title: A novel mouse model that recapitulates adult-onset glycogenosis type 4.
abstract: Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by deficiency of the glycogen-branching enzyme (GBE). The diagnostic hallmark of the disease is the accumulation of a poorly branched form of glycogen known as polyglucosan (PG). The disease is clinically heterogeneous, with variable tissue involvement and age at onset. Complete loss of enzyme activity is lethal in utero or in infancy and affects primarily the muscle and the liver. However, residual enzyme activity as low as 5-20% leads to juvenile or adult onset of a disorder that primarily affects the central and peripheral nervous system and muscles and in the latter is termed adult polyglucosan body disease (APBD). Here, we describe a mouse model of GSD IV that reflects this spectrum of disease. Homologous recombination was used to knock in the most common GBE1 mutation p.Y329S c.986A > C found in APBD patients of Ashkenazi Jewish decent. Mice homozygous for this allele (Gbe1(ys/ys)) exhibit a phenotype similar to APBD, with widespread accumulation of PG. Adult mice exhibit progressive neuromuscular dysfunction and die prematurely. While the onset of symptoms is limited to adult mice, PG accumulates in tissues of newborn mice but is initially absent from the cerebral cortex and heart muscle. Thus, PG is well tolerated in most tissues, but the eventual accumulation in neurons and their axons causes neuropathy that leads to hind limb spasticity and premature death. This mouse model mimics the pathology and pathophysiologic features of human adult-onset branching enzyme deficiency.
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA, hoa2101@cumc.columbia.edu ho_akman@yahoo.com.
authors.forename: H
authors.initials: H
authors.lastname: Orhan Akman
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Emmanuele
authors.affiliation: Department of Biochemistry and.
authors.forename: Yasemin Gülcan
authors.initials: YG
authors.lastname: Kurt
authors.affiliation: Department of Pathology, Gülhane Medical Military Academy, Ankara, Turkey.
authors.forename: Bülent
authors.initials: B
authors.lastname: Kurt
authors.affiliation: Department of Molecular and Human Genetics and.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Sheiko
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Salvatore
authors.initials: S
authors.lastname: DiMauro
authors.affiliation: Department of Molecular and Human Genetics and Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Craigen
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D006004:Glycogen Debranching Enzyme System / Q000235:genetics*; D006008:Glycogen Storage Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006011:Glycogen Storage Disease Type IV / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D054792:Muscle, Striated / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation; D009422:Nervous System Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D017933:Peripheral Nervous System / Q000378:metabolism / Q000503:physiopathology; D010641:Phenotype
chemical_list: D006004:Glycogen Debranching Enzyme System; C577876:GBE1 protein, human