Full text data of GMPPA
GMPPA
[Confidence: low (only semi-automatic identification from reviews)]
Mannose-1-phosphate guanyltransferase alpha (GDP-mannose pyrophosphorylase A; GMPP-alpha; GTP-mannose-1-phosphate guanylyltransferase alpha)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Mannose-1-phosphate guanyltransferase alpha (GDP-mannose pyrophosphorylase A; GMPP-alpha; GTP-mannose-1-phosphate guanylyltransferase alpha)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q96IJ6
ID GMPPA_HUMAN Reviewed; 420 AA.
AC Q96IJ6; A6NJ74; A8K3Q6; B3KMT4; Q53GI0; Q9NWC3; Q9Y5P5;
DT 08-APR-2008, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-DEC-2001, sequence version 1.
DT 22-JAN-2014, entry version 96.
DE RecName: Full=Mannose-1-phosphate guanyltransferase alpha;
DE AltName: Full=GDP-mannose pyrophosphorylase A;
DE Short=GMPP-alpha;
DE AltName: Full=GTP-mannose-1-phosphate guanylyltransferase alpha;
GN Name=GMPPA;
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).
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] (ISOFORM 1).
RC TISSUE=Embryo;
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 MRNA] (ISOFORM 1).
RC TISSUE=Kidney;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph;
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 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 [8]
RP VARIANTS AAMR ASP-182; MET-334; PRO-334; PRO-390 AND THR-401,
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=24035193; DOI=10.1016/j.ajhg.2013.08.002;
RA Koehler K., Malik M., Mahmood S., Giesselmann S., Beetz C.,
RA Hennings J.C., Huebner A.K., Grahn A., Reunert J., Nurnberg G.,
RA Thiele H., Altmuller J., Nurnberg P., Mumtaz R.,
RA Babovic-Vuksanovic D., Basel-Vanagaite L., Borck G., Bramswig J.,
RA Muhlenberg R., Sarda P., Sikiric A., Anyane-Yeboa K., Zeharia A.,
RA Ahmad A., Coubes C., Wada Y., Marquardt T., Vanderschaeghe D.,
RA Van Schaftingen E., Kurth I., Huebner A., Hubner C.A.;
RT "Mutations in GMPPA cause a glycosylation disorder characterized by
RT intellectual disability and autonomic dysfunction.";
RL Am. J. Hum. Genet. 93:727-734(2013).
CC -!- FUNCTION: May serve as a regulatory subunit and allow allosteric
CC feedback inhibition of GMPPB by GDP-mannose.
CC -!- SUBUNIT: Associates with GMPPB (By similarity).
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Note=Myc-tagged GMPPA shows a
CC diffuse cytoplasmic and nuclear pattern in transfected COS-7
CC cells.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q96IJ6-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96IJ6-2; Sequence=VSP_032741;
CC -!- TISSUE SPECIFICITY: Expressed in fibroblasts (at protein level).
CC -!- DISEASE: Alacrima, achalasia, and mental retardation syndrome
CC (AAMR) [MIM:615510]: An autosomal recessive disorder characterized
CC by onset of alacrima, achalasia, and mental retardation at birth
CC or in early infancy. More variable features include hypotonia,
CC gait abnormalities, anisocoria, and visual or hearing deficits.
CC The disorder shows similarity to the triple A syndrome, but
CC patients with AAMR do not have adrenal insufficiency. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the transferase hexapeptide repeat family.
CC -!- CAUTION: GMPPA is a close homolog of GMPPB, that has been shown to
CC catalyze the formation of GDP-mannose, an essential precursor of
CC glycan moieties of glycoproteins and glycolipids. However,
CC lymphocytes from AAMR patients, that exhibit very low GMPPA
CC protein levels, have unchanged GDP-mannose pyrophosphorylase
CC activity and higher GDP-mannose levels than those from healthy
CC controls. Affected individuals and control subjects show similar
CC N-glycosylation profiles, both for transferrin glycosylation and
CC for N-glycans derived from either total serum protein or
CC immunoglobulin G. These observations led to the hypothesis that
CC GMPPA might serve as a regulatory subunit and allow allosteric
CC feedback inhibition of GMPPB by GDP-mannose. Alignment of GMPPAs
CC and GMPPBs from various species shows that GMPPAs are
CC characterized by a 2 amino acid-insertion (residues 11-12) in a
CC highly conserved motif that borders the catalytic pocket and binds
CC the nucleotide substrate in homologous enzymes. This insertion
CC might inactivate the ancestral catalytic site, converting it to an
CC allosteric site (PubMed:24035193).
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD38517.1; Type=Frameshift; Positions=355;
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DR EMBL; AF135422; AAD38517.1; ALT_FRAME; mRNA.
DR EMBL; AK000999; BAA91460.1; -; mRNA.
DR EMBL; AK022578; BAG51096.1; -; mRNA.
DR EMBL; AK290671; BAF83360.1; -; mRNA.
DR EMBL; AK222951; BAD96671.1; -; mRNA.
DR EMBL; AC053503; AAY15053.1; -; Genomic_DNA.
DR EMBL; CH471063; EAW70755.1; -; Genomic_DNA.
DR EMBL; CH471063; EAW70759.1; -; Genomic_DNA.
DR EMBL; BC007456; AAH07456.1; -; mRNA.
DR RefSeq; NP_037467.2; NM_013335.3.
DR RefSeq; NP_995319.1; NM_205847.2.
DR RefSeq; XP_005246543.1; XM_005246486.1.
DR UniGene; Hs.27059; -.
DR ProteinModelPortal; Q96IJ6; -.
DR SMR; Q96IJ6; 4-348.
DR IntAct; Q96IJ6; 3.
DR MINT; MINT-3053969; -.
DR STRING; 9606.ENSP00000315925; -.
DR PhosphoSite; Q96IJ6; -.
DR DMDM; 74732065; -.
DR PaxDb; Q96IJ6; -.
DR PRIDE; Q96IJ6; -.
DR DNASU; 29926; -.
DR Ensembl; ENST00000313597; ENSP00000315925; ENSG00000144591.
DR Ensembl; ENST00000341142; ENSP00000340760; ENSG00000144591.
DR Ensembl; ENST00000358215; ENSP00000350949; ENSG00000144591.
DR Ensembl; ENST00000373908; ENSP00000363016; ENSG00000144591.
DR Ensembl; ENST00000373917; ENSP00000363027; ENSG00000144591.
DR GeneID; 29926; -.
DR KEGG; hsa:29926; -.
DR UCSC; uc002vlr.3; human.
DR CTD; 29926; -.
DR GeneCards; GC02P220327; -.
DR HGNC; HGNC:22923; GMPPA.
DR HPA; HPA035513; -.
DR MIM; 615495; gene.
DR MIM; 615510; phenotype.
DR neXtProt; NX_Q96IJ6; -.
DR PharmGKB; PA134925506; -.
DR eggNOG; COG1208; -.
DR HOVERGEN; HBG059531; -.
DR KO; K00966; -.
DR OMA; GPRIRGN; -.
DR OrthoDB; EOG7WHH9C; -.
DR PhylomeDB; Q96IJ6; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_17015; Metabolism of proteins.
DR GenomeRNAi; 29926; -.
DR NextBio; 52545; -.
DR PRO; PR:Q96IJ6; -.
DR ArrayExpress; Q96IJ6; -.
DR Bgee; Q96IJ6; -.
DR CleanEx; HS_GMPPA; -.
DR Genevestigator; Q96IJ6; -.
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; Cytoplasm; Disease mutation;
KW Mental retardation; Polymorphism; Reference proteome.
FT CHAIN 1 420 Mannose-1-phosphate guanyltransferase
FT alpha.
FT /FTId=PRO_0000327872.
FT VAR_SEQ 285 285 G -> GTQPAPIPNLWLPPQPSEPGFLTSSPELKPQSLPLP
FT DQIRFGIFAPRASLLLLG (in isoform 2).
FT /FTId=VSP_032741.
FT VARIANT 21 21 S -> F (in dbSNP:rs34218609).
FT /FTId=VAR_042434.
FT VARIANT 156 156 V -> A (in dbSNP:rs13396066).
FT /FTId=VAR_042435.
FT VARIANT 182 182 G -> D (in AAMR; drastically reduced
FT protein expression in fibroblasts and
FT altered subcellular location; no effect
FT on transferrin N-glycosylation profile).
FT /FTId=VAR_070203.
FT VARIANT 334 334 T -> M (in AAMR; no effect on transferrin
FT N-glycosylation profile).
FT /FTId=VAR_070204.
FT VARIANT 334 334 T -> P (in AAMR; drastically reduced
FT protein expression in fibroblasts,
FT altered subcellular location and
FT drastically increased GDP-mannose levels
FT in lymphoblast; no effect on GDP-mannose
FT pyrophosphorylase activity in
FT lymphoblasts, nor on transferrin N-
FT glycosylation profile).
FT /FTId=VAR_070205.
FT VARIANT 390 390 R -> P (in AAMR; drastically reduced
FT protein expression in fibroblasts; no
FT effect on transferrin N-glycosylation
FT profile).
FT /FTId=VAR_070206.
FT VARIANT 401 401 N -> T (in AAMR; drastically reduced
FT protein expression in fibroblasts and
FT drastically increased GDP-mannose levels
FT in lymphoblast; no effect on GDP-mannose
FT pyrophosphorylase activity in
FT lymphoblasts, nor on transferrin, IgG and
FT total serum protein N-glycosylation
FT profiles).
FT /FTId=VAR_070207.
FT CONFLICT 57 57 G -> C (in Ref. 3; BAD96671).
FT CONFLICT 67 67 Q -> H (in Ref. 2; BAF83360).
FT CONFLICT 118 118 C -> Y (in Ref. 2; BAA91460).
FT CONFLICT 339 339 S -> C (in Ref. 1; AAD38517).
SQ SEQUENCE 420 AA; 46291 MW; 741B77ABA198D4BC CRC64;
MLKAVILIGG PQKGTRFRPL SFEVPKPLFP VAGVPMIQHH IEACAQVPGM QEILLIGFYQ
PDEPLTQFLE AAQQEFNLPV RYLQEFAPLG TGGGLYHFRD QILAGSPEAF FVLNADVCSD
FPLSAMLEAH RRQRHPFLLL GTTANRTQSL NYGCIVENPQ THEVLHYVEK PSTFISDIIN
CGIYLFSPEA LKPLRDVFQR NQQDGQLEDS PGLWPGAGTI RLEQDVFSAL AGQGQIYVHL
TDGIWSQIKS AGSALYASRL YLSRYQDTHP ERLAKHTPGG PWIRGNVYIH PTAKVAPSAV
LGPNVSIGKG VTVGEGVRLR ESIVLHGATL QEHTCVLHSI VGWGSTVGRW ARVEGTPSDP
NPNDPRARMD SESLFKDGKL LPAITILGCR VRIPAEVLIL NSIVLPHKEL SRSFTNQIIL
//
ID GMPPA_HUMAN Reviewed; 420 AA.
AC Q96IJ6; A6NJ74; A8K3Q6; B3KMT4; Q53GI0; Q9NWC3; Q9Y5P5;
DT 08-APR-2008, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-DEC-2001, sequence version 1.
DT 22-JAN-2014, entry version 96.
DE RecName: Full=Mannose-1-phosphate guanyltransferase alpha;
DE AltName: Full=GDP-mannose pyrophosphorylase A;
DE Short=GMPP-alpha;
DE AltName: Full=GTP-mannose-1-phosphate guanylyltransferase alpha;
GN Name=GMPPA;
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).
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] (ISOFORM 1).
RC TISSUE=Embryo;
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 MRNA] (ISOFORM 1).
RC TISSUE=Kidney;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph;
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 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 [8]
RP VARIANTS AAMR ASP-182; MET-334; PRO-334; PRO-390 AND THR-401,
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=24035193; DOI=10.1016/j.ajhg.2013.08.002;
RA Koehler K., Malik M., Mahmood S., Giesselmann S., Beetz C.,
RA Hennings J.C., Huebner A.K., Grahn A., Reunert J., Nurnberg G.,
RA Thiele H., Altmuller J., Nurnberg P., Mumtaz R.,
RA Babovic-Vuksanovic D., Basel-Vanagaite L., Borck G., Bramswig J.,
RA Muhlenberg R., Sarda P., Sikiric A., Anyane-Yeboa K., Zeharia A.,
RA Ahmad A., Coubes C., Wada Y., Marquardt T., Vanderschaeghe D.,
RA Van Schaftingen E., Kurth I., Huebner A., Hubner C.A.;
RT "Mutations in GMPPA cause a glycosylation disorder characterized by
RT intellectual disability and autonomic dysfunction.";
RL Am. J. Hum. Genet. 93:727-734(2013).
CC -!- FUNCTION: May serve as a regulatory subunit and allow allosteric
CC feedback inhibition of GMPPB by GDP-mannose.
CC -!- SUBUNIT: Associates with GMPPB (By similarity).
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Note=Myc-tagged GMPPA shows a
CC diffuse cytoplasmic and nuclear pattern in transfected COS-7
CC cells.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q96IJ6-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96IJ6-2; Sequence=VSP_032741;
CC -!- TISSUE SPECIFICITY: Expressed in fibroblasts (at protein level).
CC -!- DISEASE: Alacrima, achalasia, and mental retardation syndrome
CC (AAMR) [MIM:615510]: An autosomal recessive disorder characterized
CC by onset of alacrima, achalasia, and mental retardation at birth
CC or in early infancy. More variable features include hypotonia,
CC gait abnormalities, anisocoria, and visual or hearing deficits.
CC The disorder shows similarity to the triple A syndrome, but
CC patients with AAMR do not have adrenal insufficiency. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the transferase hexapeptide repeat family.
CC -!- CAUTION: GMPPA is a close homolog of GMPPB, that has been shown to
CC catalyze the formation of GDP-mannose, an essential precursor of
CC glycan moieties of glycoproteins and glycolipids. However,
CC lymphocytes from AAMR patients, that exhibit very low GMPPA
CC protein levels, have unchanged GDP-mannose pyrophosphorylase
CC activity and higher GDP-mannose levels than those from healthy
CC controls. Affected individuals and control subjects show similar
CC N-glycosylation profiles, both for transferrin glycosylation and
CC for N-glycans derived from either total serum protein or
CC immunoglobulin G. These observations led to the hypothesis that
CC GMPPA might serve as a regulatory subunit and allow allosteric
CC feedback inhibition of GMPPB by GDP-mannose. Alignment of GMPPAs
CC and GMPPBs from various species shows that GMPPAs are
CC characterized by a 2 amino acid-insertion (residues 11-12) in a
CC highly conserved motif that borders the catalytic pocket and binds
CC the nucleotide substrate in homologous enzymes. This insertion
CC might inactivate the ancestral catalytic site, converting it to an
CC allosteric site (PubMed:24035193).
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD38517.1; Type=Frameshift; Positions=355;
CC -----------------------------------------------------------------------
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DR EMBL; AF135422; AAD38517.1; ALT_FRAME; mRNA.
DR EMBL; AK000999; BAA91460.1; -; mRNA.
DR EMBL; AK022578; BAG51096.1; -; mRNA.
DR EMBL; AK290671; BAF83360.1; -; mRNA.
DR EMBL; AK222951; BAD96671.1; -; mRNA.
DR EMBL; AC053503; AAY15053.1; -; Genomic_DNA.
DR EMBL; CH471063; EAW70755.1; -; Genomic_DNA.
DR EMBL; CH471063; EAW70759.1; -; Genomic_DNA.
DR EMBL; BC007456; AAH07456.1; -; mRNA.
DR RefSeq; NP_037467.2; NM_013335.3.
DR RefSeq; NP_995319.1; NM_205847.2.
DR RefSeq; XP_005246543.1; XM_005246486.1.
DR UniGene; Hs.27059; -.
DR ProteinModelPortal; Q96IJ6; -.
DR SMR; Q96IJ6; 4-348.
DR IntAct; Q96IJ6; 3.
DR MINT; MINT-3053969; -.
DR STRING; 9606.ENSP00000315925; -.
DR PhosphoSite; Q96IJ6; -.
DR DMDM; 74732065; -.
DR PaxDb; Q96IJ6; -.
DR PRIDE; Q96IJ6; -.
DR DNASU; 29926; -.
DR Ensembl; ENST00000313597; ENSP00000315925; ENSG00000144591.
DR Ensembl; ENST00000341142; ENSP00000340760; ENSG00000144591.
DR Ensembl; ENST00000358215; ENSP00000350949; ENSG00000144591.
DR Ensembl; ENST00000373908; ENSP00000363016; ENSG00000144591.
DR Ensembl; ENST00000373917; ENSP00000363027; ENSG00000144591.
DR GeneID; 29926; -.
DR KEGG; hsa:29926; -.
DR UCSC; uc002vlr.3; human.
DR CTD; 29926; -.
DR GeneCards; GC02P220327; -.
DR HGNC; HGNC:22923; GMPPA.
DR HPA; HPA035513; -.
DR MIM; 615495; gene.
DR MIM; 615510; phenotype.
DR neXtProt; NX_Q96IJ6; -.
DR PharmGKB; PA134925506; -.
DR eggNOG; COG1208; -.
DR HOVERGEN; HBG059531; -.
DR KO; K00966; -.
DR OMA; GPRIRGN; -.
DR OrthoDB; EOG7WHH9C; -.
DR PhylomeDB; Q96IJ6; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_17015; Metabolism of proteins.
DR GenomeRNAi; 29926; -.
DR NextBio; 52545; -.
DR PRO; PR:Q96IJ6; -.
DR ArrayExpress; Q96IJ6; -.
DR Bgee; Q96IJ6; -.
DR CleanEx; HS_GMPPA; -.
DR Genevestigator; Q96IJ6; -.
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; Cytoplasm; Disease mutation;
KW Mental retardation; Polymorphism; Reference proteome.
FT CHAIN 1 420 Mannose-1-phosphate guanyltransferase
FT alpha.
FT /FTId=PRO_0000327872.
FT VAR_SEQ 285 285 G -> GTQPAPIPNLWLPPQPSEPGFLTSSPELKPQSLPLP
FT DQIRFGIFAPRASLLLLG (in isoform 2).
FT /FTId=VSP_032741.
FT VARIANT 21 21 S -> F (in dbSNP:rs34218609).
FT /FTId=VAR_042434.
FT VARIANT 156 156 V -> A (in dbSNP:rs13396066).
FT /FTId=VAR_042435.
FT VARIANT 182 182 G -> D (in AAMR; drastically reduced
FT protein expression in fibroblasts and
FT altered subcellular location; no effect
FT on transferrin N-glycosylation profile).
FT /FTId=VAR_070203.
FT VARIANT 334 334 T -> M (in AAMR; no effect on transferrin
FT N-glycosylation profile).
FT /FTId=VAR_070204.
FT VARIANT 334 334 T -> P (in AAMR; drastically reduced
FT protein expression in fibroblasts,
FT altered subcellular location and
FT drastically increased GDP-mannose levels
FT in lymphoblast; no effect on GDP-mannose
FT pyrophosphorylase activity in
FT lymphoblasts, nor on transferrin N-
FT glycosylation profile).
FT /FTId=VAR_070205.
FT VARIANT 390 390 R -> P (in AAMR; drastically reduced
FT protein expression in fibroblasts; no
FT effect on transferrin N-glycosylation
FT profile).
FT /FTId=VAR_070206.
FT VARIANT 401 401 N -> T (in AAMR; drastically reduced
FT protein expression in fibroblasts and
FT drastically increased GDP-mannose levels
FT in lymphoblast; no effect on GDP-mannose
FT pyrophosphorylase activity in
FT lymphoblasts, nor on transferrin, IgG and
FT total serum protein N-glycosylation
FT profiles).
FT /FTId=VAR_070207.
FT CONFLICT 57 57 G -> C (in Ref. 3; BAD96671).
FT CONFLICT 67 67 Q -> H (in Ref. 2; BAF83360).
FT CONFLICT 118 118 C -> Y (in Ref. 2; BAA91460).
FT CONFLICT 339 339 S -> C (in Ref. 1; AAD38517).
SQ SEQUENCE 420 AA; 46291 MW; 741B77ABA198D4BC CRC64;
MLKAVILIGG PQKGTRFRPL SFEVPKPLFP VAGVPMIQHH IEACAQVPGM QEILLIGFYQ
PDEPLTQFLE AAQQEFNLPV RYLQEFAPLG TGGGLYHFRD QILAGSPEAF FVLNADVCSD
FPLSAMLEAH RRQRHPFLLL GTTANRTQSL NYGCIVENPQ THEVLHYVEK PSTFISDIIN
CGIYLFSPEA LKPLRDVFQR NQQDGQLEDS PGLWPGAGTI RLEQDVFSAL AGQGQIYVHL
TDGIWSQIKS AGSALYASRL YLSRYQDTHP ERLAKHTPGG PWIRGNVYIH PTAKVAPSAV
LGPNVSIGKG VTVGEGVRLR ESIVLHGATL QEHTCVLHSI VGWGSTVGRW ARVEGTPSDP
NPNDPRARMD SESLFKDGKL LPAITILGCR VRIPAEVLIL NSIVLPHKEL SRSFTNQIIL
//
MIM
615495
*RECORD*
*FIELD* NO
615495
*FIELD* TI
*615495 GDP-MANNOSE PYROPHOSPHORYLASE A; GMPPA
;;GDP-MANNOSE PYROPHOSPHORYLASE, ALPHA SUBUNIT;;
read moreGMPP-ALPHA
*FIELD* TX
DESCRIPTION
GMPPA is a homolog of GDP-mannose pyrophosphorylase B (GMPPB; 615320),
which catalyzes the synthesis of GDP-mannose from mannose-1-phosphate
and GTP. GMPPA and GMPPB are present in roughly equal amounts in native
GDP-mannose pyrophosphorylase (EC 2.7.7.13), but only GMPPB exhibits
enzymatic activity. Compared with GMPPB, GMPPA has a 2-amino acid
insertion within a highly conserved nucleotide-binding motif that likely
inactivated it after the duplication event that produced GMPPA and
GMPPB. GMPPA may serve a regulatory role for GMPPB (Koehler et al.,
2013).
CLONING
Koehler et al. (2013) identified the GMPPA gene within a region of
chromosome 2 linked to alacrima, achalasia, and mental retardation
syndrome (AAMR; 615510). The deduced GMPPA protein contains 420 amino
acids. It has a predicted N-terminal nucleotidyltransferase domain
followed by a hexapeptide repeat domain. GMPPA shares 32% amino acid
identity with GMPPB. Northern blot analysis detected variable Gmppa
expression in all 17 mouse tissues examined, with highest expression in
adrenal gland and testis, and lowest expression in lung and spleen. In
situ hybridization of day-17.5 mouse embryo found Gmppa expression in
many tissues, including cortex, stomach, intestine, submandibular gland,
and sublingual gland. Epitope-tagged human GMPPA was expressed in a
diffuse cytoplasmic pattern in transfected COS-7 cells. Database
analysis revealed orthologs of GMPPA in mammals and fish, and all had
the inactivating 2-amino acid insertion compared with GMPPB.
GENE FUNCTION
Koehler et al. (2013) stated that GMPPA binds GDP-mannose, but that it
does not show catalytic activity.
MAPPING
Hartz (2013) mapped the GMPPA gene to chromosome 2q35 based on an
alignment of the GMPPA sequence (GenBank GENBANK AF135422) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
In 13 patients from 9 unrelated families with alacrima, achalasia, and
mental retardation syndrome (AAMR; 615510), Koehler et al. (2013)
identified 9 different homozygous mutations in the GMPPA gene (see,
e.g., 615495.0001-615495.0005). The mutation in the first family was
found by linkage analysis and whole-exome sequencing. The subsequent
mutations were identified by sequencing the GMPPA gene in 63 families
with alacrima and achalasia who were negative for mutations in the AAAS
gene (605378). Immunoblot analysis of patient cells with missense
mutations showed lower levels of GMPPA compared to controls, consistent
with a loss of function. However, GDP-mannose levels were significantly
higher in patient cells compared to controls, whereas other nucleotide
diphosphate sugars were unchanged. There was no evidence of alterations
in N-glycosylation profiles in patients: serum transferrin,
immunoglobulin G, and serum Apo-CIII glycosylation profiles were similar
to those in controls. Koehler et al. (2013) suggested that changes
induced by GDP-mannose overload might only be significant in restricted
cell types or affect other glycosylation types, or may lead to
perturbations in the levels of other guanine nucleotides. Alternatively,
GMPPA might serve as a regulatory subunit. The clinical features of the
patients with mutations indicated that GMPPA is important in neurons and
autonomic nerve fibers innervating the distal esophageal sphincter or
the lacrimal glands.
*FIELD* AV
.0001
ALACRIMA, ACHALASIA, AND MENTAL RETARDATION SYNDROME
GMPPA, ARG99TER
In 3 sibs, born of consanguineous Pakistani parents, with alacrima,
achalasia, and mental retardation syndrome (AAMR; 615510), Koehler et
al. (2013) identified a homozygous c.295C-T transition in exon 5 of the
GMPPA gene, resulting in an arg99-to-ter (R99X) substitution. The
mutation, which was found by linkage analysis and whole-exome sequencing
and confirmed by Sanger sequencing, was not present in the dbSNP, 1000
Genomes Project, or Exome Variant Server databases, or in 200 in-house
control exomes. Cells transfected with the mutation showed no GMPPA
immunostaining, consistent with a loss of function.
.0002
ALACRIMA, ACHALASIA, AND MENTAL RETARDATION SYNDROME
GMPPA, THR334PRO
In 2 brothers, born of consanguineous Arab parents, with AAMR (615510),
Koehler et al. (2013) identified a homozygous c.1000A-C transversion in
exon 12 of the GMPPA gene, resulting in a thr334-to-pro (T334P)
substitution. The variant was not present in the dbSNP, 1000 Genomes
Project, or Exome Variant Server databases, or in 200 in-house control
exomes.
.0003
ALACRIMA, ACHALASIA, AND MENTAL RETARDATION SYNDROME
GMPPA, GLY182ASP
In 2 Palestinian sisters with AAMR (615510), Koehler et al. (2013)
identified a homozygous c.545G-A transition in exon 7 of the GMPPA gene,
resulting in a gly182-to-asp (G182D) substitution. The variant was not
present in the dbSNP, 1000 Genomes Project, or Exome Variant Server
databases, or in 200 in-house control exomes.
.0004
ALACRIMA, ACHALASIA, AND MENTAL RETARDATION SYNDROME
GMPPA, 1-BP DEL, 210A
In a 10.7-year-old Dominican girl, born of consanguineous parents, with
AAMR (615510), Koehler et al. (2013) identified a homozygous 1-bp
deletion (c.210delA) in exon 4 of the GMPPA gene, resulting in a
frameshift and premature truncation (Ala71ProfsTer19). The variant was
not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server
databases, or in 200 in-house control exomes.
.0005
ALACRIMA, ACHALASIA, AND MENTAL RETARDATION SYNDROME
GMPPA, TRP214TER
In a 6-year-old girl, born of consanguineous Arab parents, with AAMR
(615510), Koehler et al. (2013) identified a homozygous 642G-A
transition in exon 8 of the GMPPA gene, resulting in a trp214-to-ter
(W214X) substitution. The variant was not present in the dbSNP, 1000
Genomes Project, or Exome Variant Server databases, or in 200 in-house
control exomes.
*FIELD* RF
1. Hartz, P. A.: Personal Communication. Baltimore, Md. 10/24/2013.
2. Koehler, K.; Malik, M.; Mahmood, S.; Giebelmann, S.; Beetz, C.;
Hennings, J. C.; Huebner, A. K.; Grahn, A.; Reunert, J.; Nurnberg,
G.; Thiele, H.; Altmuller, J.; and 20 others: Mutations in GMPPA
cause a glycosylation disorder characterized by intellectual disability
and autonomic dysfunction. Am. J. Hum. Genet. 93: 727-734, 2013.
*FIELD* CN
Cassandra L. Kniffin - updated: 11/4/2013
*FIELD* CD
Patricia A. Hartz: 10/24/2013
*FIELD* ED
carol: 11/05/2013
ckniffin: 11/4/2013
mgross: 10/24/2013
*RECORD*
*FIELD* NO
615495
*FIELD* TI
*615495 GDP-MANNOSE PYROPHOSPHORYLASE A; GMPPA
;;GDP-MANNOSE PYROPHOSPHORYLASE, ALPHA SUBUNIT;;
read moreGMPP-ALPHA
*FIELD* TX
DESCRIPTION
GMPPA is a homolog of GDP-mannose pyrophosphorylase B (GMPPB; 615320),
which catalyzes the synthesis of GDP-mannose from mannose-1-phosphate
and GTP. GMPPA and GMPPB are present in roughly equal amounts in native
GDP-mannose pyrophosphorylase (EC 2.7.7.13), but only GMPPB exhibits
enzymatic activity. Compared with GMPPB, GMPPA has a 2-amino acid
insertion within a highly conserved nucleotide-binding motif that likely
inactivated it after the duplication event that produced GMPPA and
GMPPB. GMPPA may serve a regulatory role for GMPPB (Koehler et al.,
2013).
CLONING
Koehler et al. (2013) identified the GMPPA gene within a region of
chromosome 2 linked to alacrima, achalasia, and mental retardation
syndrome (AAMR; 615510). The deduced GMPPA protein contains 420 amino
acids. It has a predicted N-terminal nucleotidyltransferase domain
followed by a hexapeptide repeat domain. GMPPA shares 32% amino acid
identity with GMPPB. Northern blot analysis detected variable Gmppa
expression in all 17 mouse tissues examined, with highest expression in
adrenal gland and testis, and lowest expression in lung and spleen. In
situ hybridization of day-17.5 mouse embryo found Gmppa expression in
many tissues, including cortex, stomach, intestine, submandibular gland,
and sublingual gland. Epitope-tagged human GMPPA was expressed in a
diffuse cytoplasmic pattern in transfected COS-7 cells. Database
analysis revealed orthologs of GMPPA in mammals and fish, and all had
the inactivating 2-amino acid insertion compared with GMPPB.
GENE FUNCTION
Koehler et al. (2013) stated that GMPPA binds GDP-mannose, but that it
does not show catalytic activity.
MAPPING
Hartz (2013) mapped the GMPPA gene to chromosome 2q35 based on an
alignment of the GMPPA sequence (GenBank GENBANK AF135422) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
In 13 patients from 9 unrelated families with alacrima, achalasia, and
mental retardation syndrome (AAMR; 615510), Koehler et al. (2013)
identified 9 different homozygous mutations in the GMPPA gene (see,
e.g., 615495.0001-615495.0005). The mutation in the first family was
found by linkage analysis and whole-exome sequencing. The subsequent
mutations were identified by sequencing the GMPPA gene in 63 families
with alacrima and achalasia who were negative for mutations in the AAAS
gene (605378). Immunoblot analysis of patient cells with missense
mutations showed lower levels of GMPPA compared to controls, consistent
with a loss of function. However, GDP-mannose levels were significantly
higher in patient cells compared to controls, whereas other nucleotide
diphosphate sugars were unchanged. There was no evidence of alterations
in N-glycosylation profiles in patients: serum transferrin,
immunoglobulin G, and serum Apo-CIII glycosylation profiles were similar
to those in controls. Koehler et al. (2013) suggested that changes
induced by GDP-mannose overload might only be significant in restricted
cell types or affect other glycosylation types, or may lead to
perturbations in the levels of other guanine nucleotides. Alternatively,
GMPPA might serve as a regulatory subunit. The clinical features of the
patients with mutations indicated that GMPPA is important in neurons and
autonomic nerve fibers innervating the distal esophageal sphincter or
the lacrimal glands.
*FIELD* AV
.0001
ALACRIMA, ACHALASIA, AND MENTAL RETARDATION SYNDROME
GMPPA, ARG99TER
In 3 sibs, born of consanguineous Pakistani parents, with alacrima,
achalasia, and mental retardation syndrome (AAMR; 615510), Koehler et
al. (2013) identified a homozygous c.295C-T transition in exon 5 of the
GMPPA gene, resulting in an arg99-to-ter (R99X) substitution. The
mutation, which was found by linkage analysis and whole-exome sequencing
and confirmed by Sanger sequencing, was not present in the dbSNP, 1000
Genomes Project, or Exome Variant Server databases, or in 200 in-house
control exomes. Cells transfected with the mutation showed no GMPPA
immunostaining, consistent with a loss of function.
.0002
ALACRIMA, ACHALASIA, AND MENTAL RETARDATION SYNDROME
GMPPA, THR334PRO
In 2 brothers, born of consanguineous Arab parents, with AAMR (615510),
Koehler et al. (2013) identified a homozygous c.1000A-C transversion in
exon 12 of the GMPPA gene, resulting in a thr334-to-pro (T334P)
substitution. The variant was not present in the dbSNP, 1000 Genomes
Project, or Exome Variant Server databases, or in 200 in-house control
exomes.
.0003
ALACRIMA, ACHALASIA, AND MENTAL RETARDATION SYNDROME
GMPPA, GLY182ASP
In 2 Palestinian sisters with AAMR (615510), Koehler et al. (2013)
identified a homozygous c.545G-A transition in exon 7 of the GMPPA gene,
resulting in a gly182-to-asp (G182D) substitution. The variant was not
present in the dbSNP, 1000 Genomes Project, or Exome Variant Server
databases, or in 200 in-house control exomes.
.0004
ALACRIMA, ACHALASIA, AND MENTAL RETARDATION SYNDROME
GMPPA, 1-BP DEL, 210A
In a 10.7-year-old Dominican girl, born of consanguineous parents, with
AAMR (615510), Koehler et al. (2013) identified a homozygous 1-bp
deletion (c.210delA) in exon 4 of the GMPPA gene, resulting in a
frameshift and premature truncation (Ala71ProfsTer19). The variant was
not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server
databases, or in 200 in-house control exomes.
.0005
ALACRIMA, ACHALASIA, AND MENTAL RETARDATION SYNDROME
GMPPA, TRP214TER
In a 6-year-old girl, born of consanguineous Arab parents, with AAMR
(615510), Koehler et al. (2013) identified a homozygous 642G-A
transition in exon 8 of the GMPPA gene, resulting in a trp214-to-ter
(W214X) substitution. The variant was not present in the dbSNP, 1000
Genomes Project, or Exome Variant Server databases, or in 200 in-house
control exomes.
*FIELD* RF
1. Hartz, P. A.: Personal Communication. Baltimore, Md. 10/24/2013.
2. Koehler, K.; Malik, M.; Mahmood, S.; Giebelmann, S.; Beetz, C.;
Hennings, J. C.; Huebner, A. K.; Grahn, A.; Reunert, J.; Nurnberg,
G.; Thiele, H.; Altmuller, J.; and 20 others: Mutations in GMPPA
cause a glycosylation disorder characterized by intellectual disability
and autonomic dysfunction. Am. J. Hum. Genet. 93: 727-734, 2013.
*FIELD* CN
Cassandra L. Kniffin - updated: 11/4/2013
*FIELD* CD
Patricia A. Hartz: 10/24/2013
*FIELD* ED
carol: 11/05/2013
ckniffin: 11/4/2013
mgross: 10/24/2013
MIM
615510
*RECORD*
*FIELD* NO
615510
*FIELD* TI
#615510 ALACRIMA, ACHALASIA, AND MENTAL RETARDATION SYNDROME; AAMR
*FIELD* TX
A number sign (#) is used with this entry because alacrima, achalasia,
read moreand mental retardation syndrome (AAMR) is caused by homozygous mutation
in the GMPPA gene (615495) on chromosome 2q35.
DESCRIPTION
Alacrima, achalasia, and mental retardation syndrome (AAMR) is an
autosomal recessive disorder characterized by onset of these 3 main
features at birth or in early infancy. More variable features include
hypotonia, gait abnormalities, anisocoria, and visual or hearing
deficits. The disorder shows similarity to the triple A syndrome
(231550), but patients with AAMR do not have adrenal insufficiency
(summary by Koehler et al., 2013).
See also 300858 for a phenotypically similar disorder that shows
X-linked inheritance.
CLINICAL FEATURES
Koehler et al. (2013) reported 13 patients from 9 unrelated families
with alacrima, achalasia, and mental retardation. The families
originated from several different regions, including Pakistan, Turkey,
Palestine, and Morocco, and most were consanguineous. The patients
presented at birth or in the first years of life with alacrima, feeding
difficulties due to achalasia, and delayed psychomotor development with
speech delay. Most also had muscular hypotonia. More variable features
included gait abnormalities, spasticity, nasal speech, visual problems,
and hearing impairment. A few patients had autonomic problems, such as
decreased sweating, postural hypotension, and anisocoria. Affected
members of 1 family had hyperkeratosis. None had signs of adrenal
insufficiency. Koehler et al. (2013) noted the considerable clinical
overlap with triple A syndrome, but none of the patients had mutations
in the AAAS gene (605378).
INHERITANCE
The transmission pattern in the families with AAMR reported by Koehler
et al. (2013) was consistent with autosomal recessive inheritance.
MOLECULAR GENETICS
In 13 patients from 9 unrelated families with AAMR, Koehler et al.
(2013) identified 9 different homozygous mutations in the GMPPA gene
(see, e.g., 615495.0001-615495.0005). The mutation in the first family
was found by linkage analysis and whole-exome sequencing. The subsequent
families were identified by sequencing of the GMPPA gene in 63 families
with alacrima and achalasia who were negative for mutations in the AAAS
gene. Immunoblot analysis of patient cells with missense mutations
showed lower levels of GMPPA compared to controls, consistent with a
loss of function. However, GDP-mannose levels were significantly higher
in patient cells compared to controls, whereas other nucleotide
diphosphate sugars were unchanged. There was no evidence of alterations
in N-glycosylation profiles in patients: serum transferrin,
immunoglobulin G, and serum Apo-CIII glycosylation profiles were similar
to those in controls. Koehler et al. (2013) suggested that changes
induced by GDP-mannose overload might only be significant in restricted
cell types or affect other glycosylation types, or may lead to
perturbations in the levels of other guanine nucleotides. Alternatively,
GMPPA might serve as a regulatory subunit. The clinical features of the
patients with mutations indicated that GMPPA is important in neurons and
autonomic nerve fibers innervating the distal esophageal sphincter or
the lacrimal glands.
*FIELD* RF
1. Koehler, K.; Malik, M.; Mahmood, S.; Giebelmann, S.; Beetz, C.;
Hennings, J. C.; Huebner, A. K.; Grahn, A.; Reunert, J.; Nurnberg,
G.; Thiele, H.; Altmuller, J.; and 20 others: Mutations in GMPPA
cause a glycosylation disorder characterized by intellectual disability
and autonomic dysfunction. Am. J. Hum. Genet. 93: 727-734, 2013.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Hearing impairment (in some patients);
[Eyes];
Alacrima;
Visual problems (in some patients);
Nystagmus (in some patients);
Strabismus (in some patients);
Anisocoria (in some patients)
CARDIOVASCULAR:
[Vascular];
Postural hypotension (in some patients)
ABDOMEN:
[Gastrointestinal];
Achalasia;
Dysphagia;
Feeding difficulties
SKIN, NAILS, HAIR:
[Skin];
Hyperkeratosis (in some patients);
Hypohidrosis (in some patients)
MUSCLE, SOFT TISSUE:
Hypotonia (in some patients)
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Intellectual disability;
Gait abnormalities (in some patients);
Autonomic dysfunction;
[Peripheral nervous system];
Sensory impairment (in some patients)
VOICE:
Nasal voice (in some patients)
ENDOCRINE FEATURES:
No adrenal insufficiency
LABORATORY ABNORMALITIES:
Normal serum transferrin profiles
MISCELLANEOUS:
Onset at birth or in infancy
MOLECULAR BASIS:
Caused by mutation in the GDP-mannose pyrophosphorylase A gene (GMPPA,
615495.0001)
*FIELD* CD
Cassandra L. Kniffin: 11/4/2013
*FIELD* ED
joanna: 12/03/2013
ckniffin: 11/4/2013
*FIELD* CD
Cassandra L. Kniffin: 11/4/2013
*FIELD* ED
carol: 11/05/2013
ckniffin: 11/4/2013
*RECORD*
*FIELD* NO
615510
*FIELD* TI
#615510 ALACRIMA, ACHALASIA, AND MENTAL RETARDATION SYNDROME; AAMR
*FIELD* TX
A number sign (#) is used with this entry because alacrima, achalasia,
read moreand mental retardation syndrome (AAMR) is caused by homozygous mutation
in the GMPPA gene (615495) on chromosome 2q35.
DESCRIPTION
Alacrima, achalasia, and mental retardation syndrome (AAMR) is an
autosomal recessive disorder characterized by onset of these 3 main
features at birth or in early infancy. More variable features include
hypotonia, gait abnormalities, anisocoria, and visual or hearing
deficits. The disorder shows similarity to the triple A syndrome
(231550), but patients with AAMR do not have adrenal insufficiency
(summary by Koehler et al., 2013).
See also 300858 for a phenotypically similar disorder that shows
X-linked inheritance.
CLINICAL FEATURES
Koehler et al. (2013) reported 13 patients from 9 unrelated families
with alacrima, achalasia, and mental retardation. The families
originated from several different regions, including Pakistan, Turkey,
Palestine, and Morocco, and most were consanguineous. The patients
presented at birth or in the first years of life with alacrima, feeding
difficulties due to achalasia, and delayed psychomotor development with
speech delay. Most also had muscular hypotonia. More variable features
included gait abnormalities, spasticity, nasal speech, visual problems,
and hearing impairment. A few patients had autonomic problems, such as
decreased sweating, postural hypotension, and anisocoria. Affected
members of 1 family had hyperkeratosis. None had signs of adrenal
insufficiency. Koehler et al. (2013) noted the considerable clinical
overlap with triple A syndrome, but none of the patients had mutations
in the AAAS gene (605378).
INHERITANCE
The transmission pattern in the families with AAMR reported by Koehler
et al. (2013) was consistent with autosomal recessive inheritance.
MOLECULAR GENETICS
In 13 patients from 9 unrelated families with AAMR, Koehler et al.
(2013) identified 9 different homozygous mutations in the GMPPA gene
(see, e.g., 615495.0001-615495.0005). The mutation in the first family
was found by linkage analysis and whole-exome sequencing. The subsequent
families were identified by sequencing of the GMPPA gene in 63 families
with alacrima and achalasia who were negative for mutations in the AAAS
gene. Immunoblot analysis of patient cells with missense mutations
showed lower levels of GMPPA compared to controls, consistent with a
loss of function. However, GDP-mannose levels were significantly higher
in patient cells compared to controls, whereas other nucleotide
diphosphate sugars were unchanged. There was no evidence of alterations
in N-glycosylation profiles in patients: serum transferrin,
immunoglobulin G, and serum Apo-CIII glycosylation profiles were similar
to those in controls. Koehler et al. (2013) suggested that changes
induced by GDP-mannose overload might only be significant in restricted
cell types or affect other glycosylation types, or may lead to
perturbations in the levels of other guanine nucleotides. Alternatively,
GMPPA might serve as a regulatory subunit. The clinical features of the
patients with mutations indicated that GMPPA is important in neurons and
autonomic nerve fibers innervating the distal esophageal sphincter or
the lacrimal glands.
*FIELD* RF
1. Koehler, K.; Malik, M.; Mahmood, S.; Giebelmann, S.; Beetz, C.;
Hennings, J. C.; Huebner, A. K.; Grahn, A.; Reunert, J.; Nurnberg,
G.; Thiele, H.; Altmuller, J.; and 20 others: Mutations in GMPPA
cause a glycosylation disorder characterized by intellectual disability
and autonomic dysfunction. Am. J. Hum. Genet. 93: 727-734, 2013.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Ears];
Hearing impairment (in some patients);
[Eyes];
Alacrima;
Visual problems (in some patients);
Nystagmus (in some patients);
Strabismus (in some patients);
Anisocoria (in some patients)
CARDIOVASCULAR:
[Vascular];
Postural hypotension (in some patients)
ABDOMEN:
[Gastrointestinal];
Achalasia;
Dysphagia;
Feeding difficulties
SKIN, NAILS, HAIR:
[Skin];
Hyperkeratosis (in some patients);
Hypohidrosis (in some patients)
MUSCLE, SOFT TISSUE:
Hypotonia (in some patients)
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Intellectual disability;
Gait abnormalities (in some patients);
Autonomic dysfunction;
[Peripheral nervous system];
Sensory impairment (in some patients)
VOICE:
Nasal voice (in some patients)
ENDOCRINE FEATURES:
No adrenal insufficiency
LABORATORY ABNORMALITIES:
Normal serum transferrin profiles
MISCELLANEOUS:
Onset at birth or in infancy
MOLECULAR BASIS:
Caused by mutation in the GDP-mannose pyrophosphorylase A gene (GMPPA,
615495.0001)
*FIELD* CD
Cassandra L. Kniffin: 11/4/2013
*FIELD* ED
joanna: 12/03/2013
ckniffin: 11/4/2013
*FIELD* CD
Cassandra L. Kniffin: 11/4/2013
*FIELD* ED
carol: 11/05/2013
ckniffin: 11/4/2013