OMIA:000421-9615 : Glycogen storage disease VII in Canis lupus familiaris
Categories: Homeostasis / metabolism phene
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 232800 (trait) , 610681 (gene)
Links to MONDO diseases:
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 1996
Cross-species summary: Also known as Phosphofructokinase Deficiency
Species-specific description: Phosphofructokinase (PFK) deficiency is an inherited enzyme deficiency causing hemolytic crises and exertional myopathy. Genetic tests are available to detect causative mutations, which have beend identical in the English springer spaniel, American cocker spaniel, Whippet and Wachtelhund.
Edited by Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT and updated by IT [April 2022]
Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Smith et al. (1996) identified the causal mutation as "a nonsense mutation in the penultimate exon of the [muscle type phosphofructokinase] M-PFK gene [now called PFKM], leading to rapid degradation of a truncated (40 amino acids) and therefore unstable M-PFK protein". The single base pair mutation (G2228A) is identical in the English springer spaniel, American cocker spaniel and Whippet (Gerber et al., 2009).
Inal Gultekin et al. (2012) reported a different mutation (a point mutation (c.550C>T; p.Arg184Trp) in the same gene as being causative in Wachtelhund dogs.
Clinical features: Presenting signs include muscle cramps, exercise intolerance, and a mild increase in creatine kinase. Affected dogs can also present in hemolytic crisis with hemoglobinuria and bilirubinuria after excessive excitement, exercise, or hyperthermia. During a crisis, the dog can develop severe anemia, icterus, fever, lethargy, and anorexia. This anemia is regenerative, usually resolving within several days. Affected animals have a normal life span, usually maintaining a normal PCV but persistent bilirubinuria and reticulocytosis. Variable muscle wasting, hepatosplenomegaly, and increased total body iron stores have also been reported (Gerber et al., 2009).
Pathology: PFK, a cytosolic enzyme in the anaerobic pathway, is composed of three subunits: muscle (M-PFK), liver (L-PFK), and platelet (P-PFK) types. These subunits are present in different proportions in different tissues. Affected dogs lack PFK in skeletal muscle, and have only 20% of normal PFK activity in erythrocytes, which is from L-PFK and P-PFK expression (Gerber et al., 2009). Their PFK-deficient erythrocytes have hemoglobin with high oxygen affinity that helps to compensate for transient but severe anemic episodes (Skibild et al., 2001). Hemolytic crises in affected dogs are precipitated by hyperventilation, hyperthermia, and associated alkalemia, which induce intravascular hemolysis (Skibild et al., 2001).
Prevalence: Canine PFK deficiency has been reported in the USA, the UK, and Europe. Of 600 English Springer Spaniels screened in the USA, 14% were carriers and 6% were affected (Skibild, 2001).
Control: Dogs of breeds or families in which the disease has been reported should be tested prior to pursuing athletic work such as field trials.
Genetic testing: There is a PCR-based test available to detect the mutation in the English springer spaniel, American cocker spaniel and Whippet. A second mutation has been identified in Wachtelhund breed.
Breeds: American Cocker Spaniel, English Cocker Spaniel, Wachtelhund, Whippet.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|PFKM||phosphofructokinase, muscle||Canis lupus familiaris||27||NC_051831.1 (6732671..6687848)||PFKM||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|271||American Cocker Spaniel English Springer Spaniel Whippet||Glycogen storage disease VII||PFKM||nonsense (stop-gain)||Naturally occurring variant||CanFam3.1||27||g.6620819C>T||c.2228G>A||p.(W473*)||NM_001003199.1; NP_001003199.1||1996||8702726||Genomic and protein coordinates in CanFam3.1 provided by Robert Kuhn|
|45||Wachtelhund||Glycogen storage disease VII||PFKM||missense||Naturally occurring variant||CanFam3.1||27||g.6631627G>A||c.550C>T||p.(R184W)||NM_001003199.1; NP_001003199.1||2012||22446493||Genomic coordinates in CanFam3.1 provided by Robert Kuhn and Zoe Shmidt.|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2020||Almodóvar-Payá, A., Villarreal-Salazar, M., de Luna, N., Nogales-Gadea, G., Real-Martínez, A., Andreu, A.L., Martín, M.A., Arenas, J., Lucia, A., Vissing, J., Krag, T., Pinós, T. :|
|Preclinical research in glycogen storage diseases: A comprehensive review of current animal models. Int J Mol Sci 21:9621, 2020. Pubmed reference: 33348688 . DOI: 10.3390/ijms21249621.|
|2012||Inal Gultekin, G., Raj, K., Lehman, S., Hillström, A., Giger, U. :|
|Missense mutation in PFKM associated with muscle-type phosphofructokinase deficiency in the Wachtelhund dog. Mol Cell Probes 26:243-7, 2012. Pubmed reference: 22446493 . DOI: 10.1016/j.mcp.2012.02.004.|
|2011||Hillström, A., Tvedten, H., Rowe, A., Giger, U. :|
|Hereditary phosphofructokinase deficiency in wachtelhunds. J Am Anim Hosp Assoc 47:145-50, 2011. Pubmed reference: 21311071 . DOI: 10.5326/JAAHA-MS-5619.|
|2009||Gerber, K., Harvey, JW., D'Agorne, S., Wood, J., Giger, U. :|
|Hemolysis, myopathy, and cardiac disease associated with hereditary phosphofructokinase deficiency in two Whippets. Vet Clin Pathol 38:46-51, 2009. Pubmed reference: 19228357 . DOI: 10.1111/j.1939-165X.2008.00089.x.|
|2006||Harvey, J.W. :|
|Pathogenesis, laboratory diagnosis, and clinical implications of erythrocyte enzyme deficiencies in dogs, cats, and horses. Vet Clin Pathol 35:144-56, 2006. Pubmed reference: 16783707 .|
|2001||Skibild, E., Dahlgaard, K., Rajpurohit, Y., Smith, B.F., Giger, U. :|
|Haemolytic anaemia and exercise intolerance due to phosphofructokinase deficiency in related springer spaniels Journal of Small Animal Practice 42:298-300, 2001. Pubmed reference: 11440399 .|
|1999||McCully, K., Chance, B., Giger, U. :|
|In vivo determination of altered hemoglobin saturation in dogs with M-type phosphofructokinase deficiency Muscle & Nerve 22:621-627, 1999. Pubmed reference: 10331362 .|
|1996||Smith, B.F., Stedman, H., Rajpurohit, Y., Henthorn, P.S., Wolfe, J.H., Patterson, D.F., Giger, U. :|
|Molecular basis of canine muscle type phosphofructokinase deficiency Journal of Biological Chemistry 271:20070-20074, 1996. Pubmed reference: 8702726 .|
|Smith, B.F., Henthorn, P.S., Rajpurohit, Y., Stedman, H., Wolfe, J.H., Patterson, D.F., Giger, U. :|
|A cDNA encoding canine muscle-type phosphofructokinase. Gene 168:275-6, 1996. Pubmed reference: 8654960 .|
|1994||Brechue, W.F., Gropp, K.E., Ameredes, B.T., Odrobinak, D.M., Stainsby, W.N., Harvey, J.W. :|
|Metabolic and work capacity of skeletal muscle of PFK- deficient dogs studied in situ Journal of Applied Physiology 77:2456-2467, 1994. Pubmed reference: 7868469 .|
|Harvey, J.W., Smith, J.E. :|
|Haematology and Clinical Chemistry of English Springer Spaniel Dogs with Phosphofructokinase Deficiency Comparative Haematology International 4:70-75, 1994.|
|1992||Giger, U., Smith, B.F., Woods, C.B., Patterson, D.F., Stedman, H. :|
|Inherited Phosphofructokinase Deficiency in an American Cocker Spaniel Journal of the American Veterinary Medical Association 201:1569-1571, 1992. Pubmed reference: 1289336 .|
|Mhaskar, Y., Harvey, J.W., Dunaway, G.A. :|
|Developmental Changes of 6-Phosphofructo-1-Kinase Subunit Levels in Erythrocytes from Normal Dogs and Dogs Affected by Glycogen Storage Disease Type-VII Comparative Biochemistry and Physiology B - Comparative Biochemistry 101:303-307, 1992.|
|1991||Mhaskar, Y., Giger, U., Dunaway, G.A. :|
|Presence of a Truncated M-Type Subunit and Altered Kinetic Properties of 6-Phosphofructo-1-Kinase Isozymes in the Brain of a Dog Affected by Glycogen Storage Disease Type-VII Enzyme 45:137-144, 1991. Pubmed reference: 1840037 .|
|1990||Harvey, J.W., Mays, M.B.C., Gropp, K.E., Denaro, F.J. :|
|Polysaccharide Storage Myopathy in Canine Phosphofructokinase Deficiency (Type-VII Glycogen Storage Disease) Veterinary Pathology 27:1-8, 1990. Pubmed reference: 2137952 .|
|1988||Giger, U., Argov, Z., Schnall, M., Bank, W.J., Chance, B. :|
|Metabolic myopathy in canine muscle-type phosphofructokinase deficiency. Muscle Nerve 11:1260-5, 1988. Pubmed reference: 2976895 . DOI: 10.1002/mus.880111210.|
|1987||Giger, U., Harvey, J.W. :|
|Hemolysis caused by phosphofructokinase deficiency in English Springer Spaniels: seven cases Journal of the American Veterinary Medical Association 191:453-459, 1987. Pubmed reference: 2958437 .|
|Roudebush, P., Easley, J.R., Harvey, J.W. :|
|Nonspherocytic haemolytic anaemia due to phosphofructokinase deficiency in an English Springer Spaniel Journal of Small Animal Practice 28:513-516, 1987.|
|1986||Giger, U., Reilly, MP., Asakura, T., Baldwin, CJ., Harvey, JW. :|
|Autosomal recessive inherited phosphofructokinase deficiency in English springer spaniel dogs. Anim Genet 17:15-23, 1986. Pubmed reference: 2940948 .|
|1985||Giger, U., Harvey, JW., Yamaguchi, RA., McNulty, PK., Chiapella, A., Beutler, E. :|
|Inherited phosphofructokinase deficiency in dogs with hyperventilation-induced hemolysis: increased in vitro and in vivo alkaline fragility of erythrocytes. Blood 65:345-51, 1985. Pubmed reference: 3155631 .|
|Vora, S., Giger, U., Turchen, S., Harvey, JW. :|
|Characterization of the enzymatic lesion in inherited phosphofructokinase deficiency in the dog: an animal analogue of human glycogen storage disease type VII. Proc Natl Acad Sci U S A 82:8109-13, 1985. Pubmed reference: 2933748 .|
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