title: Deep intronic GBE1 mutation in manifesting heterozygous patients with adult polyglucosan body disease.
abstract: OBJECTIVE
  We describe a deep intronic mutation in adult polyglucosan body disease. Similar mechanisms can also explain manifesting heterozygous cases in other inborn metabolic diseases.
  
  
  OBJECTIVE
  To explain the genetic change consistently associated with manifesting heterozygous patients with adult polyglucosan body disease.
  
  
  METHODS
  This retrospective study took place from November 8, 2012, to November 7, 2014. We studied 35 typical patients with adult polyglucosan body disease, of whom 16 were heterozygous for the well-known c.986A>C mutation in the glycogen branching enzyme gene (GBE1) but harbored no other known mutation in 16 exons.
  
  
  METHODS
  All 16 manifesting heterozygous patients had lower glycogen branching activity compared with homozygous patients, which showed inactivation of the apparently normal allele. We studied the messenger ribonucleic acid (mRNA) structure and the genetic change due to the elusive second mutation.
  
  
  RESULTS
  When we reverse transcribed and sequenced the mRNA of GBE1, we found that all manifesting heterozygous patients had the c.986A>C mutant mRNA and complete lack of mRNA encoded by the second allele. We identified a deep intronic mutation in this allele, GBE1-IVS15+5289_5297delGTGTGGTGGinsTGTTTTTTACATGACAGGT, which acts as a gene trap, creating an ectopic last exon. The mRNA transcript from this allele missed the exon 16 and 3'UTR and encoded abnormal GBE causing further decrease of enzyme activity from 18% to 8%.
  
  
  CONCLUSIONS
  We identified the deep intronic mutation, which acts as a gene trap. This second-most common adult polyglucosan body disease mutation explains another founder effect in all Ashkenazi-Jewish cases.
authors: Houston Merritt Neuromuscular Disease Research Center, Columbia University Medical Center, New York, New York.
authors: H Orhan
authors: HO
authors: Akman
authors: The Agnes Ginges Center for Human Neurogenetics, Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Or
authors: O
authors: Kakhlon
authors: Houston Merritt Neuromuscular Disease Research Center, Columbia University Medical Center, New York, New York.
authors: Jorida
authors: J
authors: Coku
authors: Houston Merritt Neuromuscular Disease Research Center, Columbia University Medical Center, New York, New York.
authors: Lorenzo
authors: L
authors: Peverelli
authors: The Agnes Ginges Center for Human Neurogenetics, Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Hanna
authors: H
authors: Rosenmann
authors: The Agnes Ginges Center for Human Neurogenetics, Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Lea
authors: L
authors: Rozenstein-Tsalkovich
authors: Program in Genetics and Genome Biology, Department of Pediatrics (Neurology), Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors: Julie
authors: J
authors: Turnbull
authors: Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Vardiella
authors: V
authors: Meiner
authors: Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Liat
authors: L
authors: Chama
authors: Center for Research, Prevention, and Treatment of Atherosclerosis, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Israela
authors: I
authors: Lerer
authors: Center for Research, Prevention, and Treatment of Atherosclerosis, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Shoshi
authors: S
authors: Shpitzen
authors: Center for Research, Prevention, and Treatment of Atherosclerosis, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Eran
authors: E
authors: Leitersdorf
authors: Unidad de Enfermedades Neuromusculares, Servicio de Neurología, Hospital Universitario Virgen del Rocío, Instituto de Biomédicina de Sevilla, Consejo Superior de Investigaciónes Científicas, Universidad de Sevilla, Seville, Spain.
authors: Carmen
authors: C
authors: Paradas
authors: Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas.
authors: Mary
authors: M
authors: Wallace
authors: Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas.
authors: Raphael
authors: R
authors: Schiffmann
authors: Houston Merritt Neuromuscular Disease Research Center, Columbia University Medical Center, New York, New York.
authors: Salvatore
authors: S
authors: DiMauro
authors: The Agnes Ginges Center for Human Neurogenetics, Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Alexander
authors: A
authors: Lossos
authors: Program in Genetics and Genome Biology, Department of Pediatrics (Neurology), Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors: Berge A
authors: BA
authors: Minassian
mesh_terms: D015061:1,4-alpha-Glucan Branching Enzyme / Q000235:genetics*; D000328:Adult; D000483:Alleles; D001483:Base Sequence; D006004:Glycogen Debranching Enzyme System / Q000235:genetics*; D006008:Glycogen Storage Disease / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007438:Introns; D009154:Mutation / Q000235:genetics*; D009422:Nervous System Diseases / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D006004:Glycogen Debranching Enzyme System; D015061:1,4-alpha-Glucan Branching Enzyme; C577876:GBE1 protein, human