H Orhan Akman1, Or Kakhlon2, Jorida Coku1, Lorenzo Peverelli1, Hanna Rosenmann2, Lea Rozenstein-Tsalkovich2, Julie Turnbull3, Vardiella Meiner4, Liat Chama4, Israela Lerer5, Shoshi Shpitzen5, Eran Leitersdorf5, Carmen Paradas6, Mary Wallace7, Raphael Schiffmann7, Salvatore DiMauro1, Alexander Lossos2, Berge A Minassian3. 1. Houston Merritt Neuromuscular Disease Research Center, Columbia University Medical Center, New York, New York. 2. The Agnes Ginges Center for Human Neurogenetics, Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 3. Program in Genetics and Genome Biology, Department of Pediatrics (Neurology), Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. 4. Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 5. Center for Research, Prevention, and Treatment of Atherosclerosis, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 6. 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. 7. Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas.
Abstract
IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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.
IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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: Mitchell A Sullivan; Silvia Nitschke; Evan P Skwara; Peixiang Wang; Xiaochu Zhao; Xiao S Pan; Erin E Chown; Travis Wang; Ami M Perri; Jennifer P Y Lee; Francisco Vilaplana; Berge A Minassian; Felix Nitschke Journal: Cell Rep Date: 2019-04-30 Impact factor: 9.423
Authors: D Sean Froese; Amit Michaeli; Thomas J McCorvie; Tobias Krojer; Meitav Sasi; Esther Melaev; Amiram Goldblum; Maria Zatsepin; Alexander Lossos; Rafael Álvarez; Pablo V Escribá; Berge A Minassian; Frank von Delft; Or Kakhlon; Wyatt W Yue Journal: Hum Mol Genet Date: 2015-07-21 Impact factor: 6.150
Authors: María M Adeva-Andany; Manuel González-Lucán; Cristóbal Donapetry-García; Carlos Fernández-Fernández; Eva Ameneiros-Rodríguez Journal: BBA Clin Date: 2016-02-27