RBCC Red Blood Cell Collection

HK1 [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Hexokinase-1; 2.7.1.1 (Brain form hexokinase; Hexokinase type I; HK I)

Comments
Isoform P19367-2 was detected.

UniProt P19367
ID HXK1_HUMAN Reviewed; 917 AA.
AC P19367; E9PCK0; O43443; O43444; O75574; Q5VTC3; Q96HC8; Q9NNZ4;
read moreAC Q9NNZ5;
DT 01-NOV-1990, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 3.
DT 22-JAN-2014, entry version 172.
DE RecName: Full=Hexokinase-1;
DE EC=2.7.1.1;
DE AltName: Full=Brain form hexokinase;
DE AltName: Full=Hexokinase type I;
DE Short=HK I;
GN Name=HK1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT MET-776.
RX PubMed=3207429; DOI=10.1016/S0006-291X(88)80964-1;
RA Nishi S., Seino S., Bell G.I.;
RT "Human hexokinase: sequences of amino- and carboxyl-terminal halves
RT are homologous.";
RL Biochem. Biophys. Res. Commun. 157:937-943(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING.
RX PubMed=9531504;
RA Ruzzo A., Andreoni F., Magnani M.;
RT "Structure of the human hexokinase type I gene and nucleotide sequence
RT of the 5' flanking region.";
RL Biochem. J. 331:607-613(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-126 (ISOFORM 4), AND ALTERNATIVE
RP SPLICING.
RX PubMed=10978502; DOI=10.1016/S0167-4781(00)00147-0;
RA Andreoni F., Ruzzo A., Magnani M.;
RT "Structure of the 5' region of the human hexokinase type I (HKI) gene
RT and identification of an additional testis-specific HKI mRNA.";
RL Biochim. Biophys. Acta 1493:19-26(2000).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-20 (ISOFORM 2).
RA Murakami K., Piomelli S.;
RT "The erythrocyte-specific hexokinase isozyme (HKR) and the common
RT hexokinase isozyme (HKI) are produced from a single gene by alternate
RT promoters.";
RL Blood 90:272-272(1998).
RN [7]
RP PROTEIN SEQUENCE OF 1-20; 31-42; 382-396 AND 900-910, ACETYLATION AT
RP MET-1, AND MASS SPECTROMETRY.
RC TISSUE=Embryonic kidney;
RA Bienvenut W.V., Waridel P., Quadroni M.;
RL Submitted (MAR-2009) to UniProtKB.
RN [8]
RP PROTEIN SEQUENCE OF 11-31 AND 103-120.
RC TISSUE=Placenta;
RX PubMed=1985912;
RA Magnani M., Serafini G., Bianchi M., Casabianca A., Stocchi V.;
RT "Human hexokinase type I microheterogeneity is due to different amino-
RT terminal sequences.";
RL J. Biol. Chem. 266:502-505(1991).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 287-917, AND VARIANT MET-776.
RC TISSUE=Placenta;
RX PubMed=1637300;
RA Magnani M., Bianchi M., Casabianca A., Stocchi V., Daniele A.,
RA Altruda F., Ferrone M., Silengo L.;
RT "A recombinant human 'mini'-hexokinase is catalytically active and
RT regulated by hexose 6-phosphates.";
RL Biochem. J. 285:193-199(1992).
RN [10]
RP ALTERNATIVE SPLICING.
RX PubMed=9028305;
RA Murakami K., Piomelli S.;
RT "Identification of the cDNA for human red blood cell-specific
RT hexokinase isozyme.";
RL Blood 89:762-766(1997).
RN [11]
RP CRYSTALLIZATION.
RX PubMed=8706938; DOI=10.1016/0014-5793(96)00688-6;
RA Aleshin A.E., Zeng C., Fromm H.J., Honatko R.B.;
RT "Crystallization and preliminary X-ray analysis of human brain
RT hexokinase.";
RL FEBS Lett. 391:9-10(1996).
RN [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [13]
RP INVOLVEMENT IN HMSNR.
RX PubMed=19536174; DOI=10.1038/ejhg.2009.99;
RA Hantke J., Chandler D., King R., Wanders R.J., Angelicheva D.,
RA Tournev I., McNamara E., Kwa M., Guergueltcheva V., Kaneva R.,
RA Baas F., Kalaydjieva L.;
RT "A mutation in an alternative untranslated exon of hexokinase 1
RT associated with hereditary motor and sensory neuropathy -- Russe
RT (HMSNR).";
RL Eur. J. Hum. Genet. 17:1606-1614(2009).
RN [14]
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 [15]
RP INTERACTION WITH ATF2 AND VDAC1.
RX PubMed=22304920; DOI=10.1016/j.cell.2012.01.016;
RA Lau E., Kluger H., Varsano T., Lee K., Scheffler I., Rimm D.L.,
RA Ideker T., Ronai Z.A.;
RT "PKCepsilon promotes oncogenic functions of ATF2 in the nucleus while
RT blocking its apoptotic function at mitochondria.";
RL Cell 148:543-555(2012).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 16-914 IN COMPLEX WITH
RP GLUCOSE AND GLUCOSE-6-PHOSPHATE, AND SUBUNIT.
RX PubMed=9493266; DOI=10.1016/S0969-2126(98)00006-9;
RA Aleshin A.E., Zeng C., Bourenkov G.P., Bartunik H.D., Fromm H.J.,
RA Honzatko R.B.;
RT "The mechanism of regulation of hexokinase: new insights from the
RT crystal structure of recombinant human brain hexokinase complexed with
RT glucose and glucose-6-phosphate.";
RL Structure 6:39-50(1998).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 16-914.
RX PubMed=9735292; DOI=10.1006/jmbi.1998.2017;
RA Aleshin A.E., Zeng C., Bartunik H.D., Fromm H.J., Honzatko R.B.;
RT "Regulation of hexokinase I: crystal structure of recombinant human
RT brain hexokinase complexed with glucose and phosphate.";
RL J. Mol. Biol. 282:345-357(1998).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) IN COMPLEX WITH AMP-PNP AND
RP MAGNESIUM, AND SUBUNIT.
RX PubMed=10574795; DOI=10.1016/S0969-2126(00)80032-5;
RA Rosano C., Sabini E., Rizzi M., Deriu D., Murshudov G., Bianchi M.,
RA Serafini G., Magnani M., Bolognesi M.;
RT "Binding of non-catalytic ATP to human hexokinase I highlights the
RT structural components for enzyme-membrane association control.";
RL Structure 7:1427-1437(1999).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) IN COMPLEX WITH GLUCOSE;
RP GLUCOSE-6-PHOSPHATE AND ADP.
RX PubMed=10686099; DOI=10.1006/jmbi.1999.3494;
RA Aleshin A.E., Kirby C., Liu X., Bourenkov G.P., Bartunik H.D.,
RA Fromm H.J., Honzatko R.B.;
RT "Crystal structures of mutant monomeric hexokinase I reveal multiple
RT ADP binding sites and conformational changes relevant to allosteric
RT regulation.";
RL J. Mol. Biol. 296:1001-1015(2000).
RN [20]
RP VARIANT HK DEFICIENCY SER-529.
RX PubMed=7655856; DOI=10.1006/bcmd.1995.0002;
RA Bianchi M., Magnani M.;
RT "Hexokinase mutations that produce nonspherocytic hemolytic anemia.";
RL Blood Cells Mol. Dis. 21:2-8(1995).
RN [21]
RP VARIANT HK DEFICIENCY SER-680.
RX PubMed=12393545; DOI=10.1182/blood-2002-06-1851;
RA van Wijk R., Rijksen G., Huizinga E.G., Nieuwenhuis H.K.,
RA van Solinge W.W.;
RT "HK Utrecht: missense mutation in the active site of human hexokinase
RT associated with hexokinase deficiency and severe nonspherocytic
RT hemolytic anemia.";
RL Blood 101:345-347(2003).
CC -!- CATALYTIC ACTIVITY: ATP + D-hexose = ADP + D-hexose 6-phosphate.
CC -!- ENZYME REGULATION: Hexokinase is an allosteric enzyme inhibited by
CC its product Glc-6-P.
CC -!- PATHWAY: Carbohydrate metabolism; hexose metabolism.
CC -!- SUBUNIT: Monomer. Interacts with RABL2/RABL2A; binds
CC preferentially to GTP-bound RABL2 (By similarity). Interacts with
CC VDAC1. The HK1-VDAC1 complex interacts with ATF2.
CC -!- INTERACTION:
CC P21796:VDAC1; NbExp=2; IntAct=EBI-713162, EBI-354158;
CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane. Note=Its
CC hydrophobic N-terminal sequence may be involved in membrane
CC binding.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=Common;
CC IsoId=P19367-1; Sequence=Displayed;
CC Name=2; Synonyms=Erythrocyte, R;
CC IsoId=P19367-2; Sequence=VSP_002071;
CC Name=3; Synonyms=TA, TB;
CC IsoId=P19367-3; Sequence=VSP_002072;
CC Name=4; Synonyms=TD;
CC IsoId=P19367-4; Sequence=VSP_002073;
CC -!- TISSUE SPECIFICITY: Isoform 2 is erythrocyte specific. Isoform 3
CC and isoform 4 are testis-specific.
CC -!- DOMAIN: The N- and C-terminal halves of this hexokinase show
CC extensive sequence similarity to each other. The catalytic
CC activity is associated with the C-terminus while regulatory
CC function is associated with the N-terminus. Each domain can bind a
CC single glucose and Gluc-6-P molecule.
CC -!- DISEASE: Hexokinase deficiency (HK deficiency) [MIM:235700]: Rare
CC autosomal recessive disease with nonspherocytic hemolytic anemia
CC as the predominant clinical feature. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Hereditary motor and sensory neuropathy, Russe type
CC (HMSNR) [MIM:605285]: An autosomal recessive progressive complex
CC peripheral neuropathy characterized by onset in the first decade
CC of distal lower limb weakness and muscle atrophy resulting in
CC walking difficulties. Distal impairment of the upper limbs usually
CC occurs later, as does proximal lower limb weakness. There is
CC distal sensory impairment, with pes cavus and areflexia.
CC Laboratory studies suggest that it is a myelinopathy resulting in
CC reduced nerve conduction velocities in the demyelinating range as
CC well as a length-dependent axonopathy. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: In vertebrates there are four major glucose-
CC phosphorylating isoenzymes, designated hexokinase I, II, III and
CC IV (glucokinase).
CC -!- SIMILARITY: Belongs to the hexokinase family.
CC -!- SIMILARITY: Contains 2 hexokinase type-1 domains.
CC -!- SIMILARITY: Contains 2 hexokinase type-2 domains.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Hexokinase entry;
CC URL="http://en.wikipedia.org/wiki/Hexokinase";
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DR EMBL; M75126; AAA52646.1; -; mRNA.
DR EMBL; AF016365; AAC15862.1; -; Genomic_DNA.
DR EMBL; AF016349; AAC15862.1; JOINED; Genomic_DNA.
DR EMBL; AF016351; AAC15862.1; JOINED; Genomic_DNA.
DR EMBL; AF016352; AAC15862.1; JOINED; Genomic_DNA.
DR EMBL; AF016353; AAC15862.1; JOINED; Genomic_DNA.
DR EMBL; AF016354; AAC15862.1; JOINED; Genomic_DNA.
DR EMBL; AF016355; AAC15862.1; JOINED; Genomic_DNA.
DR EMBL; AF016356; AAC15862.1; JOINED; Genomic_DNA.
DR EMBL; AF016357; AAC15862.1; JOINED; Genomic_DNA.
DR EMBL; AF016358; AAC15862.1; JOINED; Genomic_DNA.
DR EMBL; AF016359; AAC15862.1; JOINED; Genomic_DNA.
DR EMBL; AF016360; AAC15862.1; JOINED; Genomic_DNA.
DR EMBL; AF016361; AAC15862.1; JOINED; Genomic_DNA.
DR EMBL; AF016362; AAC15862.1; JOINED; Genomic_DNA.
DR EMBL; AF016363; AAC15862.1; JOINED; Genomic_DNA.
DR EMBL; AF016364; AAC15862.1; JOINED; Genomic_DNA.
DR EMBL; AF016365; AAC15863.1; -; Genomic_DNA.
DR EMBL; AF016349; AAC15863.1; JOINED; Genomic_DNA.
DR EMBL; AF016351; AAC15863.1; JOINED; Genomic_DNA.
DR EMBL; AF016352; AAC15863.1; JOINED; Genomic_DNA.
DR EMBL; AF016353; AAC15863.1; JOINED; Genomic_DNA.
DR EMBL; AF016354; AAC15863.1; JOINED; Genomic_DNA.
DR EMBL; AF016355; AAC15863.1; JOINED; Genomic_DNA.
DR EMBL; AF016356; AAC15863.1; JOINED; Genomic_DNA.
DR EMBL; AF016357; AAC15863.1; JOINED; Genomic_DNA.
DR EMBL; AF016358; AAC15863.1; JOINED; Genomic_DNA.
DR EMBL; AF016359; AAC15863.1; JOINED; Genomic_DNA.
DR EMBL; AF016360; AAC15863.1; JOINED; Genomic_DNA.
DR EMBL; AF016361; AAC15863.1; JOINED; Genomic_DNA.
DR EMBL; AF016362; AAC15863.1; JOINED; Genomic_DNA.
DR EMBL; AF016363; AAC15863.1; JOINED; Genomic_DNA.
DR EMBL; AF016364; AAC15863.1; JOINED; Genomic_DNA.
DR EMBL; AF016365; AAF82319.1; -; Genomic_DNA.
DR EMBL; AF163910; AAF82319.1; JOINED; Genomic_DNA.
DR EMBL; AF163911; AAF82319.1; JOINED; Genomic_DNA.
DR EMBL; AF016351; AAF82319.1; JOINED; Genomic_DNA.
DR EMBL; AF016352; AAF82319.1; JOINED; Genomic_DNA.
DR EMBL; AF016353; AAF82319.1; JOINED; Genomic_DNA.
DR EMBL; AF016354; AAF82319.1; JOINED; Genomic_DNA.
DR EMBL; AF016355; AAF82319.1; JOINED; Genomic_DNA.
DR EMBL; AF016356; AAF82319.1; JOINED; Genomic_DNA.
DR EMBL; AF016357; AAF82319.1; JOINED; Genomic_DNA.
DR EMBL; AF016358; AAF82319.1; JOINED; Genomic_DNA.
DR EMBL; AF016359; AAF82319.1; JOINED; Genomic_DNA.
DR EMBL; AF016360; AAF82319.1; JOINED; Genomic_DNA.
DR EMBL; AF016361; AAF82319.1; JOINED; Genomic_DNA.
DR EMBL; AF016362; AAF82319.1; JOINED; Genomic_DNA.
DR EMBL; AF016363; AAF82319.1; JOINED; Genomic_DNA.
DR EMBL; AF016364; AAF82319.1; JOINED; Genomic_DNA.
DR EMBL; AF016365; AAF82320.1; -; Genomic_DNA.
DR EMBL; AF163912; AAF82320.1; JOINED; Genomic_DNA.
DR EMBL; AF016351; AAF82320.1; JOINED; Genomic_DNA.
DR EMBL; AF016352; AAF82320.1; JOINED; Genomic_DNA.
DR EMBL; AF016353; AAF82320.1; JOINED; Genomic_DNA.
DR EMBL; AF016354; AAF82320.1; JOINED; Genomic_DNA.
DR EMBL; AF016355; AAF82320.1; JOINED; Genomic_DNA.
DR EMBL; AF016356; AAF82320.1; JOINED; Genomic_DNA.
DR EMBL; AF016357; AAF82320.1; JOINED; Genomic_DNA.
DR EMBL; AF016358; AAF82320.1; JOINED; Genomic_DNA.
DR EMBL; AF016359; AAF82320.1; JOINED; Genomic_DNA.
DR EMBL; AF016360; AAF82320.1; JOINED; Genomic_DNA.
DR EMBL; AF016361; AAF82320.1; JOINED; Genomic_DNA.
DR EMBL; AF016362; AAF82320.1; JOINED; Genomic_DNA.
DR EMBL; AF016363; AAF82320.1; JOINED; Genomic_DNA.
DR EMBL; AF016364; AAF82320.1; JOINED; Genomic_DNA.
DR EMBL; AL596223; CAH71506.1; -; Genomic_DNA.
DR EMBL; AC016821; CAH71506.1; JOINED; Genomic_DNA.
DR EMBL; AL672126; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC008730; AAH08730.1; -; mRNA.
DR EMBL; AF073786; AAC25424.1; -; mRNA.
DR EMBL; AF029306; AAC00172.1; -; Genomic_DNA.
DR EMBL; X66957; CAA47379.1; -; mRNA.
DR PIR; A31869; A31869.
DR RefSeq; NP_000179.2; NM_000188.2.
DR RefSeq; NP_277031.1; NM_033496.2.
DR RefSeq; NP_277032.1; NM_033497.2.
DR RefSeq; NP_277033.1; NM_033498.2.
DR RefSeq; NP_277035.2; NM_033500.2.
DR RefSeq; XP_005269793.1; XM_005269736.1.
DR UniGene; Hs.370365; -.
DR PDB; 1CZA; X-ray; 1.90 A; N=1-917.
DR PDB; 1DGK; X-ray; 2.80 A; N=1-917.
DR PDB; 1HKB; X-ray; 2.80 A; A/B=1-917.
DR PDB; 1HKC; X-ray; 2.80 A; A=1-917.
DR PDB; 1QHA; X-ray; 2.25 A; A/B=1-917.
DR PDB; 4F9O; X-ray; 2.65 A; A/B=1-914.
DR PDB; 4FOE; X-ray; 2.70 A; A/B=1-917.
DR PDB; 4FOI; X-ray; 2.40 A; A/B=1-917.
DR PDB; 4FPA; X-ray; 2.48 A; A/B=1-917.
DR PDB; 4FPB; X-ray; 3.00 A; A/B=1-917.
DR PDBsum; 1CZA; -.
DR PDBsum; 1DGK; -.
DR PDBsum; 1HKB; -.
DR PDBsum; 1HKC; -.
DR PDBsum; 1QHA; -.
DR PDBsum; 4F9O; -.
DR PDBsum; 4FOE; -.
DR PDBsum; 4FOI; -.
DR PDBsum; 4FPA; -.
DR PDBsum; 4FPB; -.
DR ProteinModelPortal; P19367; -.
DR SMR; P19367; 12-914.
DR IntAct; P19367; 9.
DR MINT; MINT-1422832; -.
DR STRING; 9606.ENSP00000348697; -.
DR BindingDB; P19367; -.
DR ChEMBL; CHEMBL2688; -.
DR PhosphoSite; P19367; -.
DR DMDM; 116242516; -.
DR PaxDb; P19367; -.
DR PRIDE; P19367; -.
DR DNASU; 3098; -.
DR Ensembl; ENST00000298649; ENSP00000298649; ENSG00000156515.
DR Ensembl; ENST00000359426; ENSP00000352398; ENSG00000156515.
DR Ensembl; ENST00000360289; ENSP00000353433; ENSG00000156515.
DR Ensembl; ENST00000404387; ENSP00000384774; ENSG00000156515.
DR GeneID; 3098; -.
DR KEGG; hsa:3098; -.
DR UCSC; uc001jpl.4; human.
DR CTD; 3098; -.
DR GeneCards; GC10P071031; -.
DR HGNC; HGNC:4922; HK1.
DR HPA; CAB010052; -.
DR HPA; HPA007043; -.
DR HPA; HPA007044; -.
DR HPA; HPA011956; -.
DR MIM; 142600; gene.
DR MIM; 235700; phenotype.
DR MIM; 605285; phenotype.
DR neXtProt; NX_P19367; -.
DR Orphanet; 99953; Charcot-Marie-Tooth disease type 4G.
DR Orphanet; 90031; Non-spherocytic hemolytic anemia due to hexokinase deficiency.
DR PharmGKB; PA29300; -.
DR eggNOG; COG5026; -.
DR HOVERGEN; HBG005020; -.
DR KO; K00844; -.
DR OrthoDB; EOG7S21X5; -.
DR BioCyc; MetaCyc:HS08136-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR SABIO-RK; P19367; -.
DR UniPathway; UPA00242; -.
DR ChiTaRS; HK1; human.
DR EvolutionaryTrace; P19367; -.
DR GenomeRNAi; 3098; -.
DR NextBio; 12293; -.
DR PRO; PR:P19367; -.
DR ArrayExpress; P19367; -.
DR Bgee; P19367; -.
DR CleanEx; HS_HK1; -.
DR Genevestigator; P19367; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0045121; C:membrane raft; IEA:Ensembl.
DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0008865; F:fructokinase activity; IBA:RefGenome.
DR GO; GO:0004340; F:glucokinase activity; IBA:RefGenome.
DR GO; GO:0019158; F:mannokinase activity; IBA:RefGenome.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0001678; P:cellular glucose homeostasis; IBA:RefGenome.
DR GO; GO:0015758; P:glucose transport; TAS:Reactome.
DR GO; GO:0006096; P:glycolysis; IBA:RefGenome.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0055085; P:transmembrane transport; TAS:Reactome.
DR InterPro; IPR001312; Hexokinase.
DR InterPro; IPR022673; Hexokinase_C.
DR InterPro; IPR019807; Hexokinase_CS.
DR InterPro; IPR022672; Hexokinase_N.
DR PANTHER; PTHR19443; PTHR19443; 1.
DR Pfam; PF00349; Hexokinase_1; 2.
DR Pfam; PF03727; Hexokinase_2; 2.
DR PRINTS; PR00475; HEXOKINASE.
DR PROSITE; PS00378; HEXOKINASES; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Allosteric enzyme; Alternative splicing;
KW ATP-binding; Charcot-Marie-Tooth disease; Complete proteome;
KW Direct protein sequencing; Disease mutation; Glycolysis; Kinase;
KW Membrane; Mitochondrion; Mitochondrion outer membrane;
KW Neurodegeneration; Neuropathy; Nucleotide-binding; Polymorphism;
KW Reference proteome; Repeat; Transferase.
FT CHAIN 1 917 Hexokinase-1.
FT /FTId=PRO_0000197585.
FT DOMAIN 17 221 Hexokinase type-1 1.
FT DOMAIN 223 462 Hexokinase type-2 1.
FT DOMAIN 465 668 Hexokinase type-1 2.
FT DOMAIN 671 909 Hexokinase type-2 2.
FT NP_BIND 84 89 ATP 1 (Potential).
FT NP_BIND 425 426 ATP 1.
FT NP_BIND 532 537 ATP 2.
FT NP_BIND 747 748 ATP 2.
FT NP_BIND 784 788 ATP 2.
FT NP_BIND 863 867 ATP 2.
FT REGION 1 12 Hydrophobic.
FT REGION 13 475 Regulatory.
FT REGION 84 88 Glucose-6-phosphate 1 binding.
FT REGION 172 173 Substrate 1 binding.
FT REGION 208 209 Substrate 1 binding.
FT REGION 291 294 Substrate 1 binding.
FT REGION 413 415 Glucose-6-phosphate 1 binding.
FT REGION 476 917 Catalytic.
FT REGION 532 536 Glucose-6-phosphate 2 binding.
FT REGION 603 604 Substrate 2 binding.
FT REGION 620 621 Substrate 2 binding.
FT REGION 656 657 Substrate 2 binding.
FT REGION 682 683 Substrate 2 binding.
FT REGION 861 863 Glucose-6-phosphate 2 binding.
FT BINDING 30 30 ATP 1.
FT BINDING 155 155 Substrate 1.
FT BINDING 209 209 Glucose-6-phosphate 1.
FT BINDING 232 232 Glucose-6-phosphate 1.
FT BINDING 235 235 Substrate 1.
FT BINDING 260 260 Substrate 1.
FT BINDING 345 345 ATP 1.
FT BINDING 449 449 Glucose-6-phosphate 1.
FT BINDING 657 657 Glucose-6-phosphate 2.
FT BINDING 680 680 ATP 2.
FT BINDING 680 680 Glucose-6-phosphate 2.
FT BINDING 708 708 Substrate 2.
FT BINDING 742 742 Substrate 2.
FT BINDING 897 897 Glucose-6-phosphate 2.
FT MOD_RES 1 1 N-acetylmethionine.
FT VAR_SEQ 1 21 MIAAQLLAYYFTELKDDQVKK -> MDCEHSLSLPCRGAEA
FT WEIG (in isoform 2).
FT /FTId=VSP_002071.
FT VAR_SEQ 1 21 MIAAQLLAYYFTELKDDQVKK -> MGQICQRESATAAEKP
FT KLHLLAESE (in isoform 3).
FT /FTId=VSP_002072.
FT VAR_SEQ 1 21 MIAAQLLAYYFTELKDDQVKK -> MAKRALHDF (in
FT isoform 4).
FT /FTId=VSP_002073.
FT VARIANT 529 529 L -> S (in HK deficiency).
FT /FTId=VAR_009878.
FT VARIANT 680 680 T -> S (in HK deficiency; HK Utrecht).
FT /FTId=VAR_023780.
FT VARIANT 776 776 L -> M (in dbSNP:rs1054203).
FT /FTId=VAR_023781.
FT CONFLICT 730 730 D -> N (in Ref. 1; AAA52646 and 9;
FT CAA47379).
FT HELIX 17 25
FT HELIX 27 29
FT HELIX 33 51
FT TURN 53 55
FT HELIX 56 58
FT STRAND 78 100
FT STRAND 103 112
FT HELIX 116 119
FT STRAND 120 122
FT HELIX 123 141
FT STRAND 144 146
FT STRAND 150 154
FT STRAND 161 164
FT TURN 179 182
FT HELIX 185 196
FT STRAND 203 207
FT HELIX 209 220
FT STRAND 224 241
FT HELIX 242 244
FT STRAND 252 258
FT HELIX 261 263
FT TURN 264 273
FT HELIX 276 283
FT STRAND 285 287
FT HELIX 294 297
FT HELIX 299 315
FT HELIX 320 322
FT TURN 326 329
FT HELIX 336 342
FT TURN 345 347
FT HELIX 348 358
FT HELIX 365 401
FT STRAND 404 413
FT HELIX 415 419
FT HELIX 423 434
FT STRAND 438 444
FT HELIX 449 475
FT HELIX 481 499
FT HELIX 501 504
FT STRAND 526 546
FT STRAND 548 550
FT STRAND 552 560
FT HELIX 564 567
FT STRAND 568 570
FT HELIX 571 589
FT STRAND 597 602
FT STRAND 606 610
FT STRAND 613 616
FT HELIX 633 644
FT STRAND 650 655
FT HELIX 657 666
FT STRAND 672 689
FT TURN 690 692
FT STRAND 700 706
FT HELIX 709 711
FT TURN 712 715
FT TURN 717 721
FT HELIX 724 731
FT TURN 734 737
FT HELIX 742 744
FT TURN 747 749
FT HELIX 750 763
FT HELIX 768 770
FT TURN 774 777
FT HELIX 784 790
FT HELIX 797 807
FT HELIX 813 848
FT STRAND 852 861
FT HELIX 863 867
FT HELIX 871 882
FT STRAND 886 892
FT HELIX 898 912
SQ SEQUENCE 917 AA; 102486 MW; F29A6837531C0594 CRC64;
MIAAQLLAYY FTELKDDQVK KIDKYLYAMR LSDETLIDIM TRFRKEMKNG LSRDFNPTAT
VKMLPTFVRS IPDGSEKGDF IALDLGGSSF RILRVQVNHE KNQNVHMESE VYDTPENIVH
GSGSQLFDHV AECLGDFMEK RKIKDKKLPV GFTFSFPCQQ SKIDEAILIT WTKRFKASGV
EGADVVKLLN KAIKKRGDYD ANIVAVVNDT VGTMMTCGYD DQHCEVGLII GTGTNACYME
ELRHIDLVEG DEGRMCINTE WGAFGDDGSL EDIRTEFDRE IDRGSLNPGK QLFEKMVSGM
YLGELVRLIL VKMAKEGLLF EGRITPELLT RGKFNTSDVS AIEKNKEGLH NAKEILTRLG
VEPSDDDCVS VQHVCTIVSF RSANLVAATL GAILNRLRDN KGTPRLRTTV GVDGSLYKTH
PQYSRRFHKT LRRLVPDSDV RFLLSESGSG KGAAMVTAVA YRLAEQHRQI EETLAHFHLT
KDMLLEVKKR MRAEMELGLR KQTHNNAVVK MLPSFVRRTP DGTENGDFLA LDLGGTNFRV
LLVKIRSGKK RTVEMHNKIY AIPIEIMQGT GEELFDHIVS CISDFLDYMG IKGPRMPLGF
TFSFPCQQTS LDAGILITWT KGFKATDCVG HDVVTLLRDA IKRREEFDLD VVAVVNDTVG
TMMTCAYEEP TCEVGLIVGT GSNACYMEEM KNVEMVEGDQ GQMCINMEWG AFGDNGCLDD
IRTHYDRLVD EYSLNAGKQR YEKMISGMYL GEIVRNILID FTKKGFLFRG QISETLKTRG
IFETKFLSQI ESDRLALLQV RAILQQLGLN STCDDSILVK TVCGVVSRRA AQLCGAGMAA
VVDKIRENRG LDRLNVTVGV DGTLYKLHPH FSRIMHQTVK ELSPKCNVSF LLSEDGSGKG
AALITAVGVR LRTEASS
//

MIM 142600
*RECORD*
*FIELD* NO
142600
*FIELD* TI
*142600 HEXOKINASE 1; HK1
*FIELD* TX

DESCRIPTION

Hexokinase (EC 2.7.1.1) catalyzes the first step in glucose metabolism,
read moreusing ATP for the phosphorylation of glucose to glucose-6-phosphate.
Four different forms of hexokinase, designated type HK1, HK2 (601125),
HK3 (142570), and HK4 (138079), encoded by different genes, are present
in mammalian tissues. Among these, HK1 is the predominant glucose
phosphorylating activity in those tissues that share a strict dependence
on glucose utilization for their physiologic functions, such as brain,
erythrocytes, platelets, lymphocytes, and fibroblasts (summary by
Bianchi et al., 1997). Different isoforms of HK1 are either cytoplasmic
or associated with the outer mitochondrial membrane (OMM) through a
5-prime porin (VDAC1; 604492)-binding domain (Murakami and Piomelli,
1997).

CLONING

Nishi et al. (1988) analyzed cDNA clones encoding human hexokinase
isolated from an adult kidney library. Analysis of this 917-amino acid
protein showed that the sequences of the N- and C-terminal halves,
corresponding to the regulatory and catalytic domains, respectively, are
homologous. Eukaryotic hexokinases evolved from duplication of a gene
encoding a protein of about 450 amino acids. Griffin et al. (1991)
thought that comparisons of sequences in many species supported the
theory of Ureta (1982) that the mammalian hexokinases arose from the
duplication and fusion of an ancestral protoenzyme and that the yeast
and mammalian glucokinases arose twice in evolution. Sequence analysis
demonstrated that a 15-amino acid porin-binding domain in the N terminus
of HK1 is absolutely conserved and mediates the binding of HK1 to the
mitochondria. In the course of their work, Griffin et al. (1991)
developed a method for cloning the cDNA for a low abundance protein
using knowledge of the evolutionary conservation of amino acid and
nucleotide sequence.

By liquid chromatography, Murakami et al. (1990) identified 2 distinct
major isozymes of human red blood cell (RBC) hexokinase. One had a
molecular mass similar to that of HK1 identified in liver, and the
other, designated HKR, was larger than HK1 by several kilodaltons. RBC
from normal blood contained HK1 and HKR at an equal activity, but in
reticulocyte-rich RBC, HKR dominated. Murakami and Piomelli (1997)
isolated a cDNA clone for the red cell-specific HK isozyme HKR. Its
nucleotide sequence was identical to HK1 cDNA except for the 5-prime
end. It lacks the first 62 nucleotides of the HK1 coding region;
instead, it contains a unique sequence of 60 nucleotides at the
beginning of the coding sequence as well as another unique sequence
upstream of the putative translation initiation site. It lacks the
porin-binding domain that facilitates binding to mitochondria, thus
explaining the exclusive cytoplasmic localization of red blood cell HK.
Northern blot analysis showed that it was expressed in reticulocytes and
in an erythroleukemic cell line, but not in a lymphocytic cell line.

Mori et al. (1996) reported the cloning of cDNAs representing 3 unique
human type 1 hexokinase mRNAs expressed in testis, which were not
detected by Northern blot analysis in other human tissues. These mRNAs
contained unique sequences in the 5-prime terminus and lacked the
porin-binding domain (PBD), a conserved sequence that mediates the
binding of hexokinase to the mitochondria. The sequences were similar to
those identified by Mori et al. (1993) in mouse testis.

GENE STRUCTURE

Ruzzo et al. (1998) determined that the HK1 gene contains 18 exons and
spans about 75 kb. Analysis of the 5-prime flanking region revealed
binding sites for AP1 and CRE as well as several binding sites for SP1.
Ruzzo et al. (1998) identified an exon 1 specific to HK1 expressed in
somatic cells; an alternative exon (exon 1R) transcribed in red blood
cells replaced the somatic exon 1 by alternative splicing. Exon 1R lacks
the porin-binding domain.

Andreoni et al. (2000) found that multiple testis-specific HK1
transcripts are encoded by 6 different exons; 5 of the exons are located
upstream from the somatic exon 1, and one is located within intron 1.
With identification of these additional exons, they determined that the
gene spans at least 100 kb.

MAPPING

Shows (1974) presented evidence from somatic cell hybrid experiments
that hexokinase and cytoplasmic glutamate oxaloacetic transaminase are
syntenic on chromosome 10. By gene dosage studies of fibroblasts,
Gitelman and Simpson (1982) mapped HK1 to 10p11-q23. By dosage effect,
Dallapiccola et al. (1981) narrowed the HK1 assignment to 10pter-p13.
Dallapiccola et al. (1984) determined HK1 activity in the red cells of 5
patients with various partial duplications of 10p and concluded that the
most likely regional assignment for HK1 is 10p11.2. By in situ
hybridization, Shows et al. (1989) regionalized the HK1 gene to 10q22.
Daniele et al. (1992) used an HK1 cDNA as a probe for the study of a
panel of human-hamster somatic cell hybrids to assign the gene to the
long arm of chromosome 10 in the region q11.2-qter. This result agrees
with those reported by Gitelman and Simpson (1982) and Shows et al.
(1989) but conflicts with that reported by Dallapiccola et al. (1984).
Daniele et al. (1992) acknowledged the possibility that the HK1 probe
they used recognized more than a single locus but concluded that if 2 or
more HK loci exist they are all located on chromosome 10. Gelb et al.
(1992) demonstrated that most of the coding region of the HK1 gene is
located in a 120-kb YAC, which mapped entirely to chromosome 10.

The genes for 3 separate hexokinases have been assigned to specific
sites as of 1997: HK1, a red-cell isoform, to chromosome 10; HK2
(601125), the major hexokinase expressed in skeletal muscle, to
chromosome 2; and HK3 (142570), an isoform in white blood cells, to
chromosome 5. Hexokinase-4 (HK4) is glucokinase (GCK; 138079), which
maps to chromosome 7.

MOLECULAR GENETICS

- Nonspherocytic Hemolytic Anemia Due to Hexokinase Deficiency

Bianchi and Magnani (1995) reported the molecular characterization of
the defect in HK1 in a patient with hemolytic anemia due to hexokinase
deficiency (235700). PCR amplification and sequence of the cDNA revealed
compound heterozygosity for a deletion and a single nucleotide
substitution. The 96-bp deletion (142600.0001) involved nucleotides 577
to 672 of their cDNA sequence and was found in the cDNA of none of 14
unrelated normal subjects. The sequence of the HK1 allele without
deletion showed a T-to-C transition of nucleotide 1677, which caused the
amino acid change leu529-to-ser (142600.0002). The substitution was not
found in 10 normal controls. Bianchi and Magnani (1995) stated that to
their knowledge only 14 cases had been described, 2 of which had been
studied in their laboratory: HK-Melzo and HK-Napoli. It was in HK-Melzo
that the molecular defect was demonstrated. They showed that in the
HK-Melzo variant, the HK deficiency was expressed not only in
erythrocytes but also in platelets, lymphocytes, and fibroblasts. All
these types of cells contain HK type I as the predominant glucose
phosphorylating enzyme and, in particular, platelets and erythrocytes
share a strict dependence upon glucose utilization for their physiologic
functions.

In a girl, born of consanguineous parents, with severe nonspherocytic
hemolytic anemia due to hexokinase deficiency previously reported by
Rijksen et al. (1983), van Wijk et al. (2003) identified a homozygous
mutation in the HK1 gene (T680S; 142600.0004). The mutation, which
segregated with the disorder in the family and was not found in 50
controls, was designated 'Utrecht.' In vitro studies of the mutant
enzyme showed that it had a 2-fold decrease in affinity for Mg-ATP2 and
a markedly decreased affinity for the inhibitor glucose-1,6-diphosphate.
Patient red cells and platelets had about 25% residual activity.

- Russe Type of Hereditary Motor and Sensory Neuropathy

In all 34 European Gypsy individuals with the Russe type of hereditary
motor and sensory neuropathy (HMSNR; 605285) who were studied, Hantke et
al. (2009) identified a homozygous sequence change in the HK1 gene
(142600.0003) that mapped within the candidate disease interval on
chromosome 10q. The mutation was located at a highly conserved
nucleotide in the putative AltT2 exon located in the 5-prime region
upstream of HK1. The variant was found in heterozygous state in 5 of 790
control individuals representing a cross-section of the Gypsy
population, but not in 233 Bulgarian controls. AltT2-containing
transcripts in the mouse peripheral nerve were rare compared to the
coding region of HK1. However, 6 of 8 testis AltT2-containing isoforms
were found, with expression patterns differing between the peripheral
nerve and the brain and between newborn and adult tissues in mice. There
was no difference in HK1 mRNA in Schwann cells derived from patients or
controls, and patient cells showed no evidence of HK1 enzyme activity
compared to controls. Bioinformatic tools did not suggest an effect of
the variant on HK1 gene splicing or binding sites for interacting
proteins. However, there was evidence that the variant may cause a
ter-to-tyr substitution in 1 upstream open reading frame that had a
non-AUG start codon, which could potentially disrupt HK1 translation
regulation. Hantke et al. (2009) speculated that non-OMM-binding HK1 may
play a role in the pathogenesis of HMSNR.

Sevilla et al. (2013) found that 11 patients from 9 Roma Gypsy families
were homozygous for the HK1 variant (g.9712G-C; 142600.0003) identified
by Hantke et al. (2009), and haplotype analysis confirmed a founder
effect in this population.

HISTORY

Schimke and Grossbard (1968) reviewed studies of hexokinase isozymes.

*FIELD* AV
.0001
HEMOLYTIC ANEMIA, NONSPHEROCYTIC, DUE TO HEXOKINASE DEFICIENCY
HK1, 96-BP DEL

In the so-called HK-Melzo variant of hexokinase deficiency (235700),
Bianchi and Magnani (1995) demonstrated compound heterozygosity for
deletion of nucleotides 577 to 672 in the HK cDNA sequence and a
leu529-to-ser missense mutation (142600.0002).

.0002
HEMOLYTIC ANEMIA, NONSPHEROCYTIC, DUE TO HEXOKINASE DEFICIENCY
HK1, LEU529SER

See 142600.0001 and Bianchi and Magnani (1995).

.0003
NEUROPATHY, HEREDITARY MOTOR AND SENSORY, RUSSE TYPE
HK1, -3818-195G-C, AltT2 EXON

In all 34 individuals with the Russe type of hereditary motor and
sensory neuropathy (HMSNR; 605285) who were studied, Hantke et al.
(2009) identified 2 homozygous sequence changes in the HK1 gene, which
maps within the candidate disease interval on chromosome 10q. One was a
G-to-C transversion at a highly conserved nucleotide in the putative
AltT2 exon located in the 5-prime region upstream of HK1 (-3818-195G-C,
NM_033497; Chandler, 2013), and the other was an intronic G-to-A
transition downstream of the AltT2 change; the G-to-A transition was not
highly conserved, and thus not thought to be pathogenic. These 2
variants were found in heterozygous state in 5 of 790 control
individuals representing a cross-section of the Gypsy population, but
not in 233 Bulgarian controls. AltT2-containing transcripts in the mouse
peripheral nerve were rare compared to the coding region of HK1.
However, 6 of 8 testis AltT2-containing isoforms were found, with
expression patterns differing between the peripheral nerve and the brain
and between newborn and adult tissues in mice. There was no difference
in HK1 mRNA in Schwann cells derived from patients or controls, and
patient cells showed no evidence of HK1 enzyme activity compared to
controls. Bioinformatic tools did not suggest an effect of the G-C
change on HK1 gene splicing or binding sites for interacting proteins.
However, there was evidence that the G-C change may cause a ter-to-tyr
substitution in 1 upstream open reading frame that had a non-AUG start
codon, which could potentially disrupt HK1 translation regulation.
Hantke et al. (2009) speculated that non-OMM-binding HK1 may play a role
in the pathogenesis of HMSNR.

Sevilla et al. (2013) found that 11 patients from 9 Roma Gypsy families
with progressive hereditary motor and sensory neuropathy were homozygous
for the HK1 variant (g.9712G-C) identified by Hantke et al. (2009), and
haplotype analysis confirmed a founder effect in this population. The
founding ancestor was estimated to have lived at the end of the 18th
century, when a population split occurred from a tribal group and the
Gypsy population in Spain increased under the rule of Charles III.

.0004
HEMOLYTIC ANEMIA, NONSPHEROCYTIC, DUE TO HEXOKINASE DEFICIENCY
HK1, THR680SER

In a girl, born of consanguineous parents, with severe nonspherocytic
hemolytic anemia due to hexokinase deficiency (235700) previously
reported by Rijksen et al. (1983), van Wijk et al. (2003) identified a
homozygous c.2039C-G transversion in exon 15 of the HK1 gene, resulting
in a thr680-to-ser (T680S) substitution at a highly conserved residue in
the active site. The mutation, which segregated with the disorder in the
family and was not found in 50 controls, was designated 'Utrecht.' In
vitro studies of the mutant enzyme showed that it had a 2-fold decrease
in affinity for Mg-ATP2 and a markedly decreased affinity for the
inhibitor glucose-1,6-diphosphate.

*FIELD* SA
Chern (1976); Gitelman et al. (1980); Ritter et al. (1974); Rogers
et al. (1975); Snyder et al. (1984)
*FIELD* RF
1. Andreoni, F.; Ruzzo, A.; Magnani, M.: Structure of the 5-prime
region of the human hexokinase type I (HKI) gene and identification
of an additional testis-specific HKI mRNA. Biochim. Biophys. Acta 1493:
19-26, 2000.

2. Bianchi, M.; Crinelli, R.; Serafini, G. Giammarini, C.; Magnani,
M.: Molecular bases of hexokinase deficiency. Biochim. Biophys.
Acta 1360: 211-221, 1997.

3. Bianchi, M.; Magnani, M.: Hexokinase mutations that produce nonspherocytic
hemolytic anemia. Blood Cells Mol. Dis. 21: 2-8, 1995.

4. Chandler, D.: Personal Communication. Perth, Australia 3/16/2013.

5. Chern, C. J.: Localization of the structural genes for hexokinase-1
and inorganic pyrophosphatase on region (pter-q24) of human chromosome
10. Cytogenet. Cell Genet. 17: 338-342, 1976.

6. Dallapiccola, B.; Lungarotti, M. S.; Magnani, M.; Dacha, M.: Evidence
of gene dosage effect for HK1 in the red cells of a patient with trisomy
10pter leads to p13. Ann. Genet. 24: 45-47, 1981.

7. Dallapiccola, B.; Novelli, G.; Micara, G.; Delaroche, I.; Moric-Petrovic,
S.; Magnani, M.: Regional mapping of hexokinase-1 within the short
arm of chromosome 10. Hum. Hered. 34: 156-160, 1984.

8. Daniele, A.; Altruda, F.; Ferrone, M.; Silengo, L.; Romeo, G.;
Archidiacono, N.; Rocchi, M.: Mapping of human hexokinase 1 gene
to 10q11-qter. Hum. Hered. 42: 107-110, 1992.

9. Gelb, B. D.; Worley, K. C.; Griffin, L. D.; Adams, V.; Chinault,
A. C.; McCabe, E. R. B.: Characterization of human genomic artificial
chromosome inserts containing hexokinase 1 coding information on chromosome
10. Biochem. Med. Metab. Biol. 47: 267-269, 1992.

10. Gitelman, B. J.; Simpson, N. E.: Regional mapping of the locus
for hexokinase-1 (HK1) to 10p11-q23 by gene dosage in human fibroblasts. Hum.
Genet. 60: 227-229, 1982.

11. Gitelman, B. J.; Tomkins, D. J.; Partington, M. W.; Roberts, M.
H.; Simpson, N. E.: Gene dosage studies of glutamic oxaloacetic transaminase
(GOT) and hexokinase (HK) in two patients with possible partial trisomy
10q. (Abstract) Am. J. Hum. Genet. 32: 41A only, 1980.

12. Griffin, L. D.; Gelb, B. D.; Wheeler, D. A.; Davison, D.; Adams,
V.; McCabe, E. R. B.: Mammalian hexokinase 1: evolutionary conservation
and structure to function analysis. Genomics 11: 1014-1024, 1991.

13. Hantke, J.; Chandler, D.; King, R.; Wanders, R. J. A.; Angelicheva,
D.; Tournev, I.; McNamara, E.; Kwa, M.; Guergueltcheva, V.; Kaneva,
R.; Baas, F.; Kalaydjieva, L.: A mutation in an alternative untranslated
exon of hexokinase 1 associated with hereditary motor and sensory
neuropathy--Russe (HMSNR). Europ. J. Hum. Genet. 17: 1606-1614,
2009.

14. Mori, C.; Nakamura, N.; Welch, J. E.; Shiota, K.; Eddy, E. M.
: Testis-specific expression of mRNAs for a unique human type 1 hexokinase
lacking the porin-binding domain. Molec. Reprod. Dev. 44: 14-22,
1996.

15. Mori, C.; Welch, J. E.; Fulcher, K. D.; O'Brien, D. A.; Eddy,
E. M.: Unique hexokinase messenger ribonucleic acids lacking the
porin-binding domain are developmentally expressed in mouse spermatogenic
cells. Biol. Reprod. 49: 191-203, 1993.

16. Murakami, K.; Blei, F.; Tilton, W.; Seaman, C.; Piomelli, S.:
An isozyme of hexokinase specific for the human red blood cell (HK-R). Blood 75:
770-775, 1990.

17. Murakami, K.; Piomelli, S.: Identification of the cDNA for human
red blood cell-specific hexokinase isozyme. Blood 89: 762-766, 1997.

18. Nishi, S.; Seino, S.; Bell, G. I.: Human hexokinase: sequences
of amino- and carboxyl-terminal halves are homologous. Biochem. Biophys.
Res. Commun. 157: 937-943, 1988.

19. Rijksen, G.; Akkerman, J. W. N.; van den Wall Bake, A. W. L.;
Hofstede, D. P.; Staal, G. E. J.: Generalized hexokinase deficiency
in the blood cells of a patient with nonspherocytic hemolytic anemia. Blood 61:
12-18, 1983.

20. Ritter, H.; Friedrichson, U.; Schmitt, J.: Genetic polymorphism
of hexokinase in primates. Humangenetik 22: 265-266, 1974.

21. Rogers, P. A.; Fisher, R. A.; Harris, H.: An electrophoretic
study of the distribution and properties of human hexokinases. Biochem.
Genet. 13: 857-866, 1975.

22. Ruzzo, A.; Andreoni, F.; Magnani, M.: Structure of the human
hexokinase type I gene and nucleotide sequence of the 5-prime flanking
region. Biochem. J. 331: 607-613, 1998.

23. Schimke, R. T.; Grossbard, L.: Studies on isozymes of hexokinase
in animal tissues. Ann. N.Y. Acad. Sci. 151: 332-350, 1968.

24. Sevilla, T.; Martinez-Rubio, D.; Marquez, C.; Paradas, C.; Colomer,
J.; Jaijo, T.; Millan, J. M.; Palau, F.; Espinos, C.: Genetics of
the Charcot-Marie-Tooth disease in the Spanish Gypsy population: the
hereditary motor and sensory neuropathy-Russe in depth. Clin. Genet. 83:
565-570, 2013.

25. Shows, T. B.: Synteny of human genes for glutamic oxaloacetic
transaminase and hexokinase in somatic cell hybrids. Cytogenet. Cell
Genet. 13: 143-145, 1974.

26. Shows, T. B.; Eddy, R. L.; Byers, M. G.; Haley, L. L.; Henry,
W. M.; Nishi, S.; Bell, G. I.: Localization of the human hexokinase
I gene (HK1) to chromosome 10q22. (Abstract) Cytogenet. Cell Genet. 51:
1079 only, 1989.

27. Snyder, F. F.; Lin, C. C.; Rudd, N. L.; Shearer, J. E.; Heikkila,
E. M.; Hoo, J. J.: A de novo case of trisomy 10p: gene dosage studies
of hexokinase, inorganic pyrophosphatase and adenosine kinase. Hum.
Genet. 67: 187-189, 1984.

28. Ureta, T.: The comparative isozymology of vertebrate hexokinases. Comp.
Biochem. Physiol. 71B: 549-555, 1982.

29. van Wijk, R.; Rijksen, G,; Huizinga, E. G.; Nieuwenhuis, H. K.;
van Solinge, W. W.: HK Utrecht: missense mutation in the active site
of human hexokinase associated with hexokinase deficiency and severe
nonspherocytic hemolytic anemia. Blood 101: 345-347, 2003.

*FIELD* CN
Cassandra L. Kniffin - updated: 7/9/2013
Cassandra L. Kniffin - updated: 6/4/2013
Cassandra L. Kniffin - updated: 3/5/2013
Patricia A. Hartz - updated: 8/5/2002
Victor A. McKusick - updated: 4/4/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
tpirozzi: 07/09/2013
ckniffin: 7/9/2013
carol: 7/8/2013
carol: 6/7/2013
ckniffin: 6/4/2013
carol: 3/18/2013
carol: 3/8/2013
ckniffin: 3/5/2013
carol: 7/7/2010
carol: 8/5/2002
dkim: 7/2/1998
jenny: 4/4/1997
terry: 4/1/1997
mark: 11/6/1996
mark: 11/1/1995
davew: 8/5/1994
carol: 11/20/1992
carol: 10/13/1992
carol: 8/31/1992
carol: 8/21/1992

MIM 235700
*RECORD*
*FIELD* NO
235700
*FIELD* TI
#235700 HEMOLYTIC ANEMIA, NONSPHEROCYTIC, DUE TO HEXOKINASE DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because nonspherocytic
read morehemolytic anemia can be caused by homozygous or compound heterozygous
mutation in the HK1 gene (142600) on chromosome 10q22.

DESCRIPTION

Hexokinase deficiency is an autosomal recessive disorder characterized
by early-onset severe hemolytic anemia (summary by van Wijk et al.,
2003).

CLINICAL FEATURES

Valentine et al. (1967) described a child with anemia present from birth
and deficiency of red cell hexokinase. The father and one sib had low
levels. The mother's level was also low but within the range of normal.
The deficiency apparently did not involve leukocytes and platelets and
was different from the hexokinase deficiency identified in Fanconi
pancytopenia (227650). Necheles et al. (1970) found, however, associated
deficiency of leukocyte hexokinase.

Rijksen and Staal (1978) studied a patient with hemolytic anemia due to
hexokinase deficiency and showed that the mutant enzyme had abnormal
electrophoretic properties and abnormal behavior with respect to its
regulation by glucose-1,6-diphosphate and inorganic phosphate. They
proposed that there are two different hexokinases type I in red cells,
only one of which was mutant in this case.

Rijksen et al. (1983) reported a girl, born of consanguineous parents,
with neonatal jaundice and transfusion-dependent hemolytic anemia.
Residual HK1 activity in the patient's red cells and platelets was about
25% of normal, consistent with hexokinase deficiency. In lymphocytes, HK
activity was normal; HK1 was low but the deficiency was compensated by
HK3 (142570). The parents and 3 sibs were apparent heterozygotes, as
demonstrated by 50 to 67% residual activity in their red cells, but they
had no clinical signs of hexokinase deficiency. The patient's mutant
enzyme showed a 2-fold decrease in affinity for Mg-ATP2 and a markedly
decreased affinity for the inhibitor glucose-1,6-diphosphate.

Paglia et al. (1981) found a low activity isozyme of red cell hexokinase
in a Chinese boy with chronic hemolytic anemia. Because of subtle
differences between the hexokinases of the parents, it was proposed that
the proband might be a compound heterozygote.

INHERITANCE

The transmission pattern in the family with hemolytic anemia due to
hexokinase deficiency reported by Rijksen et al. (1983) and later by van
Wijk et al. (2003) was consistent with autosomal recessive inheritance.

MOLECULAR GENETICS

Bianchi and Magnani (1995) reported the molecular characterization of
the defect in HK1 in a patient with hemolytic anemia due to hexokinase
deficiency. PCR amplification and sequence of the cDNA revealed compound
heterozygosity for a deletion and a single nucleotide substitution. The
96-bp deletion (142600.0001) involved nucleotides 577 to 672 of their
cDNA sequence and was found in the cDNA of none of 14 unrelated normal
subjects. The sequence of the HK1 allele without deletion showed a
T-to-C transition of nucleotide 1677, which caused the amino acid change
leu529-to-ser (142600.0002). The substitution was not found in 10 normal
controls. Bianchi and Magnani (1995) stated that to their knowledge only
14 cases had been described, 2 of which had been studied in their
laboratory: HK-Melzo and HK-Napoli. It was in HK-Melzo in which the
molecular defect was demonstrated. They showed that in the HK-Melzo
variant, the HK deficiency was expressed not only in erythrocytes but
also in platelets, lymphocytes, and fibroblasts. All these types of
cells contain HK type 1 as the predominant glucose phosphorylating
enzyme and, in particular, platelets and erythrocytes share a strict
dependence upon glucose utilization for their physiologic

In a girl with severe nonspherocytic hemolytic anemia due to hexokinase
deficiency previously reported by Rijksen et al. (1983), van Wijk et al.
(2003) identified a homozygous mutation in the HK1 gene (T680S;
142600.0004). The mutation segregated with the disorder in the family
and was not found in 50 controls.

*FIELD* SA
Altay et al. (1970); Board et al. (1978); Gelsanz et al. (1978); Keitt
(1969); Magnani et al. (1985); Magnani et al. (1985); Siimes et al.
(1979)
*FIELD* RF
1. Altay, C.; Alper, C. A.; Nathan, D. G.: Normal and variant isoenzymes
of human blood cell hexokinase and the isoenzyme patterns in hemolytic
disease. Blood 36: 219-227, 1970.

2. Bianchi, M.; Magnani, M.: Hexokinase mutations that produce nonspherocytic
hemolytic anemia. Blood Cells Mol. Dis. 21: 2-8, 1995.

3. Board, P. G.; Trueworthy, R.; Smith, J. E.; Moore, K.: Congenital
nonspherocytic hemolytic anemia with an unstable hexokinase variant. Blood 51:
111-118, 1978.

4. Gelsanz, F.; Meyer, E.; Paglia, D. E.; Valentine, W. N.: Congenital
hemolytic anemia due to hexokinase deficiency. Am. J. Dis. Child. 132:
636-637, 1978.

5. Keitt, A. S.: Hemolytic anemia with impaired hexokinase activity. J.
Clin. Invest. 48: 1997-2007, 1969.

6. Magnani, M.; Stocchi, V.; Canestrari, F.; Dacha, M.; Balestri,
P.; Farnetani, M. A.; Giorgi, D.; Fois, A.; Fornaini, G.: Human erythrocyte
hexokinase deficiency: a new variant with abnormal kinetic properties. Brit.
J. Haemat. 61: 41-50, 1985.

7. Magnani, M.; Stocchi, V.; Cucchiarini, L.; Novelli, G.; Lodi, S.;
Isa, L.; Fornaini, G.: Hereditary nonspherocytic hemolytic anemia
due to a new hexokinase variant with reduced stability. Blood 66:
690-697, 1985.

8. Necheles, T. F.; Rai, U. S.; Cameron, D.: Congenital nonspherocytic
hemolytic anemia associated with an unusual erythrocyte hexokinase
abnormality. J. Lab. Clin. Med. 76: 593-602, 1970.

9. Paglia, D. E.; Shende, A.; Lanzkowsky, P.; Valentine, W. N.: Hexokinase
'New Hyde Park': a low activity erythrocyte isozyme in a Chinese kindred. Am.
J. Hemat. 10: 107-117, 1981.

10. Rijksen, G.; Akkerman, J. W. N.; van den Wall Bake, A. W. L.;
Hofstede, D. P.; Staal, G. E. J.: Generalized hexokinase deficiency
in the blood cells of a patient with nonspherocytic hemolytic anemia. Blood 61:
12-18, 1983.

11. Rijksen, G.; Staal, G. E. J.: Human erythrocyte hexokinase deficiency:
characterization of a mutant enzyme with abnormal regulatory properties. J.
Clin. Invest. 62: 294-301, 1978.

12. Siimes, M. A.; Rahiala, E. L.; Leisti, J.: Hexokinase deficiency
in erythrocytes: a new variant in 5 members of a Finnish family. Scand.
J. Haemat. 22: 214-218, 1979.

13. Valentine, W. N.; Oski, F. A.; Paglia, D. E.; Baughan, M. A.;
Schneider, A. S.; Naiman, J. L.: Hereditary hemolytic anemia with
hexokinase deficiency. Role of hexokinase in erythrocyte aging. New
Eng. J. Med. 276: 1-11, 1967.

14. van Wijk, R.; Rijksen, G.; Huizinga, E. G.; Nieuwenhuis, H. K.;
van Solinge, W. W.: HK Utrecht: missense mutation in the active site
of human hexokinase associated with hexokinase deficiency and severe
nonspherocytic hemolytic anemia. Blood 101: 345-347, 2003.

*FIELD* CS
INHERITANCE:
Autosomal recessive

ABDOMEN:
[Spleen];
Splenomegaly

SKIN, NAILS, HAIR:
[Skin];
Jaundice

HEMATOLOGY:
Hemolytic anemia;
Increased reticulocytes;
Decreased hemoglobin;
Increased fetal hemoglobin

LABORATORY ABNORMALITIES:
Hyperbilirubinemia;
Decreased hexokinase activity in red blood cells

MISCELLANEOUS:
Onset at birth

MOLECULAR BASIS:
Caused by mutation in the hexokinase 1 gene (HK1, 142600.0001)

*FIELD* CN
Cassandra L. Kniffin - revised: 7/9/2013

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

*FIELD* ED
joanna: 10/01/2013
ckniffin: 7/9/2013

*FIELD* CN
Cassandra L. Kniffin - updated: 7/9/2013

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
carol: 07/10/2013
tpirozzi: 7/9/2013
ckniffin: 7/9/2013
carol: 7/8/2013
carol: 7/7/2010
mark: 11/1/1995
mimadm: 2/19/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

MIM 605285
*RECORD*
*FIELD* NO
605285
*FIELD* TI
#605285 NEUROPATHY, HEREDITARY MOTOR AND SENSORY, RUSSE TYPE; HMSNR
;;CHARCOT-MARIE-TOOTH DISEASE, TYPE 4G; CMT4G;;
read moreCHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL RECESSIVE, TYPE 4G;;
HEREDITARY MOTOR AND SENSORY NEUROPATHY, RUSSE TYPE;;
CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 4G
*FIELD* TX
A number sign (#) is used with this entry because the Russe type of
hereditary motor and sensory neuropathy, also known as
Charcot-Marie-Tooth disease type 4G (CMT4G), is caused by homozygous
mutation in the HK1 gene (142600) on chromosome 10q22.

For a discussion of genetic heterogeneity of autosomal recessive
hereditary motor and sensory neuropathy, also known as
Charcot-Marie-Tooth disease, see CMT4A (214400).

DESCRIPTION

HMSNR is an autosomal recessive progressive complex peripheral
neuropathy characterized by onset in the first decade of distal lower
limb weakness and muscle atrophy resulting in walking difficulties.
Distal impairment of the upper limbs usually occurs later, as does
proximal lower limb weakness. There is distal sensory impairment, with
pes cavus and areflexia. Laboratory studies suggest that it is a
myelinopathy resulting in reduced nerve conduction velocities in the
demyelinating range as well as a length-dependent axonopathy (summary by
Sevilla et al., 2013).

For a discussion of genetic heterogeneity of autosomal recessive
hereditary motor and sensory neuropathy, also known as
Charcot-Marie-Tooth disease, see CMT4A (214400).

CLINICAL FEATURES

During studies of Romany (Gypsy) families with the Lom type of
hereditary motor and sensory neuropathy (CMT4D; 601455), Rogers et al.
(2000) identified a large kindred with 2 independently segregating
autosomal recessive neuropathies. The novel disorder, which the authors
called 'hereditary motor and sensory neuropathy/Russe' (HMSNR),
presented as a severe disabling form of Charcot-Marie-Tooth disease with
prominent sensory loss, moderately reduced motor nerve conduction
velocity, and a high threshold for electrical nerve stimulation.

Thomas et al. (2001) reported 21 affected individuals from 10 families
with HMSNR. Distal lower limb weakness began between ages 8 and 16
years, and upper limb involvement began between 10 and 43 years, with an
average of 22 years. This progressive disorder led to severe weakness of
the lower limbs, generalized in the oldest subject (aged 57 years), and
marked distal upper limb weakness. Prominent distal sensory loss
involved all modalities, resulting in neuropathic joint degeneration in
2 instances. All patients showed foot deformity, and most showed hand
deformity. Motor nerve conduction velocity was moderately reduced in the
upper limbs but unobtainable in the legs. Sensory nerve action
potentials were absent. There was a loss of larger myelinated nerve
fibers and profuse regenerative activity in the sural nerve.

Navarro and Teijeira (2003) provided a detailed review of neuromuscular
disorders among the Romani Gypsies.

Sevilla et al. (2013) reported 11 patients from 7 unrelated Spanish
Gypsy families with HMSNR. All except 1 developed distal lower limb
weakness in the first decade; 1 had onset at age 16 years. Distal upper
limb weakness was also present in all patients, but showed a slightly
later and more variable onset. About half of patients later had proximal
muscle involvement. All patients had distal sensory loss with areflexia
and pes cavus, and 5 had scoliosis. The majority of patients walked with
difficulty, 4 needed orthoses, and an older patient was
wheelchair-bound. Neurophysiologic studies were mostly consistent with
demyelination, although some were in the intermediate range. Sural nerve
biopsy of 1 patient showed thin myelin sheath thickness and clusters of
regenerative fibers.

MAPPING

By genome scan in 2 branches of a large kindred with hereditary motor
and sensory neuropathy, Rogers et al. (2000) detected linkage to the
10q22-q23 region containing the early growth response-2 gene (EGR2;
129010). By sequence analysis and the detection of an intragenic
polymorphism, Rogers et al. (2000) excluded EGR2 as the site of mutation
in HMSNR. By further linkage analysis and recombination mapping, the
authors refined the position of HMSNR to a small interval on 10q23.2,
flanked by markers telomeric to EGR2. In this interval, a conserved
7-marker haplotype was shared by all disease chromosomes, suggesting a
single founder mutation.

Claramunt et al. (2007) found that 3 of 20 Spanish Gypsy families with
autosomal recessive demyelinating neuropathy had HMSN-Russe as indicated
by positive linkage results to the 10q23 region.

MOLECULAR GENETICS

In all 34 individuals with Russe type of hereditary motor and sensory
neuropathy who were studied, Hantke et al. (2009) identified 2
homozygous sequence changes in the HK1 gene (142600), which maps within
the candidate disease interval on chromosome 10q. One was a G-to-C
transversion at a highly conserved nucleotide in the putative AltT2 exon
located in the 5-prime region upstream of HK1 (142600.0003), and the
other was an intronic G-to-A transition downstream of the AltT2 change;
the G-to-A transition was not highly conserved, and thus not thought to
be pathogenic. These 2 variants were found in heterozygous state in 5 of
790 control individuals representing a cross-section of the Gypsy
population, but not in 233 Bulgarian controls. AltT2-containing
transcripts in the mouse peripheral nerve were rare compared to the
coding region of HK1. However, 6 of 8 testis AltT2-containing isoforms
were found, with expression patterns differing between the peripheral
nerve and the brain and between newborn and adult tissues in mice. There
was no difference in HK1 mRNA in Schwann cells derived from patients or
controls, and patient cells showed no evidence of HK1 enzyme activity
compared to controls. Bioinformatic tools did not suggest an effect of
the G-C change on HK1 gene splicing or binding sites for interacting
proteins. However, there was evidence that the G-C change may cause a
ter-to-tyr substitution in 1 upstream open reading frame that had a
non-AUG start codon, which could potentially disrupt HK1 translation
regulation. Hantke et al. (2009) speculated that non-OMM-binding HK1 may
play a role in the pathogenesis of HMSNR.

Sevilla et al. (2013) found that 11 patients from 9 Roma Gypsy families
were homozygous for the HK1 variant (g.9712G-C; 142600.0003) identified
by Hantke et al. (2009), and haplotype analysis confirmed a founder
effect in this population.

POPULATION GENETICS

HMSNR is the second most common cause of Charcot-Marie-Tooth disease in
the Spanish Gypsy population (Roma) after CMT4C (601596), and is
associated with a homozygous founder variant in the HK1 gene
(142600.0003). Sevilla et al., 2013 found that 11 patients from 9 Roma
Gypsy families with the disorder were homozygous for the HK1 variant,
and haplotype analysis indicated a founder effect. The founding ancestor
was estimated to have lived at the end of the 18th century, when a
population split occurred from a tribal group and the Gypsy population
in Spain increased under the rule of Charles III.

NOMENCLATURE

De Sandre-Giovannoli et al. (2005) suggested that HMSNR be referred to
as Charcot-Marie-Tooth disease type 4G (CMT4G).

*FIELD* RF
1. Claramunt, R.; Sevilla, T.; Lupo, V.; Cuesta, A.; Millan, J.M.;
Vilchez, J. J.; Palau, F.; Espinos, C.: The p.R1109X mutation in
SH3TC2 gene is predominant in Spanish Gypsies with Charcot-Marie-Tooth
disease type 4. Clin. Genet. 71: 343-349, 2007.

2. De Sandre-Giovannoli, A.; Delague, V.; Hamadouche, T.; Chaouch,
M.; Krahn, M.; Boccaccio, I.; Maisonobe, T.; Chouery, E.; Jabbour,
R.; Atweh, S.; Grid, D.; Megarbane, A.; Levy, N.: Homozygosity mapping
of autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy
(CMT4H) to a novel locus on chromosome 12p11.21-q13.11. (Letter) J.
Med. Genet. 42: 260-265, 2005.

3. Hantke, J.; Chandler, D.; King, R.; Wanders, R. J. A.; Angelicheva,
D.; Tournev, I.; McNamara, E.; Kwa, M.; Guergueltcheva, V.; Kaneva,
R.; Baas, F.; Kalaydjieva, L.: A mutation in an alternative untranslated
exon of hexokinase 1 associated with hereditary motor and sensory
neuropathy - Russe (HMSNR). Europ. J. Hum. Genet. 17: 1606-1614,
2009.

4. Navarro, C.; Teijeira, S.: Neuromuscular disorders in the Gypsy
ethnic group: a short review. Acta Myol. 22: 11-14, 2003.

5. Rogers, T.; Chandler, D.; Angelicheva, D.; Thomas, P. K.; Youl,
B.; Tournev, I.; Gergelcheva, V.; Kalaydjieva, L.: A novel locus
for autosomal recessive peripheral neuropathy in the EGR2 region on
10q23. Am. J. Hum. Genet. 67: 664-671, 2000.

6. Sevilla, T.; Martinez-Rubio, D.; Marquez, C.; Paradas, C.; Colomer,
J.; Jaijo, T.; Millan, J. M.; Palau, F.; Espinos, C.: Genetics of
the Charcot-Marie-Tooth disease in the Spanish Gypsy population: the
hereditary motor and sensory neuropathy-Russe in depth. Clin. Genet. 83:
565-570, 2013.

7. Thomas, P. K.; Kalaydjieva, L.; Youl, B.; Rogers, T.; Angelicheva,
D.; King, R. H. M.; Guergueltcheva, V.; Colomer, J.; Lupu, C.; Corches,
A.; Popa, G.; Merlini, L.; Shmarov, A.; Muddle, J. R.; Nourallah,
M.; Tournev, I.: Hereditary motor and sensory neuropathy-Russe: new
autosomal recessive neuropathy in Balkan Gypsies. Ann. Neurol. 50:
452-457, 2001.

*FIELD* CS
INHERITANCE:
Autosomal recessive

SKELETAL:
[Spine];
Scoliosis (in some patients);
[Hands];
Hand deformity;
[Feet];
Foot deformity

MUSCLE, SOFT TISSUE:
Distal muscle weakness;
Proximal lower limb muscle weakness, later (in some patients)

NEUROLOGIC:
[Peripheral nervous system];
Prominent sensory loss, distal;
Distal limb weakness;
Distal limb paralysis;
Difficulty walking;
Hyporeflexia;
Reduced motor nerve conduction velocity;
Increased threshold for electrical stimulation;
Loss of larger myelinated nerve fibers;
Thin myelin sheaths;
Regenerative activity on nerve biopsy;
Hypomyelination on nerve biopsy;
Reduced nerve conduction velocities (demyelinating range)

MISCELLANEOUS:
Age of onset of distal lower limb weakness 8-16 years;
Age of onset of upper limb involvement 10-43 years;
Progressive disorder;
Described in individuals of Roma Gypsy origin (founder mutation)

MOLECULAR BASIS:
Caused by mutation in the hexokinase-1 gene (HK1, 142600.0003)

*FIELD* CN
Cassandra L. Kniffin - updated: 6/4/2013

*FIELD* CD
Cassandra L. Kniffin: 11/11/2002

*FIELD* ED
joanna: 10/22/2013
joanna: 7/24/2013
ckniffin: 6/4/2013
ckniffin: 11/11/2002

*FIELD* CN
Cassandra L. Kniffin - updated: 6/4/2013
Cassandra L. Kniffin - updated: 3/5/2013
Cassandra L. Kniffin - updated: 7/6/2007
Cassandra L. Kniffin - updated: 9/8/2004
Victor A. McKusick - updated: 12/5/2001

*FIELD* CD
Victor A. McKusick: 9/25/2000

*FIELD* ED
carol: 06/07/2013
ckniffin: 6/4/2013
carol: 3/8/2013
ckniffin: 3/5/2013
wwang: 7/16/2007
ckniffin: 7/6/2007
ckniffin: 4/20/2005
wwang: 4/18/2005
ckniffin: 4/15/2005
carol: 9/9/2004
ckniffin: 9/8/2004
mgross: 3/19/2004
alopez: 12/7/2001
terry: 12/5/2001
carol: 9/25/2000