RBCC Red Blood Cell Collection

PHKG2 [Confidence: low (only semi-automatic identification from reviews)]
Phosphorylase b kinase gamma catalytic chain, liver/testis isoform; PHK-gamma-LT; PHK-gamma-T; 2.7.11.19 (PSK-C3; Phosphorylase kinase subunit gamma-2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P15735
ID PHKG2_HUMAN Reviewed; 406 AA.
AC P15735; A8K0C7; B4DEB7; E9PEU3; P11800;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-APR-1990, sequence version 1.
DT 22-JAN-2014, entry version 158.
DE RecName: Full=Phosphorylase b kinase gamma catalytic chain, liver/testis isoform;
DE Short=PHK-gamma-LT;
DE Short=PHK-gamma-T;
DE EC=2.7.11.19;
DE AltName: Full=PSK-C3;
DE AltName: Full=Phosphorylase kinase subunit gamma-2;
GN Name=PHKG2;
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).
RX PubMed=2915644;
RA Hanks S.K.;
RT "Messenger ribonucleic acid encoding an apparent isoform of
RT phosphorylase kinase catalytic subunit is abundant in the adult
RT testis.";
RL Mol. Endocrinol. 3:110-116(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=9384616; DOI=10.1093/hmg/7.1.149;
RA Burwinkel B., Shiomi S., Al Zaben A., Kilimann M.W.;
RT "Liver glycogenosis due to phosphorylase kinase deficiency: PHKG2 gene
RT structure and mutations associated with cirrhosis.";
RL Hum. Mol. Genet. 7:149-154(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Cerebellum;
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 GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
RA Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
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 NUCLEOTIDE SEQUENCE [MRNA] OF 129-273.
RX PubMed=2948189; DOI=10.1073/pnas.84.2.388;
RA Hanks S.K.;
RT "Homology probing: identification of cDNA clones encoding members of
RT the protein-serine kinase family.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:388-392(1987).
RN [7]
RP INVOLVEMENT IN GSD9C.
RX PubMed=9245685; DOI=10.1006/bbrc.1997.7006;
RA van Beurden E.A., de Graaf M., Wendel U., Gitzelmann R., Berger R.,
RA van den Berg I.E.;
RT "Autosomal recessive liver phosphorylase kinase deficiency caused by a
RT novel splice-site mutation in the gene encoding the liver gamma
RT subunit (PHKG2).";
RL Biochem. Biophys. Res. Commun. 236:544-548(1997).
RN [8]
RP REVIEW ON FUNCTION AND STRUCTURE.
RX PubMed=10487978; DOI=10.2741/Brushia;
RA Brushia R.J., Walsh D.A.;
RT "Phosphorylase kinase: the complexity of its regulation is reflected
RT in the complexity of its structure.";
RL Front. Biosci. 4:D618-D641(1999).
RN [9]
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 [10]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 6-293 IN COMPLEX WITH
RP INHIBITOR.
RG Structural genomics consortium (SGC);
RT "Structure of human phosphorylase kinase, gamma 2.";
RL Submitted (FEB-2011) to the PDB data bank.
RN [11]
RP VARIANTS GSD9C GLU-106 AND GLU-189.
RX PubMed=8896567; DOI=10.1038/ng1196-337;
RA Maichele A.J., Burwinkel B., Maire I., Sovik O., Kilimann M.W.;
RT "Mutations in the testis/liver isoform of the phosphorylase kinase
RT gamma subunit (PHKG2) cause autosomal liver glycogenosis in the gsd
RT rat and in humans.";
RL Nat. Genet. 14:337-340(1996).
RN [12]
RP VARIANTS GSD9C LYS-157 AND ASN-215.
RX PubMed=12930917; DOI=10.1203/01.PDR.0000088069.09275.10;
RA Burwinkel B., Rootwelt T., Kvittingen E.A., Chakraborty P.K.,
RA Kilimann M.W.;
RT "Severe phenotype of phosphorylase kinase-deficient liver glycogenosis
RT with mutations in the PHKG2 gene.";
RL Pediatr. Res. 54:834-839(2003).
RN [13]
RP VARIANT [LARGE SCALE ANALYSIS] THR-317.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Catalytic subunit of the phosphorylase b kinase (PHK),
CC which mediates the neural and hormonal regulation of glycogen
CC breakdown (glycogenolysis) by phosphorylating and thereby
CC activating glycogen phosphorylase. May regulate glycogeneolysis in
CC the testis. In vitro, phosphorylates PYGM (By similarity).
CC -!- CATALYTIC ACTIVITY: 2 ATP + phosphorylase b = 2 ADP +
CC phosphorylase a.
CC -!- SUBUNIT: Hexadecamer of 4 heterotetramers, each composed of alpha,
CC beta, gamma, and delta subunits. Alpha (PHKA1 or PHKA2) and beta
CC (PHKB) are regulatory subunits, gamma (PHKG1 or PHKG2) is the
CC catalytic subunit, and delta is calmodulin.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P15735-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P15735-2; Sequence=VSP_041858, VSP_041859;
CC -!- DISEASE: Glycogen storage disease 9C (GSD9C) [MIM:613027]: A
CC metabolic disorder manifesting in infancy with hepatomegaly,
CC growth retardation, hypotonia, liver dysfunction, and elevated
CC plasma aminotransferases and lipids. These symptoms improve with
CC age in most cases; however, some patients may develop hepatic
CC fibrosis or cirrhosis. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK
CC Ser/Thr protein kinase family.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PHKG2";
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; M31606; AAA36442.1; -; mRNA.
DR EMBL; Y11950; CAA72694.1; -; Genomic_DNA.
DR EMBL; Y11951; CAA72694.1; JOINED; Genomic_DNA.
DR EMBL; AK289492; BAF82181.1; -; mRNA.
DR EMBL; AK293551; BAG57028.1; -; mRNA.
DR EMBL; AC106886; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC002541; AAH02541.1; -; mRNA.
DR EMBL; M14503; AAA36518.1; -; mRNA.
DR PIR; A40069; KIHUCT.
DR RefSeq; NP_000285.1; NM_000294.2.
DR RefSeq; NP_001165903.1; NM_001172432.1.
DR UniGene; Hs.65735; -.
DR PDB; 2Y7J; X-ray; 2.50 A; A/B/C/D=6-293.
DR PDBsum; 2Y7J; -.
DR ProteinModelPortal; P15735; -.
DR SMR; P15735; 10-293.
DR IntAct; P15735; 19.
DR STRING; 9606.ENSP00000329968; -.
DR BindingDB; P15735; -.
DR ChEMBL; CHEMBL2111324; -.
DR GuidetoPHARMACOLOGY; 2147; -.
DR PhosphoSite; P15735; -.
DR DMDM; 125536; -.
DR PaxDb; P15735; -.
DR PRIDE; P15735; -.
DR DNASU; 5261; -.
DR Ensembl; ENST00000424889; ENSP00000388571; ENSG00000156873.
DR Ensembl; ENST00000563588; ENSP00000455607; ENSG00000156873.
DR GeneID; 5261; -.
DR KEGG; hsa:5261; -.
DR UCSC; uc002dzk.2; human.
DR CTD; 5261; -.
DR GeneCards; GC16P030759; -.
DR HGNC; HGNC:8931; PHKG2.
DR MIM; 172471; gene.
DR MIM; 613027; phenotype.
DR neXtProt; NX_P15735; -.
DR Orphanet; 264580; Glycogen storage disease due to liver phosphorylase kinase deficiency.
DR PharmGKB; PA33272; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000233016; -.
DR HOVERGEN; HBG106193; -.
DR InParanoid; P15735; -.
DR KO; K00871; -.
DR OrthoDB; EOG7JMGDM; -.
DR PhylomeDB; P15735; -.
DR BioCyc; MetaCyc:HS08155-MONOMER; -.
DR BRENDA; 2.7.11.19; 2681.
DR Reactome; REACT_111217; Metabolism.
DR SignaLink; P15735; -.
DR ChiTaRS; PHKG2; human.
DR GeneWiki; PHKG2; -.
DR GenomeRNAi; 5261; -.
DR NextBio; 20322; -.
DR PRO; PR:P15735; -.
DR ArrayExpress; P15735; -.
DR Bgee; P15735; -.
DR CleanEx; HS_PHKG2; -.
DR Genevestigator; P15735; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005964; C:phosphorylase kinase complex; TAS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; NAS:UniProtKB.
DR GO; GO:0004689; F:phosphorylase kinase activity; TAS:UniProtKB.
DR GO; GO:0050321; F:tau-protein kinase activity; TAS:UniProtKB.
DR GO; GO:0006006; P:glucose metabolic process; TAS:Reactome.
DR GO; GO:0005978; P:glycogen biosynthetic process; IEA:InterPro.
DR GO; GO:0005980; P:glycogen catabolic process; TAS:Reactome.
DR GO; GO:0045819; P:positive regulation of glycogen catabolic process; TAS:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR InterPro; IPR020636; Ca/CaM-dep_Ca-dep_prot_Kinase.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR002291; Phosph_kin_gamma.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR PANTHER; PTHR24347; PTHR24347; 1.
DR Pfam; PF00069; Pkinase; 1.
DR PRINTS; PR01049; PHOSPHBKNASE.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Calmodulin-binding;
KW Carbohydrate metabolism; Complete proteome; Disease mutation;
KW Glycogen metabolism; Glycogen storage disease; Kinase;
KW Nucleotide-binding; Polymorphism; Reference proteome;
KW Serine/threonine-protein kinase; Transferase.
FT CHAIN 1 406 Phosphorylase b kinase gamma catalytic
FT chain, liver/testis isoform.
FT /FTId=PRO_0000086512.
FT DOMAIN 24 291 Protein kinase.
FT NP_BIND 30 38 ATP (By similarity).
FT REGION 306 330 Calmodulin-binding (domain-N) (By
FT similarity).
FT REGION 346 370 Calmodulin-binding (domain-C) (By
FT similarity).
FT ACT_SITE 153 153 Proton acceptor (By similarity).
FT BINDING 53 53 ATP (By similarity).
FT VAR_SEQ 362 374 VKKGEQQNRAALF -> IRKQWIGKLMACV (in
FT isoform 2).
FT /FTId=VSP_041858.
FT VAR_SEQ 375 406 Missing (in isoform 2).
FT /FTId=VSP_041859.
FT VARIANT 106 106 V -> E (in GSD9C).
FT /FTId=VAR_009517.
FT VARIANT 157 157 E -> K (in GSD9C).
FT /FTId=VAR_020854.
FT VARIANT 189 189 G -> E (in GSD9C).
FT /FTId=VAR_009518.
FT VARIANT 215 215 D -> N (in GSD9C).
FT /FTId=VAR_020855.
FT VARIANT 247 247 E -> G (in dbSNP:rs34006569).
FT /FTId=VAR_051658.
FT VARIANT 317 317 A -> T.
FT /FTId=VAR_040996.
FT CONFLICT 146 146 A -> P (in Ref. 6; AAA36518).
FT CONFLICT 176 176 C -> S (in Ref. 6; AAA36518).
FT CONFLICT 179 179 E -> D (in Ref. 6; AAA36518).
FT CONFLICT 212 214 KEV -> LVD (in Ref. 6; AAA36518).
FT CONFLICT 221 221 V -> E (in Ref. 6; AAA36518).
FT HELIX 13 23
FT STRAND 24 32
FT STRAND 34 43
FT TURN 44 46
FT STRAND 49 56
FT HELIX 64 84
FT STRAND 93 107
FT HELIX 115 122
FT HELIX 127 146
FT HELIX 156 158
FT STRAND 159 161
FT STRAND 167 169
FT HELIX 191 193
FT HELIX 196 201
FT HELIX 214 228
FT HELIX 238 247
FT HELIX 254 257
FT STRAND 258 260
FT HELIX 262 271
FT TURN 276 278
FT HELIX 282 287
FT HELIX 289 291
SQ SEQUENCE 406 AA; 46442 MW; E991CFF2D3D70F60 CRC64;
MTLDVGPEDE LPDWAAAKEF YQKYDPKDVI GRGVSSVVRR CVHRATGHEF AVKIMEVTAE
RLSPEQLEEV REATRRETHI LRQVAGHPHI ITLIDSYESS SFMFLVFDLM RKGELFDYLT
EKVALSEKET RSIMRSLLEA VSFLHANNIV HRDLKPENIL LDDNMQIRLS DFGFSCHLEP
GEKLRELCGT PGYLAPEILK CSMDETHPGY GKEVDLWACG VILFTLLAGS PPFWHRRQIL
MLRMIMEGQY QFSSPEWDDR SSTVKDLISR LLQVDPEARL TAEQALQHPF FERCEGSQPW
NLTPRQRFRV AVWTVLAAGR VALSTHRVRP LTKNALLRDP YALRSVRHLI DNCAFRLYGH
WVKKGEQQNR AALFQHRPPG PFPIMGPEEE GDSAAITEDE AVLVLG
//

MIM 172471
*RECORD*
*FIELD* NO
172471
*FIELD* TI
*172471 PHOSPHORYLASE KINASE, TESTIS/LIVER, GAMMA-2; PHKG2
*FIELD* TX

DESCRIPTION
read more
The PHKG2 gene encodes the hepatic and testis isoform of the gamma
subunit of phosphorylase kinase (PHK; EC 2.7.11.19). The skeletal muscle
isoform of the gamma subunit is encoded by the PHKG1 gene (172470).

CLONING

Whitmore et al. (1994) isolated a clone identified as the PHKG2 gene
from a heteronuclear cDNA library constructed from a mouse/human somatic
cell hybrid that contained chromosome 16. Most of the sequence showed
100% homology with the sequence of an isoform of a catalytic subunit of
phosphorylase kinase (Hanks, 1989).

GENE STRUCTURE

Burwinkel et al. (1998) determined that the PHKG2 gene contains 10 exons
and spans 9.5 kb. The positions of introns were highly conserved between
PHKG2 and PHKG1. The beginning of intron 2 harbors a highly polymorphic
GGT/GT microsatellite repeat.

MAPPING

Whitmore et al. (1994) mapped the PHKG2 gene to chromosome 16p12.1-p11.2
by use of a high-resolution somatic cell panel.

MOLECULAR GENETICS

Maichele et al. (1996) reported that autosomal liver-specific PHK
deficiency (glycogen storage disease IXc; GSD9C; 613027) was caused by
mutations in the PHKG2 gene. They found homozygous PHKG2 mutations in 3
patients of consanguineous parentage. One mutation was a single basepair
insertion in codon 89 that caused a frameshift and premature chain
termination (172471.0001). The 3 other mutations resulted in
nonconservative replacements of amino acid residues that are highly
conserved within the catalytic core regions of all protein kinases. The
findings suggested that the PHKG2 gene product is the predominant
isoform of catalytic gamma subunit of PHK not only in testis but also in
liver, erythrocytes, and possibly other nonmuscle tissues.

Burwinkel et al. (1998) identified homozygous translation-terminating
mutations in the PHKG2 gene, R442X (17241.0004) and 277delC
(172471.0005), in 2 patients with liver phosphorylase kinase deficiency
who developed cirrhosis in childhood. As liver phosphorylase kinase
deficiency is generally a benign condition and progression to cirrhosis
is very rare, the findings suggested to the authors that PHKG2 mutations
are particularly associated with an increased cirrhosis risk.

Burwinkel et al. (2000) reported compound heterozygosity for missense
mutations in the PHKG2 gene (172471.0006; 172471.0007) in a child with
phosphorylase kinase deficiency and cirrhosis.

ANIMAL MODEL

Malthus et al. (1980) described deficiency of liver phosphorylase kinase
in rats and concluded that it was an autosomal recessive trait. Apart
from hepatomegaly, the affected rats appear healthy. Clark and Haynes
(1988) described autosomal recessive glycogen storage disease in the rat
(gsd/gsd). Maichele et al. (1996) identified a homozygous mutation in
the rat Phkg2 gene (D215N) as responsible for the gsd phenotype in the
rat.

*FIELD* AV
.0001
GLYCOGEN STORAGE DISEASE IXc
PHKG2, 1-BP INS

In a Norwegian girl with autosomal recessive glycogen storage disease
IXc (613027) Sovik et al. (1982), Maichele et al. (1996) identified
homozygosity for a 1-bp insertion in codon 89 of the PHKG2 gene; the
resultant frameshift (after 22% of the normal length of the reading
frame) led to premature termination of the predicted polypeptide after
12 additional amino acids. The parents, who were fourth cousins, and a
sister were unaffected. She proband presented at 5 months of age, and
again at 3 years, with marked hepatomegaly, generalized muscular
hypotonia, growth retardation, elevated serum transaminases, and massive
liver glycogenosis. PHK activity was barely detectable in liver; in a
muscle biopsy, PHK activity was moderately reduced (35% of controls) but
muscle glycogen content was nevertheless low. No liver fibrosis was
observed. She attained a normal height of 172 cm at age 18, and menarche
was at age 17. The relative size of the liver gradually decreased, and
at age 18 serum activities of gamma-glutamyltransferase and alanine
aminotransferase were approaching normal ranges. Serum cholesterol was
normal, hypoglycemic symptoms were not noted, and body weight was
normal.

.0002
GLYCOGEN STORAGE DISEASE IXc
PHKG2, GLY189GLU

In a French girl with glycogen storage disease IXc (613027), whose
parents were first cousins, Maichele et al. (1996) identified
homozygosity for a G-to-A transition in the PHKG2 gene that led to a
gly189-to-glu (G189E) substitution. G189 is absolutely conserved between
the testicular and muscle forms of the gamma subunit of several species
and is never occupied by charged amino acids. The patient had been
hospitalized at 7 months of age because of hypoglycemic episodes and
pronounced hepatomegaly. Mild muscle hypotonia and retardation of growth
and motor development were also observed. Notable laboratory findings
were persistent hypoglycemia with acidosis, and elevated triglycerides
and transaminases. Liver histology revealed fine portal fibrosis.

.0003
GLYCOGEN STORAGE DISEASE IXc
PHKG2, VAL106GLU

In a Pakistani girl with glycogen storage disease IXc (613027), whose
parents were first cousins, Maichele et al. (1996) demonstrated
homozygosity for a val106-to-glu (V106E) missense mutation in the PHKG2
gene. The girl was admitted at the age of 15 months for investigation of
a distended abdomen due to hepatomegaly with no other clinical symptoms
except growth retardation. However, she had increased serum ALT and
triglycerides, increased liver glycogen, and severe fibrosis and
proliferation of bile ducts on liver biopsy.

.0004
GLYCOGEN STORAGE DISEASE IXc
PHKG2, ARG44TER

In a female with liver phosphorylase kinase deficiency and cirrhosis
(GSD9C; 612027), whose parents were consanguineous, Burwinkel et al.
(1998) found point mutations in the PHKG2 gene. One patient had a C-to-T
transition in exon 3, resulting in an arg44-to-ter (R44X) nonsense
mutation. In an earlier biochemical analysis of her family (Kagalwalla
et al., 1995), her father and 2 sibs had PHK activities in the
heterozygous range, whereas her mother had normal PHK activity in
repeated tests, so that a new maternal mutation was suspected in spite
of her parents' consanguinity. However, analysis of the parents' DNA
indicated that both were heterozygous for the nonsense mutation.

.0005
GLYCOGEN STORAGE DISEASE IXc
PHKG2, 1-BP DEL, 277C

In a female with deficiency of liver phosphorylase kinase and cirrhosis
(GSD9C; 613027) who had previously been described by Shiomi et al.
(1989), Burwinkel et al. (1998) identified deletion of a cytosine
residue in codon 93 (exon 4) of the PHKG2 gene, leading to a frameshift
after 23% of the coding sequence and termination of translation after 17
additional codons. The patient's parents were consanguineous.

.0006
GLYCOGEN STORAGE DISEASE IXc
PHKG2, HIS144TYR

In a male child of unrelated English parents with liver phosphorylase
kinase deficiency and cirrhosis (GSD9C; 613027), Burwinkel et al. (2000)
identified compound heterozygosity for 2 mutations in the PHKG2 gene: a
C-to-T transition resulting in a his144-to-tyr (H144Y) substitution,
which was inherited from his father, and a T-to-G transversion resulting
in a leu225-to-arg (L225R) substitution (172471.0007), which was
inherited from his mother.

.0007
GLYCOGEN STORAGE DISEASE IXc
PHKG2, LEU225ARG

See 172471.0006 and Burwinkel et al. (2000).

*FIELD* RF
1. Burwinkel, B.; Shiomi, S.; Al Zaben, A.; Kilimann, M. W.: Liver
glycogenosis due to phosphorylase kinase deficiency: PHKG2 gene structure
and mutations associated with cirrhosis. Hum. Molec. Genet. 7: 149-154,
1998.

2. Burwinkel, B.; Tanner, M. S.; Kilimann, M. W.: Phosphorylase kinase
deficient liver glycogenosis: progression to cirrhosis in infancy
associated with PHKG2 mutations (H144Y and L225R). (Letter) J. Med.
Genet. 37: 376-377, 2000.

3. Clark, D.; Haynes, D.: The glycogen storage disease (gsd/gsd)
rat. Curr. Top. Cell. Regul. 29: 217-263, 1988.

4. Hanks, S. K.: Messenger ribonucleic acid encoding an apparent
isoform of phosphorylase kinase catalytic subunit is abundant in the
adult testis. Molec. Endocr. 3: 110-116, 1989.

5. Kagalwalla, A. F.; Kagalwalla, Y. A.; al Ajaji, S.; Gorka, W.;
Ali, M. A.: Phosphorylase b kinase deficiency glycogenosis with cirrhosis
of the liver. J. Pediat. 127: 602-605, 1995.

6. Maichele, A. J.; Burwinkel, B.; Maire, I.; Sovik, O.; Kilimann,
M. W.: Mutations in the testis/liver isoform of the phosphorylase
kinase gamma subunit (PHKG2) cause autosomal liver glycogenosis in
the gsd rat and in humans. Nature Genet. 14: 337-340, 1996.

7. Malthus, R.; Clark, D. G.; Watts, C.; Sneyd, J. G. T.: Glycogen-storage
disease in rats, a genetically determined deficiency of liver phosphorylase
kinase. Biochem. J. 188: 99-106, 1980.

8. Shiomi, S.; Saeki, Y.; Kim. K.; Nishiguchi, S.; Seki, S.; Kuroki,
T.; Kobayashi, K.; Harihara, S.; Owada, M.: A female case of type
VIII glycogenosis who developed cirrhosis of the liver and hepatocellular
tumor. Gastroent. Jpn. 24: 711-714, 1989.

9. Sovik, O.; deBarsy, T.; Maehle, B.: Phosphorylase kinase deficiency:
severe glycogen storage disease with evidence of autosomal recessive
mode of inheritance. (Letter) Europ. J. Pediat. 139: 210 only, 1982.

10. Whitmore, S. A.; Apostolou, S.; Lane, S.; Nancarrow, J. K.; Phillips,
H. A.; Richards, R. I.; Sutherland, G. R.; Callen, D. F.: Isolation
and characterization of transcribed sequences from a chromosome 16
hn-cDNA library and the physical mapping of genes and transcribed
sequences using a high-resolution somatic cell panel of human chromosome
16. Genomics 20: 169-175, 1994.

*FIELD* CN
Cassandra L. Kniffin - updated: 9/24/2009
Michael J. Wright - updated: 7/20/2001
Victor A. McKusick - updated: 3/26/1998

*FIELD* CD
Victor A. McKusick: 4/4/1994

*FIELD* ED
ckniffin: 10/06/2009
carol: 10/1/2009
ckniffin: 9/24/2009
terry: 3/3/2009
carol: 1/6/2009
carol: 4/17/2007
mgross: 3/17/2004
alopez: 7/27/2001
terry: 7/20/2001
dkim: 7/7/1998
alopez: 3/26/1998
terry: 3/20/1998
jamie: 11/6/1996
terry: 10/31/1996
terry: 10/29/1996
carol: 4/4/1994

MIM 613027
*RECORD*
*FIELD* NO
613027
*FIELD* TI
#613027 GLYCOGEN STORAGE DISEASE IXc; GSD9C
;;GSD IXc
*FIELD* TX
A number sign (#) is used with this entry because glycogen storage
read moredisease IXc (GSD9C) is caused by mutation in the gene encoding the
hepatic isoform of the gamma unit of phosphorylase kinase (PHKG2;
172471).

For a general description and a discussion of genetic heterogeneity of
GSD IX (GSD9), see GSD IXa (306000).

DESCRIPTION

Glycogen storage disease IXc is characterized by onset in childhood of
hepatomegaly, hypotonia, growth retardation in childhood, and liver
dysfunction. These symptoms improve with age in most cases; however,
some patients may develop hepatic fibrosis or cirrhosis (Burwinkel et
al., 1998).

CLINICAL FEATURES

Lerner et al. (1982) described 3 sibs, a boy and 2 girls, with clinical,
laboratory, and morphologic findings suggestive of glycogen storage
disease IXa. However, the sibs in this study had an increased glycogen
content not only in the liver but also in muscle, and reduced
phosphorylase kinase activity in liver, muscle, erythrocytes, and
leukocytes. Lerner et al. (1982) labeled this condition glycogen storage
disease IXc.

Sovik et al. (1982) reported a Norwegian girl with autosomal recessive
GSD9C who was followed-up by Maichele et al. (1996). The parents, who
were fourth cousins, and a sister were unaffected. The proband presented
at 5 months of age, and again at 3 years, with marked hepatomegaly,
marked generalized muscular hypotonia, growth retardation, elevated
serum transaminases, and massive liver glycogenosis. PHK activity was
barely detectable in liver; in a muscle biopsy, PHK activity was
moderately reduced (35% of controls) but muscle glycogen content was
nevertheless low. No liver fibrosis was observed. During follow-up, she
presented fasting hypoglycemia which gradually subsided. Her growth and
development were markedly delayed, but she attained a normal height of
172 cm at age 18. Menarche was at age 17. The relative size of the liver
gradually decreased, and at age 18 serum transaminase activities were
approaching normal ranges. Serum cholesterol was normal and hypoglycemic
symptoms were not noted.

Maichele et al. (1996) reported a French girl with the disorder,
confirmed by genetic analysis (G189E; 172471.0002). She was hospitalized
at 7 months of age because of hypoglycemic episodes and pronounced
hepatomegaly. Mild muscle hypotonia and retardation of growth and motor
development were also observed. Notable laboratory findings were
persistent hypoglycemia with acidosis, and elevated triglycerides and
transaminases. Liver histology revealed fine portal fibrosis.

Maichele et al. (1996) described a Pakistani girl, whose parents were
first cousine, with glycogen storage disease IXc confirmed by genetic
analysis (V106E; 172471.0003). The girl was admitted at the age of 15
months for investigation of a distended abdomen due to hepatomegaly with
no other clinical symptoms except growth retardation. However, she had
increased serum ALT and triglycerides, increased liver glycogen, and
severe fibrosis and proliferation of bile ducts on liver biopsy.

Beauchamp et al. (2007) reported 2 unrelated Pakistani children with GSD
IXc1 confirmed by genetic analysis. Age at diagnosis was about 2 years.
Clinical features included hepatomegaly, splenomegaly, short stature in
childhood, liver dysfunction, hypoglycemia, lactic acidosis,
hyperlipidemia in 1, and fasting ketosis in the other. Muscle weakness
and fatigue were also noted. The authors emphasized that molecular
analysis results in accurate diagnosis for GSD9 when enzymology is
uninformative, and thus allows for proper genetic counseling.

MOLECULAR GENETICS

In 3 patients with GSD IXc, born of consanguineous parentage, Maichele
et al. (1996) found homozygous PHKG2 mutations
(172471.0001-172471.0003). One of the patients had been reported by
Sovik et al. (1982).

Burwinkel et al. (1998) identified homozygous translation-terminating
mutations in the PHKG2 gene, R442X (17241.0004) and 277delC
(172471.0005), in 2 patients with liver phosphorylase kinase deficiency
who developed cirrhosis in childhood. As liver phosphorylase kinase
deficiency is generally a benign condition and progression to cirrhosis
is very rare, the findings suggested to the authors that PHKG2 mutations
are particularly associated with an increased cirrhosis risk.

Burwinkel et al. (2000) reported compound heterozygosity for missense
mutations in the PHKG2 gene (172471.0006; 172471.0007) in a child with
GSD IXc.

ANIMAL MODEL

Malthus et al. (1980) described deficiency of liver phosphorylase kinase
in rats and concluded that it was an autosomal recessive trait. Apart
from hepatomegaly, the affected rats appear healthy. Clark and Haynes
(1988) described autosomal recessive glycogen storage disease in the rat
(gsd/gsd). Maichele et al. (1996) identified a homozygous mutation in
the rat Phkg2 gene (D215N) as responsible for the gsd phenotype in the
rat.

*FIELD* SA
Kagalwalla et al. (1995); Shiomi et al. (1989)
*FIELD* RF
1. Beauchamp, N. J.; Dalton, A.; Ramaswami, U.; Niinikoski, H.; Mention,
K.; Kenny, P.; Kolho, K.-L.; Raiman, J.; Walter, J.; Treacy, E.; Tanner,
S.; Sharrard, M.: Glycogen storage disease type IX: high variability
in clinical phenotype. Molec. Genet. Metab. 92: 88-99, 2007.

2. Burwinkel, B.; Shiomi, S.; Al Zaben, A.; Kilimann, M. W.: Liver
glycogenosis due to phosphorylase kinase deficiency: PHKG2 gene structure
and mutations associated with cirrhosis. Hum. Molec. Genet. 7: 149-154,
1998.

3. Burwinkel, B.; Tanner, M. S.; Kilimann, M. W.: Phosphorylase kinase
deficient liver glycogenosis: progression to cirrhosis in infancy
associated with PHKG2 mutations (H144Y and L225R). (Letter) J. Med.
Genet. 37: 376-377, 2000.

4. Clark, D.; Haynes, D.: The glycogen storage disease (gsd/gsd)
rat. Curr. Top. Cell. Regul. 29: 217-263, 1988.

5. Kagalwalla, A. F.; Kagalwalla, Y. A.; al Ajaji, S.; Gorka, W.;
Ali, M. A.: Phosphorylase b kinase deficiency glycogenosis with cirrhosis
of the liver. J. Pediat. 127: 602-605, 1995.

6. Lerner, A.; Iancu, T. C.; Bashan, N.; Potashnik, R.; Moses, S.
: A new variant of glycogen storage disease: type IXc. Am. J. Dis.
Child. 136: 406-410, 1982.

7. Maichele, A. J.; Burwinkel, B.; Maire, I.; Sovik, O.; Kilimann,
M. W.: Mutations in the testis/liver isoform of the phosphorylase
kinase gamma subunit (PHKG2) cause autosomal liver glycogenosis in
the gsd rat and in humans. Nature Genet. 14: 337-340, 1996.

8. Malthus, R.; Clark, D. G.; Watts, C.; Sneyd, J. G. T.: Glycogen-storage
disease in rats, a genetically determined deficiency of liver phosphorylase
kinase. Biochem. J. 188: 99-106, 1980.

9. Shiomi, S.; Saeki, Y.; Kim. K.; Nishiguchi, S.; Seki, S.; Kuroki,
T.; Kobayashi, K.; Harihara, S.; Owada, M.: A female case of type
VIII glycogenosis who developed cirrhosis of the liver and hepatocellular
tumor. Gastroent. Jpn. 24: 711-714, 1989.

10. Sovik, O.; deBarsy, T.; Maehle, B.: Phosphorylase kinase deficiency:
severe glycogen storage disease with evidence of autosomal recessive
mode of inheritance. (Letter) Europ. J. Pediat. 139: 210 only, 1982.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Height];
Growth retardation in childhood;
Normal final adult height

ABDOMEN:
[Liver];
Hepatomegaly;
Fibrosis;
Bile duct proliferation;
Cirrhosis;
Hepatic glycogen accumulation;
[Spleen];
Splenomegaly

MUSCLE, SOFT TISSUE:
Hypotonia

NEUROLOGIC:
[Central nervous system];
Mildly delayed motor development

LABORATORY ABNORMALITIES:
Fasting hypoglycemia;
Lactic acidosis;
Fasting ketosis;
Abnormal liver enzymes;
Increased serum triglycerides;
Decreased PHK activity in liver;
Moderately decreased to normal PHK activity in skeletal muscle

MISCELLANEOUS:
Onset in infancy or early childhood;
Clinical and biochemical abnormalities improve with age

MOLECULAR BASIS:
Caused by mutation in the testis/liver gamma-2 subunit of phosphorylase
kinase gene (PHKG2, 172471.0001)

*FIELD* CD
Cassandra L. Kniffin: 9/24/2009

*FIELD* ED
joanna: 03/28/2011
joanna: 1/14/2010
ckniffin: 9/24/2009

*FIELD* CD
Cassandra L. Kniffin: 9/23/2009

*FIELD* ED
carol: 12/01/2010
carol: 10/7/2010
ckniffin: 10/6/2009
carol: 10/1/2009
ckniffin: 9/24/2009