Full text data of GALK1
GALK1
(GALK)
[Confidence: low (only semi-automatic identification from reviews)]
Galactokinase; 2.7.1.6 (Galactose kinase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Galactokinase; 2.7.1.6 (Galactose kinase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P51570
ID GALK1_HUMAN Reviewed; 392 AA.
AC P51570; B2RC07;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 1.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Galactokinase;
DE EC=2.7.1.6;
DE AltName: Full=Galactose kinase;
GN Name=GALK1; Synonyms=GALK;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT II GALACTOSEMIA MET-32.
RX PubMed=7670469; DOI=10.1038/ng0795-307;
RA Stambolian D., Ai Y., Sidjanin D., Nesburn K., Sathe G., Rosenberg M.,
RA Bergsma D.J.;
RT "Cloning of the galactokinase cDNA and identification of mutations in
RT two families with cataracts.";
RL Nat. Genet. 10:307-312(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8908517;
RA Bergsma D.J., Ai Y., Skach W.R., Nesburn K., Anoia E., van Horn S.,
RA Stambolian D.;
RT "Fine structure of the human galactokinase GALK1 gene.";
RL Genome Res. 6:980-985(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [6]
RP PROTEIN SEQUENCE OF 6-17; 22-37; 70-97; 205-239; 257-267; 288-296 AND
RP 343-388, AND MASS SPECTROMETRY.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [7]
RP CHARACTERIZATION.
RX PubMed=7542884; DOI=10.1006/bbrc.1995.2023;
RA Ai Y., Basu M., Bergsma D.J., Stambolian D.;
RT "Comparison of the enzymatic activities of human galactokinase GALK1
RT and a related human galactokinase protein GK2.";
RL Biochem. Biophys. Res. Commun. 212:687-691(1995).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 2-392 IN COMPLEX WITH
RP D-GALACTOSE AND ATP ANALOG, SUBUNIT, AND SUBSTRATE-BINDING SITES.
RX PubMed=15590630; DOI=10.1074/jbc.M412916200;
RA Thoden J.B., Timson D.J., Reece R.J., Holden H.M.;
RT "Molecular structure of human galactokinase: implications for type II
RT galactosemia.";
RL J. Biol. Chem. 280:9662-9670(2005).
RN [10]
RP VARIANT GALCT2 THR-28.
RX PubMed=10521295; DOI=10.1086/302611;
RA Kalaydjieva L., Perez-Lezaun A., Angelicheva D., Onengut S., Dye D.,
RA Bosshard N.U., Jordanova A., Savov A., Yanakiev P., Kremensky I.,
RA Radeva B., Hallmayer J., Markov A., Nedkova V., Tournev I., Aneva L.,
RA Gitzelmann R.;
RT "A founder mutation in the GK1 gene is responsible for galactokinase
RT deficiency in Roma (Gypsies).";
RL Am. J. Hum. Genet. 65:1299-1307(1999).
RN [11]
RP VARIANTS GALCT2 THR-28; ARG-36; TYR-44; SER-346 AND SER-349.
RX PubMed=10790206;
RX DOI=10.1002/(SICI)1098-1004(200005)15:5<447::AID-HUMU6>3.3.CO;2-D;
RA Kolosha V., Anoia E., de Cespedes C., Gitzelmann R., Shih L.,
RA Casco T., Saborio M., Trejos R., Buist N., Tedesco T., Skach W.,
RA Mitelmann O., Ledee D., Huang K., Stambolian D.;
RT "Novel mutations in 13 probands with galactokinase deficiency.";
RL Hum. Mutat. 15:447-453(2000).
RN [12]
RP VARIANT GALCT2 VAL-198.
RX PubMed=11231902; DOI=10.1086/319512;
RA Okano Y., Asada M., Fujimoto A., Ohtake A., Murayama K., Hsiao K.-J.,
RA Choeh K., Yang Y., Cao Q., Reichardt J.K.V., Niihira S., Imamura T.,
RA Yamano T.;
RT "A genetic factor for age-related cataract: identification and
RT characterization of a novel galactokinase variant, 'Osaka,' in
RT Asians.";
RL Am. J. Hum. Genet. 68:1036-1042(2001).
RN [13]
RP VARIANTS GALCT2 CYS-68; MET-288 AND PRO-384.
RX PubMed=11139256;
RX DOI=10.1002/1098-1004(2001)17:1<77::AID-HUMU20>3.3.CO;2-8;
RA Hunter M., Angelicheva D., Levy H.L., Pueschel S.M., Kalaydjieva L.;
RT "Novel mutations in the GALK1 gene in patients with galactokinase
RT deficiency.";
RL Hum. Mutat. 17:77-78(2001).
RN [14]
RP CHARACTERIZATION OF VARIANTS GALCT2 THR-28; MET-32; ARG-36; TYR-44;
RP CYS-68; VAL-198; MET-288; SER-346; SER-349 AND PRO-384.
RX PubMed=12694189; DOI=10.1046/j.1432-1033.2003.03538.x;
RA Timson D.J., Reece R.J.;
RT "Functional analysis of disease-causing mutations in human
RT galactokinase.";
RL Eur. J. Biochem. 270:1767-1774(2003).
RN [15]
RP VARIANTS MET-184; ASP-274 AND ALA-338.
RX PubMed=12942049;
RA Maraini G., Hejtmancik J.F., Shiels A., Mackay D.S., Aldigeri R.,
RA Jiao X.D., Williams S.L., Sperduto R.D., Reed G.;
RT "Galactokinase gene mutations and age-related cataract. Lack of
RT association in an Italian population.";
RL Mol. Vis. 9:397-400(2003).
RN [16]
RP VARIANTS GALCT2 MET-32 AND GLN-239.
RX PubMed=15024738; DOI=10.1002/humu.9223;
RA Sangiuolo F., Magnani M., Stambolian D., Novelli G.;
RT "Biochemical characterization of two GALK1 mutations in patients with
RT galactokinase deficiency.";
RL Hum. Mutat. 23:396-396(2004).
CC -!- FUNCTION: Major enzyme for galactose metabolism.
CC -!- CATALYTIC ACTIVITY: ATP + alpha-D-galactose = ADP + alpha-D-
CC galactose 1-phosphate.
CC -!- PATHWAY: Carbohydrate metabolism; galactose metabolism.
CC -!- SUBUNIT: Homodimer (Probable).
CC -!- DISEASE: Galactosemia II (GALCT2) [MIM:230200]: Autosomal
CC recessive deficiency characterized by congenital cataracts during
CC infancy and presenile cataracts in the adult population. The
CC cataracts are secondary to accumulation of galactitol in the
CC lenses. Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the GHMP kinase family. GalK subfamily.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GALK1";
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DR EMBL; U26401; AAA96147.1; -; mRNA.
DR EMBL; L76927; AAB51607.1; -; Genomic_DNA.
DR EMBL; AK314890; BAG37404.1; -; mRNA.
DR EMBL; BT007005; AAP35651.1; -; mRNA.
DR EMBL; BC001166; AAH01166.1; -; mRNA.
DR RefSeq; NP_000145.1; NM_000154.1.
DR UniGene; Hs.407966; -.
DR PDB; 1WUU; X-ray; 2.50 A; A/B/C/D=2-392.
DR PDB; 1YH7; Model; -; A=1-392.
DR PDBsum; 1WUU; -.
DR PDBsum; 1YH7; -.
DR ProteinModelPortal; P51570; -.
DR SMR; P51570; 2-392.
DR IntAct; P51570; 4.
DR MINT; MINT-4999410; -.
DR STRING; 9606.ENSP00000225614; -.
DR ChEMBL; CHEMBL1293257; -.
DR PhosphoSite; P51570; -.
DR DMDM; 1730187; -.
DR OGP; P51570; -.
DR REPRODUCTION-2DPAGE; IPI00019383; -.
DR PaxDb; P51570; -.
DR PRIDE; P51570; -.
DR DNASU; 2584; -.
DR Ensembl; ENST00000225614; ENSP00000225614; ENSG00000108479.
DR Ensembl; ENST00000588479; ENSP00000465930; ENSG00000108479.
DR GeneID; 2584; -.
DR KEGG; hsa:2584; -.
DR UCSC; uc002jpk.3; human.
DR CTD; 2584; -.
DR GeneCards; GC17M073730; -.
DR HGNC; HGNC:4118; GALK1.
DR HPA; HPA007094; -.
DR HPA; HPA016960; -.
DR MIM; 230200; phenotype.
DR MIM; 604313; gene.
DR neXtProt; NX_P51570; -.
DR Orphanet; 79237; Galactokinase deficiency.
DR PharmGKB; PA28533; -.
DR eggNOG; COG0153; -.
DR HOGENOM; HOG000241100; -.
DR HOVERGEN; HBG051695; -.
DR KO; K00849; -.
DR OrthoDB; EOG7K3TMV; -.
DR PhylomeDB; P51570; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P51570; -.
DR UniPathway; UPA00214; -.
DR EvolutionaryTrace; P51570; -.
DR GenomeRNAi; 2584; -.
DR NextBio; 10223; -.
DR PRO; PR:P51570; -.
DR ArrayExpress; P51570; -.
DR Bgee; P51570; -.
DR CleanEx; HS_GALK1; -.
DR Genevestigator; P51570; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0004335; F:galactokinase activity; IDA:UniProtKB.
DR GO; GO:0005534; F:galactose binding; IDA:UniProtKB.
DR GO; GO:0019402; P:galactitol metabolic process; IEA:Ensembl.
DR GO; GO:0019388; P:galactose catabolic process; TAS:Reactome.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 3.30.230.10; -; 1.
DR InterPro; IPR000705; Galactokinase.
DR InterPro; IPR019741; Galactokinase_CS.
DR InterPro; IPR019539; GalKase_gal-bd.
DR InterPro; IPR013750; GHMP_kinase_C_dom.
DR InterPro; IPR006204; GHMP_kinase_N_dom.
DR InterPro; IPR006203; GHMP_knse_ATP-bd_CS.
DR InterPro; IPR006206; Mevalonate/galactokinase.
DR InterPro; IPR020568; Ribosomal_S5_D2-typ_fold.
DR InterPro; IPR014721; Ribosomal_S5_D2-typ_fold_subgr.
DR Pfam; PF10509; GalKase_gal_bdg; 1.
DR Pfam; PF08544; GHMP_kinases_C; 1.
DR Pfam; PF00288; GHMP_kinases_N; 1.
DR PIRSF; PIRSF000530; Galactokinase; 1.
DR PRINTS; PR00473; GALCTOKINASE.
DR PRINTS; PR00959; MEVGALKINASE.
DR SUPFAM; SSF54211; SSF54211; 1.
DR TIGRFAMs; TIGR00131; gal_kin; 1.
DR PROSITE; PS00106; GALACTOKINASE; 1.
DR PROSITE; PS00627; GHMP_KINASES_ATP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Carbohydrate metabolism; Cataract;
KW Complete proteome; Direct protein sequencing; Disease mutation;
KW Galactose metabolism; Kinase; Nucleotide-binding; Polymorphism;
KW Reference proteome; Transferase.
FT CHAIN 1 392 Galactokinase.
FT /FTId=PRO_0000184645.
FT NP_BIND 134 144 ATP.
FT REGION 43 46 Substrate binding.
FT REGION 183 186 Substrate binding.
FT ACT_SITE 186 186 Proton acceptor (By similarity).
FT BINDING 236 236 Substrate.
FT SITE 37 37 Transition state stabilizer (Probable).
FT VARIANT 28 28 P -> T (in GALCT2; founder Romani
FT mutation).
FT /FTId=VAR_008514.
FT VARIANT 32 32 V -> M (in GALCT2).
FT /FTId=VAR_002547.
FT VARIANT 36 36 G -> R (in GALCT2).
FT /FTId=VAR_023486.
FT VARIANT 44 44 H -> Y (in GALCT2).
FT /FTId=VAR_023487.
FT VARIANT 68 68 R -> C (in GALCT2).
FT /FTId=VAR_023488.
FT VARIANT 184 184 I -> M.
FT /FTId=VAR_023489.
FT VARIANT 198 198 A -> V (in GALCT2; mild deficiency;
FT Osaka; dbSNP:rs80084721).
FT /FTId=VAR_015746.
FT VARIANT 239 239 R -> Q (in GALCT2).
FT /FTId=VAR_023490.
FT VARIANT 274 274 G -> D.
FT /FTId=VAR_023491.
FT VARIANT 288 288 T -> M (in GALCT2).
FT /FTId=VAR_023492.
FT VARIANT 338 338 V -> A.
FT /FTId=VAR_023493.
FT VARIANT 346 346 G -> S (in GALCT2).
FT /FTId=VAR_023494.
FT VARIANT 349 349 G -> S (in GALCT2).
FT /FTId=VAR_023495.
FT VARIANT 384 384 A -> P (in GALCT2).
FT /FTId=VAR_023496.
FT HELIX 9 24
FT STRAND 29 41
FT HELIX 46 48
FT STRAND 51 68
FT STRAND 72 77
FT STRAND 80 82
FT STRAND 86 91
FT HELIX 105 107
FT HELIX 108 116
FT STRAND 118 120
FT STRAND 124 131
FT STRAND 137 139
FT HELIX 141 156
FT HELIX 163 176
FT HELIX 185 192
FT STRAND 197 202
FT TURN 203 205
FT STRAND 208 212
FT STRAND 216 228
FT TURN 233 235
FT HELIX 236 249
FT HELIX 260 263
FT HELIX 266 269
FT HELIX 272 296
FT HELIX 300 316
FT HELIX 323 333
FT STRAND 338 343
FT STRAND 348 357
FT HELIX 358 360
FT HELIX 361 371
FT STRAND 377 381
FT STRAND 387 389
SQ SEQUENCE 392 AA; 42272 MW; 8D7CFF8FDB0E4718 CRC64;
MAALRQPQVA ELLAEARRAF REEFGAEPEL AVSAPGRVNL IGEHTDYNQG LVLPMALELM
TVLVGSPRKD GLVSLLTTSE GADEPQRLQF PLPTAQRSLE PGTPRWANYV KGVIQYYPAA
PLPGFSAVVV SSVPLGGGLS SSASLEVATY TFLQQLCPDS GTIAARAQVC QQAEHSFAGM
PCGIMDQFIS LMGQKGHALL IDCRSLETSL VPLSDPKLAV LITNSNVRHS LASSEYPVRR
RQCEEVARAL GKESLREVQL EELEAARDLV SKEGFRRARH VVGEIRRTAQ AAAALRRGDY
RAFGRLMVES HRSLRDDYEV SCPELDQLVE AALAVPGVYG SRMTGGGFGG CTVTLLEASA
APHAMRHIQE HYGGTATFYL SQAADGAKVL CL
//
ID GALK1_HUMAN Reviewed; 392 AA.
AC P51570; B2RC07;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 1.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Galactokinase;
DE EC=2.7.1.6;
DE AltName: Full=Galactose kinase;
GN Name=GALK1; Synonyms=GALK;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT II GALACTOSEMIA MET-32.
RX PubMed=7670469; DOI=10.1038/ng0795-307;
RA Stambolian D., Ai Y., Sidjanin D., Nesburn K., Sathe G., Rosenberg M.,
RA Bergsma D.J.;
RT "Cloning of the galactokinase cDNA and identification of mutations in
RT two families with cataracts.";
RL Nat. Genet. 10:307-312(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8908517;
RA Bergsma D.J., Ai Y., Skach W.R., Nesburn K., Anoia E., van Horn S.,
RA Stambolian D.;
RT "Fine structure of the human galactokinase GALK1 gene.";
RL Genome Res. 6:980-985(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [6]
RP PROTEIN SEQUENCE OF 6-17; 22-37; 70-97; 205-239; 257-267; 288-296 AND
RP 343-388, AND MASS SPECTROMETRY.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [7]
RP CHARACTERIZATION.
RX PubMed=7542884; DOI=10.1006/bbrc.1995.2023;
RA Ai Y., Basu M., Bergsma D.J., Stambolian D.;
RT "Comparison of the enzymatic activities of human galactokinase GALK1
RT and a related human galactokinase protein GK2.";
RL Biochem. Biophys. Res. Commun. 212:687-691(1995).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 2-392 IN COMPLEX WITH
RP D-GALACTOSE AND ATP ANALOG, SUBUNIT, AND SUBSTRATE-BINDING SITES.
RX PubMed=15590630; DOI=10.1074/jbc.M412916200;
RA Thoden J.B., Timson D.J., Reece R.J., Holden H.M.;
RT "Molecular structure of human galactokinase: implications for type II
RT galactosemia.";
RL J. Biol. Chem. 280:9662-9670(2005).
RN [10]
RP VARIANT GALCT2 THR-28.
RX PubMed=10521295; DOI=10.1086/302611;
RA Kalaydjieva L., Perez-Lezaun A., Angelicheva D., Onengut S., Dye D.,
RA Bosshard N.U., Jordanova A., Savov A., Yanakiev P., Kremensky I.,
RA Radeva B., Hallmayer J., Markov A., Nedkova V., Tournev I., Aneva L.,
RA Gitzelmann R.;
RT "A founder mutation in the GK1 gene is responsible for galactokinase
RT deficiency in Roma (Gypsies).";
RL Am. J. Hum. Genet. 65:1299-1307(1999).
RN [11]
RP VARIANTS GALCT2 THR-28; ARG-36; TYR-44; SER-346 AND SER-349.
RX PubMed=10790206;
RX DOI=10.1002/(SICI)1098-1004(200005)15:5<447::AID-HUMU6>3.3.CO;2-D;
RA Kolosha V., Anoia E., de Cespedes C., Gitzelmann R., Shih L.,
RA Casco T., Saborio M., Trejos R., Buist N., Tedesco T., Skach W.,
RA Mitelmann O., Ledee D., Huang K., Stambolian D.;
RT "Novel mutations in 13 probands with galactokinase deficiency.";
RL Hum. Mutat. 15:447-453(2000).
RN [12]
RP VARIANT GALCT2 VAL-198.
RX PubMed=11231902; DOI=10.1086/319512;
RA Okano Y., Asada M., Fujimoto A., Ohtake A., Murayama K., Hsiao K.-J.,
RA Choeh K., Yang Y., Cao Q., Reichardt J.K.V., Niihira S., Imamura T.,
RA Yamano T.;
RT "A genetic factor for age-related cataract: identification and
RT characterization of a novel galactokinase variant, 'Osaka,' in
RT Asians.";
RL Am. J. Hum. Genet. 68:1036-1042(2001).
RN [13]
RP VARIANTS GALCT2 CYS-68; MET-288 AND PRO-384.
RX PubMed=11139256;
RX DOI=10.1002/1098-1004(2001)17:1<77::AID-HUMU20>3.3.CO;2-8;
RA Hunter M., Angelicheva D., Levy H.L., Pueschel S.M., Kalaydjieva L.;
RT "Novel mutations in the GALK1 gene in patients with galactokinase
RT deficiency.";
RL Hum. Mutat. 17:77-78(2001).
RN [14]
RP CHARACTERIZATION OF VARIANTS GALCT2 THR-28; MET-32; ARG-36; TYR-44;
RP CYS-68; VAL-198; MET-288; SER-346; SER-349 AND PRO-384.
RX PubMed=12694189; DOI=10.1046/j.1432-1033.2003.03538.x;
RA Timson D.J., Reece R.J.;
RT "Functional analysis of disease-causing mutations in human
RT galactokinase.";
RL Eur. J. Biochem. 270:1767-1774(2003).
RN [15]
RP VARIANTS MET-184; ASP-274 AND ALA-338.
RX PubMed=12942049;
RA Maraini G., Hejtmancik J.F., Shiels A., Mackay D.S., Aldigeri R.,
RA Jiao X.D., Williams S.L., Sperduto R.D., Reed G.;
RT "Galactokinase gene mutations and age-related cataract. Lack of
RT association in an Italian population.";
RL Mol. Vis. 9:397-400(2003).
RN [16]
RP VARIANTS GALCT2 MET-32 AND GLN-239.
RX PubMed=15024738; DOI=10.1002/humu.9223;
RA Sangiuolo F., Magnani M., Stambolian D., Novelli G.;
RT "Biochemical characterization of two GALK1 mutations in patients with
RT galactokinase deficiency.";
RL Hum. Mutat. 23:396-396(2004).
CC -!- FUNCTION: Major enzyme for galactose metabolism.
CC -!- CATALYTIC ACTIVITY: ATP + alpha-D-galactose = ADP + alpha-D-
CC galactose 1-phosphate.
CC -!- PATHWAY: Carbohydrate metabolism; galactose metabolism.
CC -!- SUBUNIT: Homodimer (Probable).
CC -!- DISEASE: Galactosemia II (GALCT2) [MIM:230200]: Autosomal
CC recessive deficiency characterized by congenital cataracts during
CC infancy and presenile cataracts in the adult population. The
CC cataracts are secondary to accumulation of galactitol in the
CC lenses. Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the GHMP kinase family. GalK subfamily.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GALK1";
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; U26401; AAA96147.1; -; mRNA.
DR EMBL; L76927; AAB51607.1; -; Genomic_DNA.
DR EMBL; AK314890; BAG37404.1; -; mRNA.
DR EMBL; BT007005; AAP35651.1; -; mRNA.
DR EMBL; BC001166; AAH01166.1; -; mRNA.
DR RefSeq; NP_000145.1; NM_000154.1.
DR UniGene; Hs.407966; -.
DR PDB; 1WUU; X-ray; 2.50 A; A/B/C/D=2-392.
DR PDB; 1YH7; Model; -; A=1-392.
DR PDBsum; 1WUU; -.
DR PDBsum; 1YH7; -.
DR ProteinModelPortal; P51570; -.
DR SMR; P51570; 2-392.
DR IntAct; P51570; 4.
DR MINT; MINT-4999410; -.
DR STRING; 9606.ENSP00000225614; -.
DR ChEMBL; CHEMBL1293257; -.
DR PhosphoSite; P51570; -.
DR DMDM; 1730187; -.
DR OGP; P51570; -.
DR REPRODUCTION-2DPAGE; IPI00019383; -.
DR PaxDb; P51570; -.
DR PRIDE; P51570; -.
DR DNASU; 2584; -.
DR Ensembl; ENST00000225614; ENSP00000225614; ENSG00000108479.
DR Ensembl; ENST00000588479; ENSP00000465930; ENSG00000108479.
DR GeneID; 2584; -.
DR KEGG; hsa:2584; -.
DR UCSC; uc002jpk.3; human.
DR CTD; 2584; -.
DR GeneCards; GC17M073730; -.
DR HGNC; HGNC:4118; GALK1.
DR HPA; HPA007094; -.
DR HPA; HPA016960; -.
DR MIM; 230200; phenotype.
DR MIM; 604313; gene.
DR neXtProt; NX_P51570; -.
DR Orphanet; 79237; Galactokinase deficiency.
DR PharmGKB; PA28533; -.
DR eggNOG; COG0153; -.
DR HOGENOM; HOG000241100; -.
DR HOVERGEN; HBG051695; -.
DR KO; K00849; -.
DR OrthoDB; EOG7K3TMV; -.
DR PhylomeDB; P51570; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P51570; -.
DR UniPathway; UPA00214; -.
DR EvolutionaryTrace; P51570; -.
DR GenomeRNAi; 2584; -.
DR NextBio; 10223; -.
DR PRO; PR:P51570; -.
DR ArrayExpress; P51570; -.
DR Bgee; P51570; -.
DR CleanEx; HS_GALK1; -.
DR Genevestigator; P51570; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0004335; F:galactokinase activity; IDA:UniProtKB.
DR GO; GO:0005534; F:galactose binding; IDA:UniProtKB.
DR GO; GO:0019402; P:galactitol metabolic process; IEA:Ensembl.
DR GO; GO:0019388; P:galactose catabolic process; TAS:Reactome.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 3.30.230.10; -; 1.
DR InterPro; IPR000705; Galactokinase.
DR InterPro; IPR019741; Galactokinase_CS.
DR InterPro; IPR019539; GalKase_gal-bd.
DR InterPro; IPR013750; GHMP_kinase_C_dom.
DR InterPro; IPR006204; GHMP_kinase_N_dom.
DR InterPro; IPR006203; GHMP_knse_ATP-bd_CS.
DR InterPro; IPR006206; Mevalonate/galactokinase.
DR InterPro; IPR020568; Ribosomal_S5_D2-typ_fold.
DR InterPro; IPR014721; Ribosomal_S5_D2-typ_fold_subgr.
DR Pfam; PF10509; GalKase_gal_bdg; 1.
DR Pfam; PF08544; GHMP_kinases_C; 1.
DR Pfam; PF00288; GHMP_kinases_N; 1.
DR PIRSF; PIRSF000530; Galactokinase; 1.
DR PRINTS; PR00473; GALCTOKINASE.
DR PRINTS; PR00959; MEVGALKINASE.
DR SUPFAM; SSF54211; SSF54211; 1.
DR TIGRFAMs; TIGR00131; gal_kin; 1.
DR PROSITE; PS00106; GALACTOKINASE; 1.
DR PROSITE; PS00627; GHMP_KINASES_ATP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Carbohydrate metabolism; Cataract;
KW Complete proteome; Direct protein sequencing; Disease mutation;
KW Galactose metabolism; Kinase; Nucleotide-binding; Polymorphism;
KW Reference proteome; Transferase.
FT CHAIN 1 392 Galactokinase.
FT /FTId=PRO_0000184645.
FT NP_BIND 134 144 ATP.
FT REGION 43 46 Substrate binding.
FT REGION 183 186 Substrate binding.
FT ACT_SITE 186 186 Proton acceptor (By similarity).
FT BINDING 236 236 Substrate.
FT SITE 37 37 Transition state stabilizer (Probable).
FT VARIANT 28 28 P -> T (in GALCT2; founder Romani
FT mutation).
FT /FTId=VAR_008514.
FT VARIANT 32 32 V -> M (in GALCT2).
FT /FTId=VAR_002547.
FT VARIANT 36 36 G -> R (in GALCT2).
FT /FTId=VAR_023486.
FT VARIANT 44 44 H -> Y (in GALCT2).
FT /FTId=VAR_023487.
FT VARIANT 68 68 R -> C (in GALCT2).
FT /FTId=VAR_023488.
FT VARIANT 184 184 I -> M.
FT /FTId=VAR_023489.
FT VARIANT 198 198 A -> V (in GALCT2; mild deficiency;
FT Osaka; dbSNP:rs80084721).
FT /FTId=VAR_015746.
FT VARIANT 239 239 R -> Q (in GALCT2).
FT /FTId=VAR_023490.
FT VARIANT 274 274 G -> D.
FT /FTId=VAR_023491.
FT VARIANT 288 288 T -> M (in GALCT2).
FT /FTId=VAR_023492.
FT VARIANT 338 338 V -> A.
FT /FTId=VAR_023493.
FT VARIANT 346 346 G -> S (in GALCT2).
FT /FTId=VAR_023494.
FT VARIANT 349 349 G -> S (in GALCT2).
FT /FTId=VAR_023495.
FT VARIANT 384 384 A -> P (in GALCT2).
FT /FTId=VAR_023496.
FT HELIX 9 24
FT STRAND 29 41
FT HELIX 46 48
FT STRAND 51 68
FT STRAND 72 77
FT STRAND 80 82
FT STRAND 86 91
FT HELIX 105 107
FT HELIX 108 116
FT STRAND 118 120
FT STRAND 124 131
FT STRAND 137 139
FT HELIX 141 156
FT HELIX 163 176
FT HELIX 185 192
FT STRAND 197 202
FT TURN 203 205
FT STRAND 208 212
FT STRAND 216 228
FT TURN 233 235
FT HELIX 236 249
FT HELIX 260 263
FT HELIX 266 269
FT HELIX 272 296
FT HELIX 300 316
FT HELIX 323 333
FT STRAND 338 343
FT STRAND 348 357
FT HELIX 358 360
FT HELIX 361 371
FT STRAND 377 381
FT STRAND 387 389
SQ SEQUENCE 392 AA; 42272 MW; 8D7CFF8FDB0E4718 CRC64;
MAALRQPQVA ELLAEARRAF REEFGAEPEL AVSAPGRVNL IGEHTDYNQG LVLPMALELM
TVLVGSPRKD GLVSLLTTSE GADEPQRLQF PLPTAQRSLE PGTPRWANYV KGVIQYYPAA
PLPGFSAVVV SSVPLGGGLS SSASLEVATY TFLQQLCPDS GTIAARAQVC QQAEHSFAGM
PCGIMDQFIS LMGQKGHALL IDCRSLETSL VPLSDPKLAV LITNSNVRHS LASSEYPVRR
RQCEEVARAL GKESLREVQL EELEAARDLV SKEGFRRARH VVGEIRRTAQ AAAALRRGDY
RAFGRLMVES HRSLRDDYEV SCPELDQLVE AALAVPGVYG SRMTGGGFGG CTVTLLEASA
APHAMRHIQE HYGGTATFYL SQAADGAKVL CL
//
MIM
230200
*RECORD*
*FIELD* NO
230200
*FIELD* TI
#230200 GALACTOKINASE DEFICIENCY
;;GALK DEFICIENCY;;
GALACTOSEMIA II
*FIELD* TX
A number sign (#) is used with this entry because galactokinase
read moredeficiency is caused by mutation in the GALK1 gene (604313) on
chromosome 17q24.
Classic galactosemia (230400) is a distinct disorder caused by mutation
in the gene encoding galactose-1-phosphate uridyltransferase (GALT;
606999) on chromosome 9p13.
DESCRIPTION
Galactokinase deficiency is an autosomal recessive disorder which causes
cataract formation in children not maintained on a lactose-free diet.
Cataract formation is the result of osmotic phenomena caused by the
accumulation of galactitol in the lens (Asada et al., 1999).
CLINICAL FEATURES
Gitzelmann (1967) reported juvenile cataracts related to galactokinase
deficiency in 2 sibs of a consanguineous Gypsy family, Fanconi had
previously reported the cases as instances of 'galactose diabetes;'
however, GALT activity in red cells was normal. There was no mental
retardation. Several close relatives had reduced red cell galactokinase
activity, suggesting that they were heterozygotes.
Cook et al. (1971) described an affected newborn, ascertained because of
hyperbilirubinemia, who had resolution of the cataracts with dietary
management. Segal et al. (1979), who studied affected brothers,
suggested that mental retardation may occur with galactokinase
deficiency.
Prachal et al. (1978) associated presenile cataracts with heterozygosity
for galactokinase deficiency and galactose-uridyl transferase
deficiency.
Bosch et al. (2002) reviewed the clinical features of galactokinase
deficiency in describing 55 patients in 25 publications. Cataract was
reported in most patients. Clinical abnormalities other than cataract
were reported in 15 (35%) of 43 cases for which information was
available. However, all symptoms were reported infrequently and a causal
relationship with the galactokinase deficiency could not be determined.
Pseudotumor cerebri is a rare but consistently reported abnormality in
this disorder.
MOLECULAR GENETICS
In 2 patients with galactokinase deficiency and cataracts, Stambolian et
al. (1995) identified 2 different homozygous mutations in the GALK1 gene
(604313.0001; 604313.0002). One of the patients had been reported by
Pickering and Howell (1972).
In affected members of 6 Romani (Gypsy) families from Bulgaria with
galactokinase deficiency, Kalaydjieva et al. (1999) identified a
homozygous mutation in the GALK1 gene (P28T; 604313.0003). The authors
concluded that this mutation was most likely responsible for the
galactokinase deficiency in the cases originally described by Gitzelmann
(1967).
Asada et al. (1999) identified 5 mutations in the GALK1 gene in 7
unrelated Japanese patients with galactokinase deficiency.
POPULATION GENETICS
Mayes and Guthrie (1968) found 6 heterozygotes for galactokinase
deficiency among 642 persons in Buffalo, N.Y.
In Italy, Magnani et al. (1982) estimated the heterozygote frequency to
be 1 in 310; 2 persons presumably heterozygous by biochemical criteria
were detected among 620 persons studied.
*FIELD* SA
Beutler et al. (1973); Kaloud and Sitzmann (1974); Kerr et al. (1971);
Levy et al. (1972); Litman et al. (1975); Oberman et al. (1972); Thalhammer
et al. (1968)
*FIELD* RF
1. Asada, M.; Okano, Y.; Imamura, T.; Suyama, I.; Hase, Y.; Isshiki,
G.: Molecular characterization of galactokinase deficiency in Japanese
patients. J. Hum. Genet. 44: 377-382, 1999.
2. Beutler, E.; Matsumoto, F.; Kuhl, W.; Krill, A. E.; Levy, N.; Sparkes,
R.; Degnan, M.: Galactokinase deficiency as a cause of cataracts. New
Eng. J. Med. 288: 1203-1206, 1973.
3. Bosch, A. M.; Bakker, H. D.; van Gennip, A. H.; van Kempen, J.
V.; Wanders, R. J. A.; Wijburg, F. A.: Clinical features of galactokinase
deficiency: a review of the literature. J. Inherit. Metab. Dis. 25:
629-634, 2002.
4. Cook, J. G. H.; Don, N. A.; Mann, T. P.: Hereditary galactokinase
deficiency. Arch. Dis. Child. 46: 465-469, 1971.
5. Gitzelmann, R.: Hereditary galactokinase deficiency, a newly recognized
cause of juvenile cataracts. Pediat. Res. 1: 14-23, 1967.
6. Kalaydjieva, L.; Perez-Lezaun, A.; Angelicheva, D.; Onengut, S.;
Dye, D.; Bosshard, N. U.; Jordanova, A.; Savov, A.; Yanakiev, P.;
Kremensky, I.; Radeva, B.; Hallmayer, J.; Markov, A.; Nedkova, V.;
Tournev, I.; Aneva, L.; Gitzelmann, R.: A founder mutation in the
GK1 gene is responsible for galactokinase deficiency in Roma (Gypsies). Am.
J. Hum. Genet. 65: 1299-1307, 1999.
7. Kaloud, H.; Sitzmann, F. C.: The galactokinase deficiency in two
human populations: Styria (Austria) and Franconia (Bavaria): a comparative
investigation on gene frequency. Z. Kinderheilk. 116: 185-192, 1974.
8. Kerr, M. M.; Logan, R. W.; Cant, J. S.; Hutchison, J. H.: Galactokinase
deficiency in a newborn infant. Arch. Dis. Child. 46: 864-866, 1971.
9. Levy, N. S.; Krill, A. E.; Beutler, E.: Galactokinase deficiency
and cataracts. Am. J. Ophthal. 74: 41-48, 1972.
10. Litman, N.; Kanter, A. I.; Finberg, L.: Galactokinase deficiency
presenting as pseudotumor cerebri. J. Pediat. 86: 410-411, 1975.
11. Magnani, M.; Cucchiarini, L.; Stocchi, V.; Stocchi, O.; Carnevali,
G.; Dacha, M.; Fornaini, G.: Human erythrocyte galactokinase: a population
survey. Hum. Hered. 32: 274-279, 1982.
12. Mayes, J. S.; Guthrie, R.: Detection of heterozygotes for galactokinase
deficiency in a human population. Biochem. Genet. 2: 219-230, 1968.
13. Oberman, A. E.; Wilson, W. A.; Fraiser, S. D.; Donnell, G. N.;
Bergren, W. R.: Galactokinase-deficiency cataracts in identical twins. Am.
J. Ophthal. 74: 887-892, 1972.
14. Pickering, W. R.; Howell, R. R.: Galactokinase deficiency: clinical
and biochemical findings in a new kindred. J. Pediat. 81: 50-55,
1972.
15. Prachal, J. T.; Conrad, M. E.; Skalka, H. W.: Association of
presenile cataracts with heterozygosity for galactosaemic states and
with riboflavin deficiency. Lancet 311: 12-13, 1978. Note: Originally
Volume I.
16. Segal, S.; Rutman, J. Y.; Frimpter, G. W.: Galactokinase deficiency
and mental retardation. J. Pediat. 95: 750-752, 1979.
17. Stambolian, D.; Ai, Y.; Sidjanin, D.; Nesburn, K.; Sathe, G.;
Rosenberg, M.; Bergsma, D. J.: Cloning of the galactokinase cDNA
and identification of mutations in two families with cataracts. Nature
Genet. 10: 307-312, 1995.
18. Thalhammer, O.; Gitzelmann, R.; Pantlitschko, M.: Hypergalactosemia
and galactosuria due to galactokinase deficiency in a newborn. Pediatrics 42:
441-445, 1968.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Cataracts, formation may be reversible with early dietary management
NEUROLOGIC:
[Central nervous system];
Pseudotumor cerebri
LABORATORY ABNORMALITIES:
Galactosuria;
Galactosemia;
Decreased galactokinase activity
MISCELLANEOUS:
Distinct disorder from galactosemia (230400)
MOLECULAR BASIS:
Caused by mutation in the galactokinase 1 gene (GALK1, 604313.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 9/6/2006
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 12/01/2008
ckniffin: 9/6/2006
*FIELD* CN
Cassandra L. Kniffin - reorganized: 9/7/2006
Cassandra L. Kniffin - updated: 9/6/2006
Victor A. McKusick - updated: 9/14/2004
Ada Hamosh - updated: 10/2/2003
Victor A. McKusick - updated: 11/15/1999
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
terry: 02/27/2009
carol: 9/7/2006
ckniffin: 9/6/2006
tkritzer: 9/16/2004
terry: 9/14/2004
cwells: 10/2/2003
mgross: 11/24/1999
terry: 11/15/1999
dkim: 7/21/1998
terry: 12/3/1996
terry: 11/12/1996
mark: 10/23/1995
terry: 6/30/1995
davew: 6/2/1994
carol: 4/11/1994
warfield: 3/30/1994
mimadm: 2/19/1994
*RECORD*
*FIELD* NO
230200
*FIELD* TI
#230200 GALACTOKINASE DEFICIENCY
;;GALK DEFICIENCY;;
GALACTOSEMIA II
*FIELD* TX
A number sign (#) is used with this entry because galactokinase
read moredeficiency is caused by mutation in the GALK1 gene (604313) on
chromosome 17q24.
Classic galactosemia (230400) is a distinct disorder caused by mutation
in the gene encoding galactose-1-phosphate uridyltransferase (GALT;
606999) on chromosome 9p13.
DESCRIPTION
Galactokinase deficiency is an autosomal recessive disorder which causes
cataract formation in children not maintained on a lactose-free diet.
Cataract formation is the result of osmotic phenomena caused by the
accumulation of galactitol in the lens (Asada et al., 1999).
CLINICAL FEATURES
Gitzelmann (1967) reported juvenile cataracts related to galactokinase
deficiency in 2 sibs of a consanguineous Gypsy family, Fanconi had
previously reported the cases as instances of 'galactose diabetes;'
however, GALT activity in red cells was normal. There was no mental
retardation. Several close relatives had reduced red cell galactokinase
activity, suggesting that they were heterozygotes.
Cook et al. (1971) described an affected newborn, ascertained because of
hyperbilirubinemia, who had resolution of the cataracts with dietary
management. Segal et al. (1979), who studied affected brothers,
suggested that mental retardation may occur with galactokinase
deficiency.
Prachal et al. (1978) associated presenile cataracts with heterozygosity
for galactokinase deficiency and galactose-uridyl transferase
deficiency.
Bosch et al. (2002) reviewed the clinical features of galactokinase
deficiency in describing 55 patients in 25 publications. Cataract was
reported in most patients. Clinical abnormalities other than cataract
were reported in 15 (35%) of 43 cases for which information was
available. However, all symptoms were reported infrequently and a causal
relationship with the galactokinase deficiency could not be determined.
Pseudotumor cerebri is a rare but consistently reported abnormality in
this disorder.
MOLECULAR GENETICS
In 2 patients with galactokinase deficiency and cataracts, Stambolian et
al. (1995) identified 2 different homozygous mutations in the GALK1 gene
(604313.0001; 604313.0002). One of the patients had been reported by
Pickering and Howell (1972).
In affected members of 6 Romani (Gypsy) families from Bulgaria with
galactokinase deficiency, Kalaydjieva et al. (1999) identified a
homozygous mutation in the GALK1 gene (P28T; 604313.0003). The authors
concluded that this mutation was most likely responsible for the
galactokinase deficiency in the cases originally described by Gitzelmann
(1967).
Asada et al. (1999) identified 5 mutations in the GALK1 gene in 7
unrelated Japanese patients with galactokinase deficiency.
POPULATION GENETICS
Mayes and Guthrie (1968) found 6 heterozygotes for galactokinase
deficiency among 642 persons in Buffalo, N.Y.
In Italy, Magnani et al. (1982) estimated the heterozygote frequency to
be 1 in 310; 2 persons presumably heterozygous by biochemical criteria
were detected among 620 persons studied.
*FIELD* SA
Beutler et al. (1973); Kaloud and Sitzmann (1974); Kerr et al. (1971);
Levy et al. (1972); Litman et al. (1975); Oberman et al. (1972); Thalhammer
et al. (1968)
*FIELD* RF
1. Asada, M.; Okano, Y.; Imamura, T.; Suyama, I.; Hase, Y.; Isshiki,
G.: Molecular characterization of galactokinase deficiency in Japanese
patients. J. Hum. Genet. 44: 377-382, 1999.
2. Beutler, E.; Matsumoto, F.; Kuhl, W.; Krill, A. E.; Levy, N.; Sparkes,
R.; Degnan, M.: Galactokinase deficiency as a cause of cataracts. New
Eng. J. Med. 288: 1203-1206, 1973.
3. Bosch, A. M.; Bakker, H. D.; van Gennip, A. H.; van Kempen, J.
V.; Wanders, R. J. A.; Wijburg, F. A.: Clinical features of galactokinase
deficiency: a review of the literature. J. Inherit. Metab. Dis. 25:
629-634, 2002.
4. Cook, J. G. H.; Don, N. A.; Mann, T. P.: Hereditary galactokinase
deficiency. Arch. Dis. Child. 46: 465-469, 1971.
5. Gitzelmann, R.: Hereditary galactokinase deficiency, a newly recognized
cause of juvenile cataracts. Pediat. Res. 1: 14-23, 1967.
6. Kalaydjieva, L.; Perez-Lezaun, A.; Angelicheva, D.; Onengut, S.;
Dye, D.; Bosshard, N. U.; Jordanova, A.; Savov, A.; Yanakiev, P.;
Kremensky, I.; Radeva, B.; Hallmayer, J.; Markov, A.; Nedkova, V.;
Tournev, I.; Aneva, L.; Gitzelmann, R.: A founder mutation in the
GK1 gene is responsible for galactokinase deficiency in Roma (Gypsies). Am.
J. Hum. Genet. 65: 1299-1307, 1999.
7. Kaloud, H.; Sitzmann, F. C.: The galactokinase deficiency in two
human populations: Styria (Austria) and Franconia (Bavaria): a comparative
investigation on gene frequency. Z. Kinderheilk. 116: 185-192, 1974.
8. Kerr, M. M.; Logan, R. W.; Cant, J. S.; Hutchison, J. H.: Galactokinase
deficiency in a newborn infant. Arch. Dis. Child. 46: 864-866, 1971.
9. Levy, N. S.; Krill, A. E.; Beutler, E.: Galactokinase deficiency
and cataracts. Am. J. Ophthal. 74: 41-48, 1972.
10. Litman, N.; Kanter, A. I.; Finberg, L.: Galactokinase deficiency
presenting as pseudotumor cerebri. J. Pediat. 86: 410-411, 1975.
11. Magnani, M.; Cucchiarini, L.; Stocchi, V.; Stocchi, O.; Carnevali,
G.; Dacha, M.; Fornaini, G.: Human erythrocyte galactokinase: a population
survey. Hum. Hered. 32: 274-279, 1982.
12. Mayes, J. S.; Guthrie, R.: Detection of heterozygotes for galactokinase
deficiency in a human population. Biochem. Genet. 2: 219-230, 1968.
13. Oberman, A. E.; Wilson, W. A.; Fraiser, S. D.; Donnell, G. N.;
Bergren, W. R.: Galactokinase-deficiency cataracts in identical twins. Am.
J. Ophthal. 74: 887-892, 1972.
14. Pickering, W. R.; Howell, R. R.: Galactokinase deficiency: clinical
and biochemical findings in a new kindred. J. Pediat. 81: 50-55,
1972.
15. Prachal, J. T.; Conrad, M. E.; Skalka, H. W.: Association of
presenile cataracts with heterozygosity for galactosaemic states and
with riboflavin deficiency. Lancet 311: 12-13, 1978. Note: Originally
Volume I.
16. Segal, S.; Rutman, J. Y.; Frimpter, G. W.: Galactokinase deficiency
and mental retardation. J. Pediat. 95: 750-752, 1979.
17. Stambolian, D.; Ai, Y.; Sidjanin, D.; Nesburn, K.; Sathe, G.;
Rosenberg, M.; Bergsma, D. J.: Cloning of the galactokinase cDNA
and identification of mutations in two families with cataracts. Nature
Genet. 10: 307-312, 1995.
18. Thalhammer, O.; Gitzelmann, R.; Pantlitschko, M.: Hypergalactosemia
and galactosuria due to galactokinase deficiency in a newborn. Pediatrics 42:
441-445, 1968.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Cataracts, formation may be reversible with early dietary management
NEUROLOGIC:
[Central nervous system];
Pseudotumor cerebri
LABORATORY ABNORMALITIES:
Galactosuria;
Galactosemia;
Decreased galactokinase activity
MISCELLANEOUS:
Distinct disorder from galactosemia (230400)
MOLECULAR BASIS:
Caused by mutation in the galactokinase 1 gene (GALK1, 604313.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 9/6/2006
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 12/01/2008
ckniffin: 9/6/2006
*FIELD* CN
Cassandra L. Kniffin - reorganized: 9/7/2006
Cassandra L. Kniffin - updated: 9/6/2006
Victor A. McKusick - updated: 9/14/2004
Ada Hamosh - updated: 10/2/2003
Victor A. McKusick - updated: 11/15/1999
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
terry: 02/27/2009
carol: 9/7/2006
ckniffin: 9/6/2006
tkritzer: 9/16/2004
terry: 9/14/2004
cwells: 10/2/2003
mgross: 11/24/1999
terry: 11/15/1999
dkim: 7/21/1998
terry: 12/3/1996
terry: 11/12/1996
mark: 10/23/1995
terry: 6/30/1995
davew: 6/2/1994
carol: 4/11/1994
warfield: 3/30/1994
mimadm: 2/19/1994
MIM
604313
*RECORD*
*FIELD* NO
604313
*FIELD* TI
*604313 GALACTOKINASE 1; GALK1
;;GALK;;
GK1
*FIELD* TX
DESCRIPTION
Galactokinase (EC 2.7.1.6) catalyzes the phosphorylation of galactose to
read moregalactose-1-phosphate, the first step in galactose metabolism
(Stambolian et al., 1995).
CLONING
Stambolian et al. (1995) isolated cDNAs encoding human galactokinase.
The 392-residue protein has a calculated molecular mass of 42.3 kD and
shows 34.6% amino acid identity with the product of the human GALK2 gene
(137028). Northern blot analysis detected a 1.35-kb mRNA transcript.
Ai et al. (1995) isolated the mouse cDNA for galactokinase, which shares
88% amino acid sequence % identity with human galactokinase. Mouse Galk1
was expressed in all tissues examined.
GENE STRUCTURE
Bergsma et al. (1996) found that the human GALK1 gene contains 8 exons
and spans approximately 7.3 kb of genomic DNA. The GALK1 promoter was
found to have many features in common with other housekeeping genes,
including high GC content, several copies of the binding site for the
Sp1 transcription factor (189906), and the absence of TATA-box and
CCAAT-box motifs typically present in eukaryotic polymerase II
promoters. Analysis by 5-prime-RACE PCR indicated that the GALK1 mRNA is
heterogeneous at the 5-prime end, with transcription sites occurring at
many locations between 21 and 61 bp upstream of the ATG start site of
the coding region. In vitro translation experiments of the GALK1 cDNA
indicated that the protein is cytosolic and not associated with
endoplasmic reticulum membrane.
MAPPING
In the African green monkey, the structural genes for galactokinase and
thymidine kinase (TK1; 188300) are on a chromosome similar to human
chromosome 17 in size, shape, and Giemsa banding pattern (Croce et al.,
1974). Elsevier et al. (1975) assigned the human GALK locus to
chromosome 17q21-q22.
By chromosome-mediated gene transfer (CMGT), Klobutcher and Ruddle
(1979) found the following gene order on 17q: cen--GALK--(TK1--COL1A1;
120150). Later studies (Ruddle, 1982) put the growth hormone gene
cluster between GALK and (TK1--COL1A1). From the pattern of cotransfer
by CMGT into mouse cells, de Jonge et al. (1985) concluded that the
sequence is cen--GALK--TK1--GAA (606800). Xu et al. (1988) concluded
that GALK lies on the telomeric side of TK1.
By fluorescence in situ hybridization, Stambolian et al. (1995)
demonstrated that the GALK gene lies in 17q24, not in the 17q21-q22
region as previously concluded.
By interspecific backcross analysis, Ai et al. (1995) mapped the mouse
Galk1 gene to a distal region of chromosome 11 that shows syntenic
homology with human 17q22-q25.
GENE FUNCTION
Schoen et al. (1984) found that cultured fibroblasts from GALK
homozygotes and heterozygotes were also deficient in TK activity. A
qualitative change in the TK molecule was suggested by apparent
alteration in the sensitivity of the enzyme to trifluorothymidine.
Interdependence of the 2 enzymes had been demonstrated in the Chinese
hamster. Evolutionary conservation of the close linkage may be based on
this interdependence. The level of TK was about the same in homozygotes
and heterozygotes, suggesting a dominant effect on the GALK mutation on
the TK1 locus. Okajima et al. (1987) reported the same finding in
cultured lymphoblasts.
MOLECULAR GENETICS
Vigneron (1971) reported electrophoretic studies of erythrocyte
galactokinase. Tedesco et al. (1972, 1977) presented evidence that red
blood cell galactokinase activity is significantly lower in American
black populations compared to comparable groups of white individuals,
and concluded that the difference is due to a polymorphism, referred to
as the 'Philadelphia' variant, symbolized GALK(P). Soni et al. (1988)
reported that the GALK(P) variant is present in racially unmixed black
Americans.
In 2 unrelated patients with galactokinase deficiency (230200),
Stambolian et al. (1995) identified 2 different homozygous mutations in
the GALK1 gene (604313.0001; 604313.0002). One of the patients had been
reported previously by Pickering and Howell (1972).
Asada et al. (1999) identified 5 mutations in the GALK1 gene in 7
unrelated Japanese patients with galactokinase deficiency.
Kolosha et al. (2000) identified 12 different mutations in the GALK1
gene in 13 patients with galactokinase deficiency. One of the mutations
(Q382X; 604313.0004) occurred in 6 of the 13 probands examined, and the
remaining 11 were unique mutations. Expression of each of the mutant
genes in Xenopus oocytes resulted in very low galactokinase activity
levels.
Through mass screening of newborn infants, Okano et al. (2001)
identified a novel and prevalent GALK variant, designated the Osaka
variant, associated with an A198V mutation (604313.0006) in 3 infants
with mild GALK deficiency. A population study revealed that the
prevalence of A198V is 4.1% in Japanese and 2.8% in Koreans, with a
lower incidence in Taiwanese and Chinese, no incidence in blacks or
whites from the United States, and a significantly higher frequency
(7.8%; P less than 0.023) in Japanese with bilateral cataract. They
suggested that the variant originated in Japanese and Korean ancestors
and is a factor in cataract in elderly individuals.
ANIMAL MODEL
Ai et al. (2000) cloned the mouse Galk1 gene and disrupted it by gene
targeting. As expected, galactose was very poorly metabolized in
Galk1-deficient mice. In addition, both galactose and galactitol
accumulated in several tissues of Galk1-deficient mice. Surprisingly,
the Galk1-deficient animals did not form cataracts even when fed a
high-galactose diet for 6 months. Since aldose reductase (ALDR1; 103880)
is present in very small amounts in the mouse lens, Galk1-deficient mice
were crossed with mice expressing human ALDR1. The introduction of this
transgene into the Galk1-deficient background resulted in cataract
formation within the first postnatal day.
*FIELD* AV
.0001
GALACTOKINASE DEFICIENCY
GALK1, VAL32MET
In a child with galactokinase deficiency and congenital cataracts
(230200), Stambolian et al. (1995) identified a homozygous 94G-A
transition in the GALK1 gene, resulting in a val32-to-met (V32M)
substitution. In vitro functional expression studies showed that the
V32M mutation resulted in significantly decreased enzyme activity.
.0002
GALACTOKINASE DEFICIENCY
GALK1, GLU80TER
In an infant with galactokinase deficiency and cataracts (230200) within
the first year of life, Stambolian et al. (1995) identified a homozygous
238G-T transversion in the GALK1 gene, resulting in a glu80-to-ter
(E80X) substitution. Galactokinase activity was close to zero,
consistent with homozygosity. The parents, who were first cousins, both
had galactokinase activity consistent with heterozygosity and did not
have cataracts.
.0003
GALACTOKINASE DEFICIENCY
GALK1, PRO28THR
In affected members from 6 Romani (Gypsy) families from Bulgaria with
galactokinase deficiency (230200), Kalaydjieva et al. (1999) identified
a homozygous 563C-A transversion in the GALK1 gene, resulting in a
pro28-to-thr (P28T) mutation. The P28T carrier rate in this endogamous
population is approximately 5%. The authors concluded that this mutation
was most likely responsible for the galactokinase deficiency in the
cases originally described by Gitzelmann (1967).
Kolosha et al. (2000) found the P28T mutation in homozygous form in an
affected 5-day-old male infant of Turkish extraction.
Morar et al. (2004) used the P28T mutation and 4 other private mutations
among the Roma (Gypsies) to infer some of the missing parameters
relevant to the comprehensive characterization of the population history
of the Gypsies. Sharing of mutations and high carrier rates supported a
strong founder effect.
.0004
GALACTOKINASE DEFICIENCY
GALK1, GLN382TER
In 5 Costa Rican infants of European extraction with galactokinase
deficiency and cataracts (230200), Kolosha et al. (2000) found
homozygosity for a 1144C-T transition in the GALK1 gene, resulting in a
gln382-to-ter (Q382X) substitution. In another Costa Rican child, the
same Q382X mutation was found in compound heterozygous state with
761delG (604313.0005), which produced a frameshift at codon 254.
.0005
GALACTOKINASE DEFICIENCY
GALK1, 1-BP DEL, 761G
See 604313.0004 and Kolosha et al. (2000).
.0006
GALACTOKINASE DEFICIENCY
GALK1, ALA198VAL
In 3 infants with mild GALK deficiency (230200), Okano et al. (2001)
identified a 593C-T transition in exon 4 of the GALK1 gene, resulting in
an ala198-to-val (A198V) substitution. This variant, designated Osaka,
was found to have an appreciable frequency in Japanese and Koreans, with
a lower incidence in Taiwanese and Chinese and no incidence in blacks or
whites from the United States. It appeared to be related to cataract in
elderly individuals.
*FIELD* SA
Orkwiszewski et al. (1976); Spielman et al. (1978)
*FIELD* RF
1. Ai, Y.; Jenkins, N. A.; Copeland, N. G.; Gilbert, D. J.; Bergsma,
D. J.; Stambolian, D.: Mouse galactokinase: isolation, characterization,
and location on chromosome 11. Genome Res. 5: 53-59, 1995.
2. Ai, Y.; Zheng, Z.; O'Brien-Jenkins, A.; Bernard, D. J.; Wynshaw-Boris,
T.; Ning, C.; Reynolds, R.; Segal, S.; Huang, K.; Stambolian, D.:
A mouse model of galactose-induced cataracts. Hum. Molec. Genet. 9:
1821-1827, 2000.
3. Asada, M.; Okano, Y.; Imamura, T.; Suyama, I.; Hase, Y.; Isshiki,
G.: Molecular characterization of galactokinase deficiency in Japanese
patients. J. Hum. Genet. 44: 377-382, 1999.
4. Bergsma, D. J.; Ai, Y.; Skach, W. R.; Nesburn, K.; Anoia, E.; Van
Horn, S.; Stambolian, D.: Fine structure of the human galactokinase
GALK1 gene. Genome Res. 6: 980-985, 1996.
5. Croce, C. M.; Huebner, K.; Koprowski, H.: Chromosome assignment
of the T-antigen gene of simian virus 40 in African green monkey cells
transformed by adeno 7-SV 40 hybrid. Proc. Nat. Acad. Sci. 71: 4116-4119,
1974.
6. de Jonge, A. J. R.; de Smit, S.; Kroos, M. A.; Reuser, A. J. J.
: Cotransfer of syntenic human genes into mouse cells using isolated
metaphase chromosomes or cellular DNA. Hum. Genet. 69: 32-38, 1985.
7. Elsevier, S. M.; Kucherlapati, R. S.; Nichols, E. A.; Willecke,
K.; Creagan, R. P.; Giles, R. E.; McDougall, J. K.; Ruddle, F. H.
: Assignment and regional localization of a gene coding for galactokinase
to human chromosome 17q21-22. Birth Defects Orig. Art. Ser. 11(3):
117-119, 1975. Note: Alternate: Cytogenet. Cell Genet. 14: 287-289,
1975.
8. Gitzelmann, R.: Hereditary galactokinase deficiency, a newly recognized
cause of juvenile cataracts. Pediat. Res. 1: 14-23, 1967.
9. Kalaydjieva, L.; Perez-Lezaun, A.; Angelicheva, D.; Onengut, S.;
Dye, D.; Bosshard, N. U.; Jordanova, A.; Savov, A.; Yanakiev, P.;
Kremensky, I.; Radeva, B.; Hallmayer, J.; Markov, A.; Nedkova, V.;
Tournev, I.; Aneva, L.; Gitzelmann, R.: A founder mutation in the
GK1 gene is responsible for galactokinase deficiency in Roma (Gypsies). Am.
J. Hum. Genet. 65: 1299-1307, 1999.
10. Klobutcher, L. A.; Ruddle, F. H.: Phenotype stabilisation and
integration of transferred material in chromosome-mediated gene transfer. Nature 280:
657-660, 1979.
11. Kolosha, V.; Anoia, E.; de Cespedes, C.; Gitzelmann, R.; Shih,
L.; Casco, T.; Saborio, M.; Trejos, R.; Buist, N.; Tedesco, T.; Skach,
W.; Mitelmann, O.; Ledee, D.; Huang, K.; Stambolian, D.: Novel mutations
in 13 probands with galactokinase deficiency. Hum. Mutat. 15: 447-453,
2000.
12. Morar, B.; Gresham, D.; Angelicheva, D.; Tournev, I.; Gooding,
R.; Guergueltcheva, V.; Schmidt, C.; Abicht, A.; Lochmuller, H.; Tordai,
A.; Kalmar, L.; Nagy, M.; and 10 others: Mutation history of the
Roma/Gypsies. Am. J. Hum. Genet. 75: 596-609, 2004.
13. Okajima, K.; Yazaki, M.; Wada, Y.: Thymidine kinase activity
in individuals with galactokinase deficiency. (Letter) Am. J. Hum.
Genet. 41: 503-504, 1987.
14. Okano, Y.; Asada, M.; Fujimoto, A.; Ohtake, A.; Murayama, K.;
Hsiao, K.-J.; Choeh, K.; Yang, Y.; Cao, Q.; Reichardt, J. K. V.; Niihira,
S.; Imamura, T.; Yamano, T.: A genetic factor for age-related cataract:
identification and characterization of a novel galactokinase variant,
'Osaka,' in Asians. Am. J. Hum. Genet. 68: 1036-1042, 2001.
15. Orkwiszewski, K. G.; Tedesco, T. A.; Mellman, W. J.; Croce, C.
M.: Linkage relationship between the genes for thymidine kinase and
galactokinase in different primates. Somat. Cell Genet. 2: 21-26,
1976.
16. Pickering, W. R.; Howell, R. R.: Galactokinase deficiency: clinical
and biochemical findings in a new kindred. J. Pediat. 81: 50-55,
1972.
17. Ruddle, F. H.: Personal Communication. New Haven, Conn. 5/4/1982.
18. Schoen, R. C.; Cox, S. H.; Wagner, R. P.: Thymidine-kinase activity
of cultured cells from individuals with inherited galactokinase deficiency. Am.
J. Hum. Genet. 36: 815-822, 1984.
19. Soni, T.; Brivet, M.; Blanc, M.; Jaeger, G.; Lemonnier, A.: Screening
of the Philadelphia variant of galactokinase in racially unmixed black
Africans: first results. Am. J. Hum. Genet. 42: 96-103, 1988.
20. Spielman, R. S.; Harris, H.; Mellman, W. J.; Gershowitz, H.:
Dissection of a continuous distribution: red cell galactokinase activity
in blacks. Am. J. Hum. Genet. 30: 237-248, 1978.
21. Stambolian, D.; Ai, Y.; Sidjanin, D.; Nesburn, K.; Sathe, G.;
Rosenberg, M.; Bergsma, D. J.: Cloning of the galactokinase cDNA
and identification of mutations in two families with cataracts. Nature
Genet. 10: 307-312, 1995.
22. Tedesco, T. A.; Bonow, R.; Miller, K.; Mellman, W. J.: Galactokinase:
evidence for a new racial polymorphism. Science 178: 176-178, 1972.
23. Tedesco, T. A.; Miller, K. L.; Rawnsley, B. E.; Adams, M. C.;
Markus, H. B.; Orkwiszewski, K. G.; Mellman, W. J.: The Philadelphia
variant of galactokinase. Am. J. Hum. Genet. 29: 240-247, 1977.
24. Vigneron, C.: Electrophoresis of erythrocyte galactokinase. Enzyme 12:
426-432, 1971.
25. Xu, W.; Gorman, P. A.; Rider, S. H.; Hedge, P. J.; Moore, G.;
Prichard, C.; Sheer, D.; Solomon, E.: Construction of a genetic map
of human chromosome 17 by use of chromosome-mediated gene transfer. Proc.
Nat. Acad. Sci. 85: 8563-8567, 1988.
*FIELD* CN
Cassandra L. Kniffin - reorganized: 9/7/2006
Cassandra L. Kniffin - updated: 9/6/2006
Victor A. McKusick - updated: 9/14/2004
Victor A. McKusick - updated: 5/4/2001
George E. Tiller - updated: 9/21/2000
Victor A. McKusick - updated: 5/19/2000
*FIELD* CD
Victor A. McKusick: 11/24/1999
*FIELD* ED
carol: 08/05/2013
carol: 9/7/2006
ckniffin: 9/6/2006
tkritzer: 9/16/2004
terry: 9/14/2004
joanna: 9/28/2001
mcapotos: 5/17/2001
mcapotos: 5/10/2001
terry: 5/4/2001
alopez: 9/21/2000
mcapotos: 6/6/2000
mcapotos: 6/5/2000
mcapotos: 5/26/2000
terry: 5/19/2000
mgross: 11/29/1999
mgross: 11/24/1999
*RECORD*
*FIELD* NO
604313
*FIELD* TI
*604313 GALACTOKINASE 1; GALK1
;;GALK;;
GK1
*FIELD* TX
DESCRIPTION
Galactokinase (EC 2.7.1.6) catalyzes the phosphorylation of galactose to
read moregalactose-1-phosphate, the first step in galactose metabolism
(Stambolian et al., 1995).
CLONING
Stambolian et al. (1995) isolated cDNAs encoding human galactokinase.
The 392-residue protein has a calculated molecular mass of 42.3 kD and
shows 34.6% amino acid identity with the product of the human GALK2 gene
(137028). Northern blot analysis detected a 1.35-kb mRNA transcript.
Ai et al. (1995) isolated the mouse cDNA for galactokinase, which shares
88% amino acid sequence % identity with human galactokinase. Mouse Galk1
was expressed in all tissues examined.
GENE STRUCTURE
Bergsma et al. (1996) found that the human GALK1 gene contains 8 exons
and spans approximately 7.3 kb of genomic DNA. The GALK1 promoter was
found to have many features in common with other housekeeping genes,
including high GC content, several copies of the binding site for the
Sp1 transcription factor (189906), and the absence of TATA-box and
CCAAT-box motifs typically present in eukaryotic polymerase II
promoters. Analysis by 5-prime-RACE PCR indicated that the GALK1 mRNA is
heterogeneous at the 5-prime end, with transcription sites occurring at
many locations between 21 and 61 bp upstream of the ATG start site of
the coding region. In vitro translation experiments of the GALK1 cDNA
indicated that the protein is cytosolic and not associated with
endoplasmic reticulum membrane.
MAPPING
In the African green monkey, the structural genes for galactokinase and
thymidine kinase (TK1; 188300) are on a chromosome similar to human
chromosome 17 in size, shape, and Giemsa banding pattern (Croce et al.,
1974). Elsevier et al. (1975) assigned the human GALK locus to
chromosome 17q21-q22.
By chromosome-mediated gene transfer (CMGT), Klobutcher and Ruddle
(1979) found the following gene order on 17q: cen--GALK--(TK1--COL1A1;
120150). Later studies (Ruddle, 1982) put the growth hormone gene
cluster between GALK and (TK1--COL1A1). From the pattern of cotransfer
by CMGT into mouse cells, de Jonge et al. (1985) concluded that the
sequence is cen--GALK--TK1--GAA (606800). Xu et al. (1988) concluded
that GALK lies on the telomeric side of TK1.
By fluorescence in situ hybridization, Stambolian et al. (1995)
demonstrated that the GALK gene lies in 17q24, not in the 17q21-q22
region as previously concluded.
By interspecific backcross analysis, Ai et al. (1995) mapped the mouse
Galk1 gene to a distal region of chromosome 11 that shows syntenic
homology with human 17q22-q25.
GENE FUNCTION
Schoen et al. (1984) found that cultured fibroblasts from GALK
homozygotes and heterozygotes were also deficient in TK activity. A
qualitative change in the TK molecule was suggested by apparent
alteration in the sensitivity of the enzyme to trifluorothymidine.
Interdependence of the 2 enzymes had been demonstrated in the Chinese
hamster. Evolutionary conservation of the close linkage may be based on
this interdependence. The level of TK was about the same in homozygotes
and heterozygotes, suggesting a dominant effect on the GALK mutation on
the TK1 locus. Okajima et al. (1987) reported the same finding in
cultured lymphoblasts.
MOLECULAR GENETICS
Vigneron (1971) reported electrophoretic studies of erythrocyte
galactokinase. Tedesco et al. (1972, 1977) presented evidence that red
blood cell galactokinase activity is significantly lower in American
black populations compared to comparable groups of white individuals,
and concluded that the difference is due to a polymorphism, referred to
as the 'Philadelphia' variant, symbolized GALK(P). Soni et al. (1988)
reported that the GALK(P) variant is present in racially unmixed black
Americans.
In 2 unrelated patients with galactokinase deficiency (230200),
Stambolian et al. (1995) identified 2 different homozygous mutations in
the GALK1 gene (604313.0001; 604313.0002). One of the patients had been
reported previously by Pickering and Howell (1972).
Asada et al. (1999) identified 5 mutations in the GALK1 gene in 7
unrelated Japanese patients with galactokinase deficiency.
Kolosha et al. (2000) identified 12 different mutations in the GALK1
gene in 13 patients with galactokinase deficiency. One of the mutations
(Q382X; 604313.0004) occurred in 6 of the 13 probands examined, and the
remaining 11 were unique mutations. Expression of each of the mutant
genes in Xenopus oocytes resulted in very low galactokinase activity
levels.
Through mass screening of newborn infants, Okano et al. (2001)
identified a novel and prevalent GALK variant, designated the Osaka
variant, associated with an A198V mutation (604313.0006) in 3 infants
with mild GALK deficiency. A population study revealed that the
prevalence of A198V is 4.1% in Japanese and 2.8% in Koreans, with a
lower incidence in Taiwanese and Chinese, no incidence in blacks or
whites from the United States, and a significantly higher frequency
(7.8%; P less than 0.023) in Japanese with bilateral cataract. They
suggested that the variant originated in Japanese and Korean ancestors
and is a factor in cataract in elderly individuals.
ANIMAL MODEL
Ai et al. (2000) cloned the mouse Galk1 gene and disrupted it by gene
targeting. As expected, galactose was very poorly metabolized in
Galk1-deficient mice. In addition, both galactose and galactitol
accumulated in several tissues of Galk1-deficient mice. Surprisingly,
the Galk1-deficient animals did not form cataracts even when fed a
high-galactose diet for 6 months. Since aldose reductase (ALDR1; 103880)
is present in very small amounts in the mouse lens, Galk1-deficient mice
were crossed with mice expressing human ALDR1. The introduction of this
transgene into the Galk1-deficient background resulted in cataract
formation within the first postnatal day.
*FIELD* AV
.0001
GALACTOKINASE DEFICIENCY
GALK1, VAL32MET
In a child with galactokinase deficiency and congenital cataracts
(230200), Stambolian et al. (1995) identified a homozygous 94G-A
transition in the GALK1 gene, resulting in a val32-to-met (V32M)
substitution. In vitro functional expression studies showed that the
V32M mutation resulted in significantly decreased enzyme activity.
.0002
GALACTOKINASE DEFICIENCY
GALK1, GLU80TER
In an infant with galactokinase deficiency and cataracts (230200) within
the first year of life, Stambolian et al. (1995) identified a homozygous
238G-T transversion in the GALK1 gene, resulting in a glu80-to-ter
(E80X) substitution. Galactokinase activity was close to zero,
consistent with homozygosity. The parents, who were first cousins, both
had galactokinase activity consistent with heterozygosity and did not
have cataracts.
.0003
GALACTOKINASE DEFICIENCY
GALK1, PRO28THR
In affected members from 6 Romani (Gypsy) families from Bulgaria with
galactokinase deficiency (230200), Kalaydjieva et al. (1999) identified
a homozygous 563C-A transversion in the GALK1 gene, resulting in a
pro28-to-thr (P28T) mutation. The P28T carrier rate in this endogamous
population is approximately 5%. The authors concluded that this mutation
was most likely responsible for the galactokinase deficiency in the
cases originally described by Gitzelmann (1967).
Kolosha et al. (2000) found the P28T mutation in homozygous form in an
affected 5-day-old male infant of Turkish extraction.
Morar et al. (2004) used the P28T mutation and 4 other private mutations
among the Roma (Gypsies) to infer some of the missing parameters
relevant to the comprehensive characterization of the population history
of the Gypsies. Sharing of mutations and high carrier rates supported a
strong founder effect.
.0004
GALACTOKINASE DEFICIENCY
GALK1, GLN382TER
In 5 Costa Rican infants of European extraction with galactokinase
deficiency and cataracts (230200), Kolosha et al. (2000) found
homozygosity for a 1144C-T transition in the GALK1 gene, resulting in a
gln382-to-ter (Q382X) substitution. In another Costa Rican child, the
same Q382X mutation was found in compound heterozygous state with
761delG (604313.0005), which produced a frameshift at codon 254.
.0005
GALACTOKINASE DEFICIENCY
GALK1, 1-BP DEL, 761G
See 604313.0004 and Kolosha et al. (2000).
.0006
GALACTOKINASE DEFICIENCY
GALK1, ALA198VAL
In 3 infants with mild GALK deficiency (230200), Okano et al. (2001)
identified a 593C-T transition in exon 4 of the GALK1 gene, resulting in
an ala198-to-val (A198V) substitution. This variant, designated Osaka,
was found to have an appreciable frequency in Japanese and Koreans, with
a lower incidence in Taiwanese and Chinese and no incidence in blacks or
whites from the United States. It appeared to be related to cataract in
elderly individuals.
*FIELD* SA
Orkwiszewski et al. (1976); Spielman et al. (1978)
*FIELD* RF
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1975.
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*FIELD* CN
Cassandra L. Kniffin - reorganized: 9/7/2006
Cassandra L. Kniffin - updated: 9/6/2006
Victor A. McKusick - updated: 9/14/2004
Victor A. McKusick - updated: 5/4/2001
George E. Tiller - updated: 9/21/2000
Victor A. McKusick - updated: 5/19/2000
*FIELD* CD
Victor A. McKusick: 11/24/1999
*FIELD* ED
carol: 08/05/2013
carol: 9/7/2006
ckniffin: 9/6/2006
tkritzer: 9/16/2004
terry: 9/14/2004
joanna: 9/28/2001
mcapotos: 5/17/2001
mcapotos: 5/10/2001
terry: 5/4/2001
alopez: 9/21/2000
mcapotos: 6/6/2000
mcapotos: 6/5/2000
mcapotos: 5/26/2000
terry: 5/19/2000
mgross: 11/29/1999
mgross: 11/24/1999