FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / Mamm Genome / Glycogen branching enzyme (GBE1) mutation causing equine gly...
Mammalian genome : official journal of the International Mammalian Genome Society2004; 15(7); 570-577; doi: 10.1007/s00335-004-2369-1

Glycogen branching enzyme (GBE1) mutation causing equine glycogen storage disease IV.

Abstract: Comparative biochemical and histopathological evidence suggests that a deficiency in the glycogen branching enzyme, encoded by the GBE1 gene, is responsible for a recently identified recessive fatal fetal and neonatal glycogen storage disease (GSD) in American Quarter Horses termed GSD IV. We have now derived the complete GBE1 cDNA sequences for control horses and affected foals, and identified a C to A substitution at base 102 that results in a tyrosine (Y) to stop (X) mutation in codon 34 of exon 1. All 11 affected foals were homozygous for the X34 allele, their 11 available dams and sires were heterozygous, and all 16 control horses were homozygous for the Y34 allele. The previous findings of poorly branched glycogen, abnormal polysaccharide accumulation, lack of measurable GBE1 enzyme activity and immunodetectable GBE1 protein, coupled with the present observation of abundant GBE1 mRNA in affected foals, are all consistent with the nonsense mutation in the 699 amino acid GBE1 protein. The affected foal pedigrees have a common ancestor and contain prolific stallions that are likely carriers of the recessive X34 allele. Defining the molecular basis of equine GSD IV will allow for accurate DNA testing and the ability to prevent occurrence of this devastating disease affecting American Quarter Horses and related breeds.
Get Full Text
Publication Date: 2004-09-16 PubMed ID: 15366377DOI: 10.1007/s00335-004-2369-1Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research reveals that a specific mutation in the glycogen branching enzyme gene (GBE1) is the cause of a fatal glycogen storage disease (GSD IV) in American Quarter Horses. This information will support accurate DNA testing and disease prevention measures.

Background

  • Glycogen storage disease IV (GSD IV) is a fatal genetic disorder observed in newborn foals, specifically in a breed known as the American Quarter Horses.
  • The illness is associated with difficulties in digesting glycogen, a primary source of energy for the body, due to the lack of an enzyme named glycogen branching enzyme (GBE1).

Findings

  • The research team analyzed the complete GBE1 gene sequences of both healthy and affected foals.
  • They found a mutation in the gene, specifically a C to A substitution at base 102. This alteration caused a codon to switch from tyrosine (Y) to stop (X) in position 34 of exon 1, resulting in the production of a non-working protein, which explained the foals’ inability to produce the crucial GBE1 enzyme.
  • All affected foals had two copies of the faulty gene (homozygous for the X34 allele), which is necessary for the disease to manifest. Both parents (the dams and sires) carried one copy of the faulty gene and one normal gene, making them carriers (heterozygous) without showing signs of the disease. The normal horses were homozygous for the Y34 allele (or they have two normal genes).
  • They observed lack of measurable GBE1 enzyme activity and proper protein, presence of poorly branched glycogen and abnormal polysaccharide accumulation. These findings were consistent with the identified mutation in the protein sequence.

Implications and Future Directions

  • The research highlights that the mutation in the GBE1 gene is what leads to GSD IV in American Quarter Horses, providing a clear molecular basis for the disease.
  • The finding can now be used as the basis for accurate DNA testing to identify carriers and affected foals.
  • Ultimately, this discovery paves the way for the development of preventative measures and possible treatments to combat this devastating disease in horses.

Cite This Article

APA
Ward TL, Valberg SJ, Adelson DL, Abbey CA, Binns MM, Mickelson JR. (2004). Glycogen branching enzyme (GBE1) mutation causing equine glycogen storage disease IV. Mamm Genome, 15(7), 570-577. https://doi.org/10.1007/s00335-004-2369-1

Publication

Mammalian genome : official journal of the International Mammalian Genome Society
ISSN: 0938-8990
NlmUniqueID: 9100916
Country: United States
Language: English
Volume: 15
Issue: 7
Pages: 570-577

Researcher Affiliations

Ward, Tara L
  • Department of Veterinary PathoBiology, College of Veterinary Medicine, University of Minnesota, 295 AS/VM, 1988 Fitch Ave., St. Paul, Minnesota 55108-6009, USA.
Valberg, Stephanie J
    Adelson, David L
      Abbey, Colette A
        Binns, Matthew M
          Mickelson, James R

            MeSH Terms

            • 1,4-alpha-Glucan Branching Enzyme / genetics
            • Alleles
            • Animals
            • Base Sequence
            • Codon
            • Codon, Terminator
            • DNA / chemistry
            • DNA Mutational Analysis
            • DNA, Complementary / metabolism
            • Exons
            • Genes, Recessive
            • Genotype
            • Glycogen Storage Disease Type IV / genetics
            • Homozygote
            • Horses
            • Humans
            • Molecular Sequence Data
            • Mutation
            • Polysaccharides
            • RNA, Messenger / metabolism
            • Reverse Transcriptase Polymerase Chain Reaction
            • Tyrosine / chemistry

            References

            This article includes 20 references
            1. Render JA, Common RS, Kennedy FA, Jones MZ, Fyfe JC. Amylopectinosis in fetal and neonatal Quarter Horses.. Vet Pathol 1999 Mar;36(2):157-60.
              pubmed: 10098645doi: 10.1354/vp.36-2-157google scholar: lookup
            2. Valberg SJ, Ward TL, Rush B, Kinde H, Hiraragi H, Nahey D, Fyfe J, Mickelson JR. Glycogen branching enzyme deficiency in quarter horse foals.. J Vet Intern Med 2001 Nov-Dec;15(6):572-80.
              pubmed: 11817063doi: 10.1892/0891-6640(2001)015<0572:gbediq>2.3.co;2google scholar: lookup
            3. Bruno C, Servidei S, Shanske S, Karpati G, Carpenter S, McKee D, Barohn RJ, Hirano M, Rifai Z, DiMauro S. Glycogen branching enzyme deficiency in adult polyglucosan body disease.. Ann Neurol 1993 Jan;33(1):88-93.
              pubmed: 8494336doi: 10.1002/ana.410330114google scholar: lookup
            4. Santschi EM, Purdy AK, Valberg SJ, Vrotsos PD, Kaese H, Mickelson JR. Endothelin receptor B polymorphism associated with lethal white foal syndrome in horses.. Mamm Genome 1998 Apr;9(4):306-9.
              pubmed: 9530628doi: 10.1007/s003359900754google scholar: lookup
            5. Brown BI, Brown DH. Lack of an alpha-1,4-glucan: alpha-1,4-glucan 6-glycosyl transferase in a case of type IV glycogenosis.. Proc Natl Acad Sci U S A 1966 Aug;56(2):725-9.
              pubmed: 5229990doi: 10.1073/pnas.56.2.725google scholar: lookup
            6. Fyfe JC, Giger U, Van Winkle TJ, Haskins ME, Steinberg SA, Wang P, Patterson DF. Glycogen storage disease type IV: inherited deficiency of branching enzyme activity in cats.. Pediatr Res 1992 Dec;32(6):719-25.
              pubmed: 1337588doi: 10.1203/00006450-199212000-00020google scholar: lookup
            7. Shin EK, Perryman LE, Meek K. A kinase-negative mutation of DNA-PK(CS) in equine SCID results in defective coding and signal joint formation.. J Immunol 1997 Apr 15;158(8):3565-9.
              pubmed: 9103416
            8. Spirito F, Charlesworth A, Linder K, Ortonne JP, Baird J, Meneguzzi G. Animal models for skin blistering conditions: absence of laminin 5 causes hereditary junctional mechanobullous disease in the Belgian horse.. J Invest Dermatol 2002 Sep;119(3):684-91.
              pubmed: 12230513doi: 10.1046/j.1523-1747.2002.01852.xgoogle scholar: lookup
            9. Mercier C, Whelan WJ. Further characterization of glycogen from type-IV glycogen-storage disease.. Eur J Biochem 1973 Dec 3;40(1):221-3.
              pubmed: 4520957doi: 10.1111/j.1432-1033.1973.tb03189.xgoogle scholar: lookup
            10. ANDERSEN DH. Familial cirrhosis of the liver with storage of abnormal glycogen.. Lab Invest 1956 Jan-Feb;5(1):11-20.
              pubmed: 13279125
            11. Pellissier JF, de Barsy T, Bille J, Serratrice G, Toga M. Polysaccharide (amylopectin-like) storage myopathy histochemical ultrastructural and biochemical studies.. Acta Neuropathol Suppl 1981;7:292-6.
              pubmed: 6939255doi: 10.1007/978-3-642-81553-9_84google scholar: lookup
            12. Rudolph JA, Spier SJ, Byrns G, Rojas CV, Bernoco D, Hoffman EP. Periodic paralysis in quarter horses: a sodium channel mutation disseminated by selective breeding.. Nat Genet 1992 Oct;2(2):144-7.
              pubmed: 1338908doi: 10.1038/ng1092-144google scholar: lookup
            13. Moses SW, Parvari R. The variable presentations of glycogen storage disease type IV: a review of clinical, enzymatic and molecular studies.. Curr Mol Med 2002 Mar;2(2):177-88.
              pubmed: 11949934doi: 10.2174/1566524024605815google scholar: lookup
            14. DiMauro S, Lamperti C. Muscle glycogenoses.. Muscle Nerve 2001 Aug;24(8):984-99.
              pubmed: 11439374doi: 10.1002/mus.1103google scholar: lookup
            15. Thon VJ, Khalil M, Cannon JF. Isolation of human glycogen branching enzyme cDNAs by screening complementation in yeast.. J Biol Chem 1993 Apr 5;268(10):7509-13.
              pubmed: 8463281
            16. Ward TL, Valberg SJ, Lear TL, Guérin G, Milenkovic D, Swinburne JE, Binns MM, Raudsepp T, Skow L, Chowdhary BP, Mickelson JR. Genetic mapping of GBE1 and its association with glycogen storage disease IV in American Quarter horses.. Cytogenet Genome Res 2003;102(1-4):201-6.
              pubmed: 14970703doi: 10.1159/000075749google scholar: lookup
            17. de La Blanchardière A, Vayssier C, Duboc D, Jacquemin IE, Eymard B, Fardeau M, Maire I, Dreyfus G, Guérin F. [Severe cardiomyopathy revealing amylopectinosis. Two cases in adolescents from the same family].. Presse Med 1994 Jun 25;23(24):1124-7.
              pubmed: 7971833
            18. Servidei S, Riepe RE, Langston C, Tani LY, Bricker JT, Crisp-Lindgren N, Travers H, Armstrong D, DiMauro S. Severe cardiopathy in branching enzyme deficiency.. J Pediatr 1987 Jul;111(1):51-6.
              pubmed: 3474393doi: 10.1016/s0022-3476(87)80341-4google scholar: lookup
            19. Greene GM, Weldon DC, Ferrans VJ, Cheatham JP, McComb RD, Brown BI, Gumbiner CH, Vanderhoof JA, Itkin PG, McManus BM. Juvenile polysaccharidosis with cardioskeletal myopathy.. Arch Pathol Lab Med 1987 Oct;111(10):977-82.
              pubmed: 2957974
            20. Bao Y, Kishnani P, Wu JY, Chen YT. Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene.. J Clin Invest 1996 Feb 15;97(4):941-8.
              pubmed: 8613547doi: 10.1172/JCI118517google scholar: lookup

            Citations

            This article has been cited 24 times.
            1. Neumann GB, Korkuć P, Arends D, Wolf MJ, May K, König S, Brockmann GA. Genomic diversity and relationship analyses of endangered German Black Pied cattle (DSN) to 68 other taurine breeds based on whole-genome sequencing. Front Genet 2022;13:993959.
              doi: 10.3389/fgene.2022.993959pubmed: 36712857google scholar: lookup
            2. He S, Yan L, Zhu R, Wei H, Wang J, Zheng L, Zhang Y. Skeletal-Muscle-Specific Overexpression of Chrono Leads to Disruption of Glucose Metabolism and Exercise Capacity. Life (Basel) 2022 Aug 15;12(8).
              doi: 10.3390/life12081233pubmed: 36013411google scholar: lookup
            3. Ravi M, Lacson A, Pybus M, Ball MC. Lafora Disease and Alpha-Synucleinopathy in Two Adult Free-Ranging Moose (Alces alces) Presenting with Signs of Blindness and Circling. Animals (Basel) 2022 Jun 25;12(13).
              doi: 10.3390/ani12131633pubmed: 35804532google scholar: lookup
            4. Valberg SJ, Henry ML, Herrick KL, Velez-Irizarry D, Finno CJ, Petersen JL. Absence of myofibrillar myopathy in Quarter Horses with a histopathological diagnosis of type 2 polysaccharide storage myopathy and lack of association with commercial genetic tests. Equine Vet J 2023 Mar;55(2):230-238.
              doi: 10.1111/evj.13574pubmed: 35288976google scholar: lookup
            5. Durward-Akhurst SA, Schaefer RJ, Grantham B, Carey WK, Mickelson JR, McCue ME. Genetic Variation and the Distribution of Variant Types in the Horse. Front Genet 2021;12:758366.
              doi: 10.3389/fgene.2021.758366pubmed: 34925451google scholar: lookup
            6. Derks TGJ, Peeks F, de Boer F, Fokkert-Wilts M, van der Doef HPJ, van den Heuvel MC, Szymańska E, Rokicki D, Ryan PT, Weinstein DA. The potential of dietary treatment in patients with glycogen storage disease type IV. J Inherit Metab Dis 2021 May;44(3):693-704.
              doi: 10.1002/jimd.12339pubmed: 33332610google scholar: lookup
            7. Valberg SJ, Finno CJ, Henry ML, Schott M, Velez-Irizarry D, Peng S, McKenzie EC, Petersen JL. Commercial genetic testing for type 2 polysaccharide storage myopathy and myofibrillar myopathy does not correspond to a histopathological diagnosis. Equine Vet J 2021 Jul;53(4):690-700.
              doi: 10.1111/evj.13345pubmed: 32896939google scholar: lookup
            8. Williams ZJ, Velez-Irizarry D, Petersen JL, Ochala J, Finno CJ, Valberg SJ. Candidate gene expression and coding sequence variants in Warmblood horses with myofibrillar myopathy. Equine Vet J 2021 Mar;53(2):306-315.
              doi: 10.1111/evj.13286pubmed: 32453872google scholar: lookup
            9. Pinzon-Arteaga C, Snyder MD, Lazzarotto CR, Moreno NF, Juras R, Raudsepp T, Golding MC, Varner DD, Long CR. Efficient correction of a deleterious point mutation in primary horse fibroblasts with CRISPR-Cas9. Sci Rep 2020 May 4;10(1):7411.
              doi: 10.1038/s41598-020-62723-3pubmed: 32366884google scholar: lookup
            10. Corley KTT. Metabolic disorders in foals. Equine Vet Educ 2012 Aug;24(8):392-395.
              doi: 10.1111/j.2042-3292.2011.00376.xpubmed: 32313388google scholar: lookup
            11. Aleman M, Costa LRR, Crowe C, Kass PH. Presumed Neuroglycopenia Caused by Severe Hypoglycemia in Horses. J Vet Intern Med 2018 Sep;32(5):1731-1739.
              doi: 10.1111/jvim.15245pubmed: 30084236google scholar: lookup
            12. Hoff JL, Decker JE, Schnabel RD, Taylor JF. Candidate lethal haplotypes and causal mutations in Angus cattle. BMC Genomics 2017 Oct 18;18(1):799.
              doi: 10.1186/s12864-017-4196-2pubmed: 29047335google scholar: lookup
            13. Shinde V, Hoelting L, Srinivasan SP, Meisig J, Meganathan K, Jagtap S, Grinberg M, Liebing J, Bluethgen N, Rahnenführer J, Rempel E, Stoeber R, Schildknecht S, Förster S, Godoy P, van Thriel C, Gaspar JA, Hescheler J, Waldmann T, Hengstler JG, Leist M, Sachinidis A. Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Tox(ukn) and STOP-Tox(ukk) tests. Arch Toxicol 2017 Feb;91(2):839-864.
              doi: 10.1007/s00204-016-1741-8pubmed: 27188386google scholar: lookup
            14. Zmasek CM, Godzik A. Phylogenomic analysis of glycogen branching and debranching enzymatic duo. BMC Evol Biol 2014 Aug 23;14:183.
              doi: 10.1186/s12862-014-0183-2pubmed: 25148856google scholar: lookup
            15. Metzger J, Tonda R, Beltran S, Agueda L, Gut M, Distl O. Next generation sequencing gives an insight into the characteristics of highly selected breeds versus non-breed horses in the course of domestication. BMC Genomics 2014 Jul 4;15(1):562.
              doi: 10.1186/1471-2164-15-562pubmed: 24996778google scholar: lookup
            16. Gazzerro E, Andreu AL, Bruno C. Neuromuscular disorders of glycogen metabolism. Curr Neurol Neurosci Rep 2013 Mar;13(3):333.
              doi: 10.1007/s11910-012-0333-0pubmed: 23335027google scholar: lookup
            17. Doan R, Cohen ND, Sawyer J, Ghaffari N, Johnson CD, Dindot SV. Whole-genome sequencing and genetic variant analysis of a Quarter Horse mare. BMC Genomics 2012 Feb 17;13:78.
              doi: 10.1186/1471-2164-13-78pubmed: 22340285google scholar: lookup
            18. Brosnahan MM, Brooks SA, Antczak DF. Equine clinical genomics: A clinician's primer. Equine Vet J 2010 Oct;42(7):658-70.
              doi: 10.1111/j.2042-3306.2010.00166.xpubmed: 20840582google scholar: lookup
            19. Barrey E, Mucher E, Jeansoule N, Larcher T, Guigand L, Herszberg B, Chaffaux S, Guérin G, Mata X, Benech P, Canale M, Alibert O, Maltere P, Gidrol X. Gene expression profiling in equine polysaccharide storage myopathy revealed inflammation, glycogenesis inhibition, hypoxia and mitochondrial dysfunctions. BMC Vet Res 2009 Aug 7;5:29.
              doi: 10.1186/1746-6148-5-29pubmed: 19664222google scholar: lookup
            20. Bruno C, Cassandrini D, Assereto S, Akman HO, Minetti C, Di Mauro S. Neuromuscular forms of glycogen branching enzyme deficiency. Acta Myol 2007 Jul;26(1):75-8.
              pubmed: 17915577
            21. Fyfe JC, Kurzhals RL, Hawkins MG, Wang P, Yuhki N, Giger U, Van Winkle TJ, Haskins ME, Patterson DF, Henthorn PS. A complex rearrangement in GBE1 causes both perinatal hypoglycemic collapse and late-juvenile-onset neuromuscular degeneration in glycogen storage disease type IV of Norwegian forest cats. Mol Genet Metab 2007 Apr;90(4):383-92.
              doi: 10.1016/j.ymgme.2006.12.003pubmed: 17257876google scholar: lookup
            22. Durward-Akhurst SA, Marlowe JL, Schaefer RJ, Springer K, Grantham B, Carey WK, Bellone RR, Mickelson JR, McCue ME. Predicted genetic burden and frequency of phenotype-associated variants in the horse. Sci Rep 2024 Apr 10;14(1):8396.
              doi: 10.1038/s41598-024-57872-8pubmed: 38600096google scholar: lookup
            23. De Coster T, Zhao Y, Tšuiko O, Demyda-Peyrás S, Van Soom A, Vermeesch JR, Smits K. Genome-wide equine preimplantation genetic testing enabled by simultaneous haplotyping and copy number detection. Sci Rep 2024 Jan 23;14(1):2003.
              doi: 10.1038/s41598-023-48103-7pubmed: 38263320google scholar: lookup
            24. Koeberl DD, Koch RL, Lim JA, Brooks ED, Arnson BD, Sun B, Kishnani PS. Gene therapy for glycogen storage diseases. J Inherit Metab Dis 2024 Jan;47(1):93-118.
              doi: 10.1002/jimd.12654pubmed: 37421310google scholar: lookup
            Subscribe to our newsletter
            Join 99,357 horse owners like you who receive our email updates on horse health and nutrition.