Deep intronic GBE1 mutation in manifesting heterozygous patients with adult polyglucosan body disease

H. Orhan Akman*, Or Kakhlon, Jorida Coku, Lorenzo Peverelli, Hanna Rosenmann, Lea Rozenstein-Tsalkovich, Julie Turnbull, Vardiella Meiner, Liat Chama, Israela Lerer, Shoshi Shpitzen, Eran Leitersdorf, Carmen Paradas, Mary Wallace, Raphael Schiffmann, Salvatore DiMauro, Alexander Lossos, Berge A. Minassian

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


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.

Original languageAmerican English
Pages (from-to)441-445
Number of pages5
JournalJAMA Neurology
Issue number4
StatePublished - 1 Apr 2015
Externally publishedYes

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Copyright 2015 American Medical Association. All rights reserved.


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