;
Inability to walk unsupported;
Pontine hypoplasia;
Cerebellar hypoplasia
PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Oligohydramnios
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Onset at birth;
One patient has been reported (last curated July 2013)
MOLECULAR BASIS:
Caused by mutation in the GDP-mannose pyrophosphorylase B gene (GMPPB,
615320.0001)
*FIELD* CD
Cassandra L. Kniffin: 7/31/2013
*FIELD* ED
joanna: 10/02/2013
ckniffin: 7/31/2013
*FIELD* CD
Cassandra L. Kniffin: 7/31/2013
*FIELD* ED
carol: 08/06/2013
ckniffin: 7/31/2013
MIM
615351
*RECORD*
*FIELD* NO
615351
*FIELD* TI
#615351 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION),
read moreTYPE B, 14; MDDGB14
;;MUSCULAR DYSTROPHY, CONGENITAL, GMPPB-RELATED
*FIELD* TX
A number sign (#) is used with this entry because this form of
congenital muscular dystrophy-dystroglycanopathy with mental retardation
(type B14; MDDGB14) is caused by homozygous or compound heterozygous
mutation in the GMPPB gene (615320) on chromosome 3p21.
Mutation in the GMPPB gene can also cause a more severe congenital
muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type
A14; MDDGA14; 615350) and a less severe limb-girdle muscular
dystrophy-dystroglycanopathy (type C14; MDDGC14; 615352).
DESCRIPTION
MDDGB14 is an autosomal recessive congenital muscular dystrophy
characterized by severe muscle weakness apparent in infancy and mental
retardation. Some patients may have additional features, such as
microcephaly, cardiac dysfunction, seizures, or cerebellar hypoplasia.
It is part of a group of similar disorders resulting from defective
glycosylation of DAG1 (128239), collectively known as
'dystroglycanopathies' (summary by Carss et al., 2013).
For a discussion of genetic heterogeneity of congenital muscular
dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).
CLINICAL FEATURES
Carss et al. (2013) reported 4 unrelated patients, 2 of Mexican descent
and 2 girls of southern Italian descent, with congenital muscular
dystrophy with mental retardation. The patients presented between birth
and 4 months of age with severe hypotonia. Three had shown decreased
fetal movements in utero. There was some variation in additional
features. The 2 Mexican patients had mild mental retardation, delayed
walking at about 3 years, cataracts, strabismus, ptosis, and cardiac
anomalies. One had long QT syndrome and the other had left ventricular
dilatation. One also had microcephaly, ileal atresia, and torticollis.
Brain MRI in both patients was normal. The 2 Italian patients,
previously reported by Messina et al. (2009), had severe hypotonia,
microcephaly, generalized muscle weakness, feeding difficulties,
drug-resistant epilepsy, and severe mental retardation. One was unable
to sit, and 1 could sit at age 2 years. Brain MRI of both girls showed
cerebellar hypoplasia. One died at age 14 years and the other was
bedridden and unable to speak at age 10 years. All patients had
increased serum creatine kinase and muscle biopsies consistent with
muscular dystrophy showing hypoglycosylation of DAG1. Isoelectric
focusing of serum transferrin was normal.
INHERITANCE
The transmission pattern in the families with MDDGB14 reported by Carss
et al. (2013) was consistent with autosomal recessive inheritance.
MOLECULAR GENETICS
In 2 Mexican patients with MDDGB14, Carss et al. (2013) identified a
homozygous mutation in the GMPPB gene (615320.0004). Two unrelated
Italian girls with the disorder were compound heterozygous for mutations
in the GMPPB gene (615320.0005 and 615320.0006). The mutations, which
were found by exome sequencing and confirmed by Sanger sequencing,
segregated with the disorder.
*FIELD* RF
1. Carss, K. J.; Stevens, E.; Foley, A. R.; Cirak, S.; Riemersma,
M.; Torelli, S.; Hoischen, A.; Willer, T.; van Scherpenzeel, M.; Moore,
S. A.; Messina, S.; Bertini, E.; and 24 others: Mutations in GDP-mannose
pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies
associated with hypoglycosylation of alpha-dystroglycan. Am. J. Hum.
Genet. 93: 29-41, 2013.
2. Messina, S.; Tortorella, G.; Concolino, D.; Spano, M.; D'Amico,
A.; Bruno, C.; Santorelli, F. M.; Mercuri, E.; Bertini, E.: Congenital
muscular dystrophy with defective alpha-dystroglycan, cerebellar hypoplasia,
and epilepsy. Neurology 73: 1599-1601, 2009.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly;
Poor head control;
[Face];
Myopathic face;
[Eyes];
Cataracts (in some patients);
Strabismus (in some patients);
Ptosis (in some patients);
Nystagmus (in some patients)
CARDIOVASCULAR:
[Heart];
Long QT syndrome (1 patient);
Left ventricular dilatation (1 patient)
ABDOMEN:
[Gastrointestinal];
Feeding difficulties
SKELETAL:
Contractures (in some patients)
MUSCLE, SOFT TISSUE:
Muscular dystrophy;
Hypotonia;
Muscle weakness, severe;
Generalized muscle wasting;
Increased muscle tone (early in life);
Dystrophic features seen on muscle biopsy;
Hypoglycosylation of alpha-dystroglycan seen on muscle biopsy
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation, mild to severe;
Absent speech;
Delayed or absent independent walking;
Seizures (in some patients);
Cerebellar hypoplasia (in some patients)
PRENATAL MANIFESTATIONS:
[Movement];
Decreased fetal movements
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Onset at birth or in early infancy;
Variable severity
MOLECULAR BASIS:
Caused by mutation in the GDP-mannose pyrophosphorylase B gene (GMPPB,
615320.0004)
*FIELD* CD
Cassandra L. Kniffin: 7/31/2013
*FIELD* ED
joanna: 10/01/2013
ckniffin: 7/31/2013
*FIELD* CD
Cassandra L. Kniffin: 7/31/2013
*FIELD* ED
carol: 08/06/2013
ckniffin: 7/31/2013
*RECORD*
*FIELD* NO
615351
*FIELD* TI
#615351 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH MENTAL RETARDATION),
read moreTYPE B, 14; MDDGB14
;;MUSCULAR DYSTROPHY, CONGENITAL, GMPPB-RELATED
*FIELD* TX
A number sign (#) is used with this entry because this form of
congenital muscular dystrophy-dystroglycanopathy with mental retardation
(type B14; MDDGB14) is caused by homozygous or compound heterozygous
mutation in the GMPPB gene (615320) on chromosome 3p21.
Mutation in the GMPPB gene can also cause a more severe congenital
muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type
A14; MDDGA14; 615350) and a less severe limb-girdle muscular
dystrophy-dystroglycanopathy (type C14; MDDGC14; 615352).
DESCRIPTION
MDDGB14 is an autosomal recessive congenital muscular dystrophy
characterized by severe muscle weakness apparent in infancy and mental
retardation. Some patients may have additional features, such as
microcephaly, cardiac dysfunction, seizures, or cerebellar hypoplasia.
It is part of a group of similar disorders resulting from defective
glycosylation of DAG1 (128239), collectively known as
'dystroglycanopathies' (summary by Carss et al., 2013).
For a discussion of genetic heterogeneity of congenital muscular
dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).
CLINICAL FEATURES
Carss et al. (2013) reported 4 unrelated patients, 2 of Mexican descent
and 2 girls of southern Italian descent, with congenital muscular
dystrophy with mental retardation. The patients presented between birth
and 4 months of age with severe hypotonia. Three had shown decreased
fetal movements in utero. There was some variation in additional
features. The 2 Mexican patients had mild mental retardation, delayed
walking at about 3 years, cataracts, strabismus, ptosis, and cardiac
anomalies. One had long QT syndrome and the other had left ventricular
dilatation. One also had microcephaly, ileal atresia, and torticollis.
Brain MRI in both patients was normal. The 2 Italian patients,
previously reported by Messina et al. (2009), had severe hypotonia,
microcephaly, generalized muscle weakness, feeding difficulties,
drug-resistant epilepsy, and severe mental retardation. One was unable
to sit, and 1 could sit at age 2 years. Brain MRI of both girls showed
cerebellar hypoplasia. One died at age 14 years and the other was
bedridden and unable to speak at age 10 years. All patients had
increased serum creatine kinase and muscle biopsies consistent with
muscular dystrophy showing hypoglycosylation of DAG1. Isoelectric
focusing of serum transferrin was normal.
INHERITANCE
The transmission pattern in the families with MDDGB14 reported by Carss
et al. (2013) was consistent with autosomal recessive inheritance.
MOLECULAR GENETICS
In 2 Mexican patients with MDDGB14, Carss et al. (2013) identified a
homozygous mutation in the GMPPB gene (615320.0004). Two unrelated
Italian girls with the disorder were compound heterozygous for mutations
in the GMPPB gene (615320.0005 and 615320.0006). The mutations, which
were found by exome sequencing and confirmed by Sanger sequencing,
segregated with the disorder.
*FIELD* RF
1. Carss, K. J.; Stevens, E.; Foley, A. R.; Cirak, S.; Riemersma,
M.; Torelli, S.; Hoischen, A.; Willer, T.; van Scherpenzeel, M.; Moore,
S. A.; Messina, S.; Bertini, E.; and 24 others: Mutations in GDP-mannose
pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies
associated with hypoglycosylation of alpha-dystroglycan. Am. J. Hum.
Genet. 93: 29-41, 2013.
2. Messina, S.; Tortorella, G.; Concolino, D.; Spano, M.; D'Amico,
A.; Bruno, C.; Santorelli, F. M.; Mercuri, E.; Bertini, E.: Congenital
muscular dystrophy with defective alpha-dystroglycan, cerebellar hypoplasia,
and epilepsy. Neurology 73: 1599-1601, 2009.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly;
Poor head control;
[Face];
Myopathic face;
[Eyes];
Cataracts (in some patients);
Strabismus (in some patients);
Ptosis (in some patients);
Nystagmus (in some patients)
CARDIOVASCULAR:
[Heart];
Long QT syndrome (1 patient);
Left ventricular dilatation (1 patient)
ABDOMEN:
[Gastrointestinal];
Feeding difficulties
SKELETAL:
Contractures (in some patients)
MUSCLE, SOFT TISSUE:
Muscular dystrophy;
Hypotonia;
Muscle weakness, severe;
Generalized muscle wasting;
Increased muscle tone (early in life);
Dystrophic features seen on muscle biopsy;
Hypoglycosylation of alpha-dystroglycan seen on muscle biopsy
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation, mild to severe;
Absent speech;
Delayed or absent independent walking;
Seizures (in some patients);
Cerebellar hypoplasia (in some patients)
PRENATAL MANIFESTATIONS:
[Movement];
Decreased fetal movements
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Onset at birth or in early infancy;
Variable severity
MOLECULAR BASIS:
Caused by mutation in the GDP-mannose pyrophosphorylase B gene (GMPPB,
615320.0004)
*FIELD* CD
Cassandra L. Kniffin: 7/31/2013
*FIELD* ED
joanna: 10/01/2013
ckniffin: 7/31/2013
*FIELD* CD
Cassandra L. Kniffin: 7/31/2013
*FIELD* ED
carol: 08/06/2013
ckniffin: 7/31/2013
MIM
615352
*RECORD*
*FIELD* NO
615352
*FIELD* TI
#615352 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 14; MDDGC14
;;MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY, LIMB-GIRDLE, GMPPB-RELATED;;
read moreMUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2T; LGMD2T
*FIELD* TX
A number sign (#) is used with this entry because this form of
limb-girdle muscular dystrophy-dystroglycanopathy (type C14; MDDGC14) is
caused by homozygous or compound heterozygous mutation in the GMPPB gene
(615320) on chromosome 3p21.
Mutation in the GMPPB gene can also cause a more severe congenital
muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type
A14; MDDGA14; 615350) and a congenital muscular
dystrophy-dystroglycanopathy with mental retardation (type B14; MDDGB14;
615351).
DESCRIPTION
MDDGC14 is an autosomal recessive form of muscular dystrophy
characterized by onset in early childhood of mild proximal muscle
weakness. Some patients may have additional features, such as mild
intellectual disability or seizures. It is part of a group of similar
disorders resulting from defective glycosylation of DAG1 (128239),
collectively known as 'dystroglycanopathies' (summary by Carss et al.,
2013).
For a discussion of genetic heterogeneity of muscular
dystrophy-dystroglycanopathy type C, see MDDGC1 (609308).
CLINICAL FEATURES
Carss et al. (2013) reported 3 unrelated patients with limb-girdle
muscular dystrophy. The patients were of Indian, English, and Egyptian
descent, and the phenotype was variable. A 12-year-old girl (P2)
presented at birth with hypotonia and microcephaly. She had mild
intellectual delay and seizures, but was able to run. An 18-year-old
Egyptian boy (P8) presented at age 2.5 years with microcephaly and
difficulty climbing stairs. He also had mild intellectual delay and
seizures, but was able to run. Other features included cataracts,
nystagmus, cardiomyopathy, and respiratory insufficiency. Brain MRI in
both patients was normal. The patient with the mildest phenotype (P7)
presented at age 4 years with mild exercise intolerance. He had normal
cognition, and brain MRI was not performed. All 3 patients had increased
serum creatine kinase and dystrophic findings on muscle biopsy. Muscle
biopsy showed hypoglycosylation of DAG1.
INHERITANCE
The transmission pattern in the families with MDDGC14 reported by Carss
et al. (2013) was consistent with autosomal recessive inheritance.
MOLECULAR GENETICS
In 3 unrelated patients with MDDGC14, Carss et al. (2013) identified
homozygous or compound heterozygous mutations in the GMPPB gene
(615320.0001, 615320.0003, 615320.0004, and 615320.0007-615320.0008).
The initial mutations were found by exome sequencing.
*FIELD* RF
1. Carss, K. J.; Stevens, E.; Foley, A. R.; Cirak, S.; Riemersma,
M.; Torelli, S.; Hoischen, A.; Willer, T.; van Scherpenzeel, M.; Moore,
S. A.; Messina, S.; Bertini, E.; and 24 others: Mutations in GDP-mannose
pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies
associated with hypoglycosylation of alpha-dystroglycan. Am. J. Hum.
Genet. 93: 29-41, 2013.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly (in some patients);
[Eyes];
Cataracts (1 patient);
Nystagmus (1 patient)
CARDIOVASCULAR:
[Heart];
Cardiomyopathy (1 patient)
RESPIRATORY:
Respiratory insufficiency (1 patient)
MUSCLE, SOFT TISSUE:
Muscular dystrophy;
Muscle weakness, proximal;
Hypotonia;
Exercise intolerance;
Muscle biopsy shows dystrophic changes;
Muscle biopsy shows hypoglycosylation of alpha-dystroglycan
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild (in some patients);
Seizures (in some patients)
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Variable phenotype;
Onset ranges from birth to age 4 years;
Three unrelated patients have been reported (last curated July 2013)
MOLECULAR BASIS:
Caused by mutation in the GDP-mannose pyrophosphorylase B gene (GMPPB,
615320.0001)
*FIELD* CD
Cassandra L. Kniffin: 7/31/2013
*FIELD* ED
joanna: 10/01/2013
ckniffin: 7/31/2013
*FIELD* CD
Cassandra L. Kniffin: 7/31/2013
*FIELD* ED
carol: 08/06/2013
carol: 8/6/2013
ckniffin: 7/31/2013
*RECORD*
*FIELD* NO
615352
*FIELD* TI
#615352 MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 14; MDDGC14
;;MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY, LIMB-GIRDLE, GMPPB-RELATED;;
read moreMUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2T; LGMD2T
*FIELD* TX
A number sign (#) is used with this entry because this form of
limb-girdle muscular dystrophy-dystroglycanopathy (type C14; MDDGC14) is
caused by homozygous or compound heterozygous mutation in the GMPPB gene
(615320) on chromosome 3p21.
Mutation in the GMPPB gene can also cause a more severe congenital
muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type
A14; MDDGA14; 615350) and a congenital muscular
dystrophy-dystroglycanopathy with mental retardation (type B14; MDDGB14;
615351).
DESCRIPTION
MDDGC14 is an autosomal recessive form of muscular dystrophy
characterized by onset in early childhood of mild proximal muscle
weakness. Some patients may have additional features, such as mild
intellectual disability or seizures. It is part of a group of similar
disorders resulting from defective glycosylation of DAG1 (128239),
collectively known as 'dystroglycanopathies' (summary by Carss et al.,
2013).
For a discussion of genetic heterogeneity of muscular
dystrophy-dystroglycanopathy type C, see MDDGC1 (609308).
CLINICAL FEATURES
Carss et al. (2013) reported 3 unrelated patients with limb-girdle
muscular dystrophy. The patients were of Indian, English, and Egyptian
descent, and the phenotype was variable. A 12-year-old girl (P2)
presented at birth with hypotonia and microcephaly. She had mild
intellectual delay and seizures, but was able to run. An 18-year-old
Egyptian boy (P8) presented at age 2.5 years with microcephaly and
difficulty climbing stairs. He also had mild intellectual delay and
seizures, but was able to run. Other features included cataracts,
nystagmus, cardiomyopathy, and respiratory insufficiency. Brain MRI in
both patients was normal. The patient with the mildest phenotype (P7)
presented at age 4 years with mild exercise intolerance. He had normal
cognition, and brain MRI was not performed. All 3 patients had increased
serum creatine kinase and dystrophic findings on muscle biopsy. Muscle
biopsy showed hypoglycosylation of DAG1.
INHERITANCE
The transmission pattern in the families with MDDGC14 reported by Carss
et al. (2013) was consistent with autosomal recessive inheritance.
MOLECULAR GENETICS
In 3 unrelated patients with MDDGC14, Carss et al. (2013) identified
homozygous or compound heterozygous mutations in the GMPPB gene
(615320.0001, 615320.0003, 615320.0004, and 615320.0007-615320.0008).
The initial mutations were found by exome sequencing.
*FIELD* RF
1. Carss, K. J.; Stevens, E.; Foley, A. R.; Cirak, S.; Riemersma,
M.; Torelli, S.; Hoischen, A.; Willer, T.; van Scherpenzeel, M.; Moore,
S. A.; Messina, S.; Bertini, E.; and 24 others: Mutations in GDP-mannose
pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies
associated with hypoglycosylation of alpha-dystroglycan. Am. J. Hum.
Genet. 93: 29-41, 2013.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly (in some patients);
[Eyes];
Cataracts (1 patient);
Nystagmus (1 patient)
CARDIOVASCULAR:
[Heart];
Cardiomyopathy (1 patient)
RESPIRATORY:
Respiratory insufficiency (1 patient)
MUSCLE, SOFT TISSUE:
Muscular dystrophy;
Muscle weakness, proximal;
Hypotonia;
Exercise intolerance;
Muscle biopsy shows dystrophic changes;
Muscle biopsy shows hypoglycosylation of alpha-dystroglycan
NEUROLOGIC:
[Central nervous system];
Mental retardation, mild (in some patients);
Seizures (in some patients)
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Variable phenotype;
Onset ranges from birth to age 4 years;
Three unrelated patients have been reported (last curated July 2013)
MOLECULAR BASIS:
Caused by mutation in the GDP-mannose pyrophosphorylase B gene (GMPPB,
615320.0001)
*FIELD* CD
Cassandra L. Kniffin: 7/31/2013
*FIELD* ED
joanna: 10/01/2013
ckniffin: 7/31/2013
*FIELD* CD
Cassandra L. Kniffin: 7/31/2013
*FIELD* ED
carol: 08/06/2013
carol: 8/6/2013
ckniffin: 7/31/2013