Alternative titles; symbols
HGNC Approved Gene Symbol: PFKM
SNOMEDCT: 89597008; ICD10CM: E74.09;
Cytogenetic location: 12q13.11 Genomic coordinates (GRCh38): 12:48,105,353-48,146,404 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.11 | Glycogen storage disease VII | 232800 | Autosomal recessive | 3 |
The PFKM gene encodes the muscle isoform of phosphofructokinase (PFK) (ATP:D-fructose-6-phosphate-1-phosphotransferase, EC 2.7.1.11). PFK catalyzes the irreversible conversion of fructose-6-phosphate to fructose-1,6-bisphosphate and is a key regulatory enzyme in glycolysis.
Mammalian PFK is a tetramer made up of various combinations of 3 subunits: muscle (PFKM), liver (PFKL; 171860), and platelet (PFKP; 171840), the genes for which are located on chromosomes 12q13, 21q22, and 10p, respectively. The composition of the tetramers differs according to the tissue type. Muscle and liver PFK are a homotetramers of 4M and 4L subunits, respectively. Erythrocytes contain both L and M subunits, which randomly tetramerize to form M4, L4, and M3L, M2L2, and ML3 hybrid forms of the holoenzyme (Vora et al., 1980; Raben and Sherman, 1995).
Layzer et al. (1969) demonstrated that PFK of muscle and erythrocyte are immunologically related but not identical. Layzer et al. (1967) suggested that red cell PFK is composed of 2 different subunits.
Nakajima et al. (1987) reported the cloning of a full-length cDNA corresponding to the human PFKM gene. The deduced 779-residue protein has a molecular mass of 85 kD and shares 95% homology with the rabbit protein.
Nakajima et al. (1990) found that the human PFKM gene encodes 3 different mRNAs, termed A (131 bp), B (220 bp), and C (54 bp). Type B is the major gene product and contains an extra noncoding sequence within the 5-prime untranslated region of type A mRNA. Types A and B share a common promoter and undergo alternative splicing, whereas type C appears to have a different promoter. Yamasaki et al. (1991) confirmed that the PFKM gene contains 2 promoters in the upstream regions of exons 1 and 2, respectively. Promoter 1 contains Sp1 (SP1; 189906)-binding sites and drives the transcription of type C mRNA; promoter 2 contains a TATA-box-like sequence and a CAAT-box-like sequence and drives the expression of types A and B mRNA.
Yamasaki et al. (1991) determined that the PFKM gene contains 24 exons and spans approximately 30 kb.
Yi et al. (2012) demonstrated that the dynamic posttranslational modification of proteins by O-linked beta-N-acetylglucosamine (O-GlcNAcylation) is a key metabolic regulator of glucose metabolism. O-GlcNAcylation was induced at ser529 of phosphofructokinase-1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway, thereby conferring a selective growth advantage on cancer cells. Blocking glycosylation of PFK1 at ser529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo.
Crystal Structure
Webb et al. (2015) reported the first structures of the mammalian PFK1 tetramer, for the human platelet isoform (PFKP), in complex with ATP-Mg(2+) and ADP at 3.1 and 3.4 angstroms, respectively. The structures revealed substantial conformational changes in the enzyme upon nucleotide hydrolysis as well as a unique tetramer interface. Mutations of residues in this interface can affect tetramer formation, enzyme catalysis, and regulation, indicating the functional importance of the tetramer. With altered glycolytic flux being a hallmark of cancers, these structures allowed a molecular understanding of the functional consequences of somatic PFK1 mutations identified in human cancers.
Using mouse/human somatic cell hybridization, Ashley et al. (1987) identified an expressed PFK gene on human chromosome 12, which turned out to represent PFKM (see HISTORY). The authors assigned the homologous mouse gene to chromosome 15 using a panel of hamster/mouse somatic cell hybrids.
By fluorescence in situ hybridization with a CEPH YAC, Howard et al. (1996) localized the PFKM gene to chromosome 12q13, centromeric to the diacylglycerol kinase gene (DGKA; 125855) at 12q13.3. A highly informative genetic marker isolated from the same YAC was used to map PFKM between markers D12S1090 and D12S390.
In 1 of the original Japanese patients with glycogen storage disease type VII (GSD7; 232800) reported by Tarui et al. (1965), Nakajima et al. (1990) identified a homozygous mutation in the PFKM gene (610681.0001).
In 2 Ashkenazi Jewish sisters with GSD VII, Raben et al. (1993) identified a homozygous splice site mutation in the PFKM gene resulting in the deletion of exon 5 (610681.0005). Sherman et al. (1994) identified the exon 5 deletion mutation in 11 (61%) of 18 abnormal alleles in 9 Ashkenazi Jewish families with GSD VII, making it as the most common PFKM mutation in this population.
Raben and Sherman (1995) tabulated 15 GSD VII disease-inducing mutations of the PFKM gene and several polymorphisms and noted that the disorder is especially prevalent among people of Ashkenazi Jewish descent. The authors found that the frequent exon 5 splicing defect accounted for approximately 68% of mutant alleles in Ashkenazim.
In 4 Italian patients, including 2 brothers, with GSD VII, Tsujino et al. (1994) identified 3 novel mutations in the PFKM gene (610681.0002-610681.0004). The authors emphasized that these patients were not of Ashkenazi Jewish descent.
In a 22-year-old Japanese man, born of consanguineous parents, with a mild form of GSD VII, Nakagawa et al. (1995) and Hamaguchi et al. (1996) identified a homozygous mutation in the PFKM gene (610681.0008).
Vora et al. (1982) originally assigned the PFKM gene to chromosome 1cen-q32 by somatic cell hybridization. Because of this assignment, Ashley et al. (1987) concluded that the PFK gene they identified on chromosome 12 was a different gene, which they termed 'PFKX.' With subsequent confirmation of the mapping of PFKM to chromosome 12 (Howard et al., 1996), it was determined that the 'PFKX' locus actually represents the PFKM locus.
In 1 of the original Japanese patients with glycogen storage disease type VII (GSD7; 232800) reported by Tarui et al. (1965), Nakajima et al. (1990) identified a G-to-T transversion at the 5-prime end of intron 13 of the PFKM gene, resulting in a splice site mutation and a 75-bp (25-residue) in-frame deletion in the 3-prime portion of exon 13. A cryptic splice site located 75 bases upstream from the normal splice site was identified. The mutation was predicted to result in drastic configurational changes in the protein, leading to loss of catalytic activity. Since the parents were consanguineous, Nakajima et al. (1990) assumed that the mutation was homozygous.
Nakajima (1997) noted that at the original publication of this mutation in 1990, only the rabbit gene was sequenced; therefore, the exon numbering followed that of rabbit Pfkm. Later studies by Yamasaki et al. (1991) determined the full genomic structure of the gene and showed that intron 15 is the appropriate numbering for this mutation.
In an Italian patient with glycogen storage disease VII (GSD7; 232800), Tsujino et al. (1994) identified a homozygous A-to-C transversion at the 3-prime end of intron 6 of the PFKM gene, resulting in a splicing defect. The mutation led to activation of 2 cryptic splice sites in exon 7, resulting in one 5 bp- and one 12 bp-deleted transcript. An affected brother was also homozygous, and both parents were heterozygous, for the splice junction mutation.
In an Italian patient with GSD VII (GSD7; 232800), born of consanguineous parents, Tsujino et al. (1994) identified a homozygous 116G-C transversion in the PFKM gene, resulting in an arg39-to-pro (R39P) substitution. The proband was a 35-year-old man who had complained since adolescence of exercise intolerance, exercise-related myalgia, and cramps, with a few episodes of myoglobinuria after intense exercise. He had first been seen by an internist for mild jaundice.
Bruno et al. (1998) described a 14-year-old boy with exercise-related myalgia and cramps who had had several episodes of myoglobinuria since early childhood. An episode at 2 years of age had caused acute renal failure. Histochemical and biochemical analysis of muscle showed a combined defect of phosphofructokinase and adenosine monophosphate deaminase-1 (AMPD1; 102770). DNA analysis showed that the patient was homozygous for the PFKM R39P substitution and also homozygous for a common mutation found in AMP deaminase deficiency (102770.0001); the latter mutation is found in homozygous state in about 2% of muscle biopsies.
Another pathogenic mutation in the PFKM gene has been described in the same codon (R39L; 610681.0006) (Sherman et al., 1994).
In an Italian patient with GSD VII (GSD7; 232800), Tsujino et al. (1994) identified compound heterozygosity for 2 mutations in the PFKM gene. One allele carried an A-to-C transversion in exon 18, resulting in an asp543-to-ala (D543A) substitution, and the other allele did not express the PFKM gene at all; however, sequencing of the reported regulatory region of the gene revealed no mutation. The proband was a 43-year-old man who had had difficulty keeping up with his peers in physical activities since childhood. At age 33, he developed proximal weakness, myalgia, and exercise intolerance. He was jaundiced, but because he had no signs of hemolysis, Gilbert syndrome (143500) had originally been diagnosed clinically.
In 2 Ashkenazi Jewish sisters with GSD VII (GSD7; 232800), Raben et al. (1993) identified a homozygous G-to-A transition at the 5-prime end of intron 5 of the PFKM gene, resulting in a splicing defect and an in-frame deletion of exon 5.
Sherman et al. (1994) identified this splice site mutation in 11 (61%) of 18 abnormal alleles in 9 Ashkenazi Jewish families with GSD VII, making it the most common PFKM mutation in this population.
Ristow et al. (1997) reported an Ashkenazi Jewish family in which a a father and son with GSD VII were compound heterozygous for 2 mutations in the PFKM gene: the common exon 5 deletion and a 1-bp deletion in exon 22 (610681.0010). The family had previously been reported by Vorgerd et al. (1996) and was unusual because 2 members in subsequent generations were affected.
In an Ashkenazi Jewish patient with GSD VII (GSD7; 232800), Sherman et al. (1994) identified compound heterozygosity for 2 mutations in the PFKM gene: a 116G-T transversion in exon 4 of the PFKM gene resulting in an arg39-to-leu (R39L) substitution and the common exon 5 deletion (610681.0005). Another pathogenic mutation in the PFKM gene has been described in the same codon (R39P; 610681.0003).
In 3 affected members of an Ashkenazi Jewish family with GSD VII (GSD7; 232800), Vasconcelos et al. (1995) identified a homozygous C-to-T transition in exon 6 of the PFKM gene, resulting in an arg95-to-ter (R95X) substitution. In addition, RT-PCR studies identified an unusual transcript resulting from a 252-bp insertion corresponding to intron 10, which the authors postulated resulted from differential pre-mRNA processing. The R95X substitution was considered to be solely responsible for the disease phenotype. The family showed pseudodominance: an affected woman married to her uncle had 2 affected daughters. She herself was the product of a first-cousin marriage.
In a 22-year-old Japanese man, born of consanguineous parents, with a mild form of GSD VII (GSD7; 232800), Nakagawa et al. (1995) and Hamaguchi et al. (1996) identified a homozygous 2058G-T transversion in exon 22 of the PFKM gene, resulting in a trp686-to-cys (W686C) substitution. The patient was a 22-year-old man with gastric ulcer, gouty arthritis, and compensated hemolysis. An episodic increase in serum creatine kinase after exercising was detected. Although he did not experience muscle pain or cramps, PFK activity in a skeletal muscle specimen was approximately 1% of normal.
In Ashkenazi Jewish patients with GSD VII (GSD7; 232800), Sherman et al. (1994) identified a 1-bp deletion (2003delC) in exon 22 of the PFKM gene, resulting in a frameshift and a truncated PFKM protein with 16 altered amino acids at the C terminus. Two patients were homozygous for the mutation and 2 were compound heterozygous for the deletion and another pathogenic mutation.
Ristow et al. (1997) identified the 1-bp deletion in compound heterozygosity with the common exon 5 deletion (610681.0005) in an Ashkenazi Jewish father and son with GSD VII. The family had previously been reported by Vorgerd et al. (1996) and was unusual because 2 members in subsequent generations were affected.
Ashley, P. L., Price, E. R., Lebo, R. V., Cox, D. R. An expressed phosphofructokinase gene (PFKX) maps to human chromosome 12 and mouse chromosome 15. (Abstract) Cytogenet. Cell Genet. 46: 573 only, 1987.
Bruno, C., Minetti, C., Shanske, S., Morreale, G., Bado, M., Cordone, G., DiMauro, S. Combined defects of muscle phosphofructokinase and AMP deaminase in a child with myoglobinuria. Neurology 50: 296-298, 1998. [PubMed: 9443500] [Full Text: https://doi.org/10.1212/wnl.50.1.296]
Hamaguchi, T., Nakajima, H., Noguchi, T., Nakagawa, C., Kuwajima, M., Kono, N., Tarui, S., Matsuzawa, Y. Novel missense mutation (W686C) of the phosphofructokinase-M gene in a Japanese patient with a mild form of glycogenosis VII. Hum. Mutat. 8: 273-275, 1996. [PubMed: 8889589] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1996)8:3<273::AID-HUMU13>3.0.CO;2-#]
Howard, T. D., Akots, G., Bowden, D. W. Physical and genetic mapping of the muscle phosphofructokinase gene (PFKM): reassignment to human chromosome 12q. Genomics 34: 122-127, 1996. [PubMed: 8661033] [Full Text: https://doi.org/10.1006/geno.1996.0250]
Layzer, R. B., Rowland, L. P., Bank, W. J. Physical and kinetic properties of human phosphofructokinase from skeletal muscle and erythrocytes. J. Biol. Chem. 244: 3823-3831, 1969. [PubMed: 4241008]
Layzer, R. B., Rowland, L. P., Ranney, H. M. Muscle phosphofructokinase deficiency. Arch. Neurol. 17: 512-523, 1967. [PubMed: 4228297] [Full Text: https://doi.org/10.1001/archneur.1967.00470290066009]
Nakagawa, C., Mineo, I., Kaido, M., Fujimura, H., Shimizu, T., Hamaguchi, T., Nakajima, H., Tarui, S. A new variant case of muscle phosphofructokinase deficiency, coexisting with gastric ulcer, gouty arthritis, and increased hemolysis. Muscle Nerve Suppl. 3: S39-S44, 1995. [PubMed: 7603526] [Full Text: https://doi.org/10.1002/mus.880181410]
Nakajima, H. Personal Communication. Osaka, Japan 6/15/1997.
Nakajima, H., Kono, N., Yamasaki, T., Hotta, K., Kawachi, M., Kuwajima, M., Noguchi, T., Tanaka, T., Tarui, S. Genetic defect in muscle phosphofructokinase deficiency: abnormal splicing of the muscle phosphofructokinase gene due to a point mutation at the 5-prime-splice site. J. Biol. Chem. 265: 9392-9395, 1990. [PubMed: 2140573]
Nakajima, H., Noguchi, T., Yamasaki, T., Kono, N., Tanaka, T., Tarui, S. Cloning of human muscle phosphofructokinase cDNA. FEBS Lett. 223: 113-116, 1987. [PubMed: 2822475] [Full Text: https://doi.org/10.1016/0014-5793(87)80519-7]
Nakajima, H., Yamasaki, T., Noguchi, T., Tanaka, T., Kono, N., Tarui, S. Evidence for alternative RNA splicing and possible alternative promoters in the human muscle phosphofructokinase gene at the 5-prime untranslated region. Biochem. Biophys. Res. Commun. 166: 637-641, 1990. [PubMed: 2137340] [Full Text: https://doi.org/10.1016/0006-291x(90)90856-i]
Raben, N., Sherman, J., Miller, F., Mena, H., Plotz, P. A 5-prime splice junction mutation leading to exon deletion in an Ashkenazic Jewish family with phosphofructokinase deficiency (Tarui disease). J. Biol. Chem. 268: 4963-4967, 1993. [PubMed: 8444874]
Raben, N., Sherman, J. B. Mutations in muscle phosphofructokinase gene. Hum. Mutat. 6: 1-6, 1995. [PubMed: 7550225] [Full Text: https://doi.org/10.1002/humu.1380060102]
Ristow, M., Vorgerd, M., Mohlig, M., Schatz, H., Pfeiffer, A. Deficiency of phosphofructo-1-kinase/muscle subtype in humans impairs insulin secretion and causes insulin resistance. J. Clin. Invest. 100: 2833-2841, 1997. [PubMed: 9389749] [Full Text: https://doi.org/10.1172/JCI119831]
Sherman, J. B., Raben, N., Nicastri, C., Argov, Z., Nakajima, H., Adams, E. M., Eng, C. M., Cowan, T. M., Plotz, P. H. Common mutations in the phosphofructokinase-M gene in Ashkenazi Jewish patients with glycogenesis (sic) VII--and their population frequency. Am. J. Hum. Genet. 55: 305-313, 1994. [PubMed: 8037209]
Tarui, S., Okuno, G., Ikura, Y., Tanaka, T., Suda, M., Nishikawa, M. Phosphofructokinase deficiency in skeletal muscle: a new type of glycogenosis. Biochem. Biophys. Res. Commun. 19: 517-523, 1965. [PubMed: 14339001] [Full Text: https://doi.org/10.1016/0006-291x(65)90156-7]
Tsujino, S., Servidei, S., Tonin, P., Shanske, S., Azan, G., DiMauro, S. Identification of three novel mutations in non-Ashkenazi Italian patients with muscle phosphofructokinase deficiency. Am. J. Hum. Genet. 54: 812-819, 1994. [PubMed: 7513946]
Vasconcelos, O., Sivakumar, K., Dalakas, M. C., Quezado, M., Nagle, J., Leon-Monzon, M., Dubnick, M., Gajdusek, D. C., Goldfarb, L. G. Nonsense mutation in the phosphofructokinase muscle subunit gene associated with retention of intron 10 in one of the isolated transcripts in Ashkenazi Jewish patients with Tarui disease. Proc. Nat. Acad. Sci. 92: 10322-10326, 1995. [PubMed: 7479776] [Full Text: https://doi.org/10.1073/pnas.92.22.10322]
Vora, S., Durham, S., de Martinville, B., Francke, U. Assignment of the human gene for muscle-type phosphofructokinase (PFKM) to chromosome 1 (region cen-q32) using somatic cell hybrids and monoclonal anti-M antibody. Somat. Cell Genet. 8: 95-104, 1982. [PubMed: 6213050] [Full Text: https://doi.org/10.1007/BF01538653]
Vora, S., Seaman, C., Durham, S., Piomelli, S. Isozymes of human phosphofructokinase: identification and subunit structural characterization of a new system. Proc. Nat. Acad. Sci. 77: 62-66, 1980. [PubMed: 6444721] [Full Text: https://doi.org/10.1073/pnas.77.1.62]
Vorgerd, M., Karitzky, J., Ristow, M., Van Schaftingen, E., Tegenthoff, M., Jerusalem, F., Malin, J. P. Muscle phosphofructokinase deficiency in two generations. J. Neurol. Sci. 141: 95-99, 1996. [PubMed: 8880699] [Full Text: https://doi.org/10.1016/0022-510x(96)00131-1]
Webb, B. A., Forouhar, F., Szu, F.-E., Seetharaman, J., Tong, L., Barber, D. L. Structures of human phosphofructokinase-1 and atomic basis of cancer-associated mutations. Nature 523: 111-114, 2015. [PubMed: 25985179] [Full Text: https://doi.org/10.1038/nature14405]
Yamasaki,, Nakajima, H., Kono, N., Hotta, K., Yamada, K., Imai, E., Kuwajima, M., Noguchi, T., Tanaka, T., Tarui, S. Structure of the entire human muscle phosphofructokinase-encoding gene: a two-promoter system. Gene 104: 277-282, 1991. [PubMed: 1833270] [Full Text: https://doi.org/10.1016/0378-1119(91)90262-a]
Yi, W., Clark, P. M., Mason, D. E., Keenan, M. C., Hill, C., Goddard, W. A., III, Peters, E. C., Driggers, E. M., Hsieh-Wilson, L. C. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 337: 975-980, 2012. [PubMed: 22923583] [Full Text: https://doi.org/10.1126/science.1222278]