Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)

Authors

  • Kathleen S. Hruska,

    1. Section on Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
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  • Mary E. LaMarca,

    1. Section on Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
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  • C. Ronald Scott,

    1. Department of Pediatrics, University of Washington, Seattle, Washington
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  • Ellen Sidransky

    Corresponding author
    1. Section on Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
    • Chief, Section on Molecular Neurogenetics, National Human Genome Research Institute, Building 35, Room 1A-213, 35 Convent Drive, MSC 3708, Bethesda, Maryland 20892-3708
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  • Communicated by William S. Sly

  • This article is a US Government work, and, as such, is in the public domain in the United States of America.

Abstract

Gaucher disease (GD) is an autosomal recessive disorder caused by the deficiency of glucocerebrosidase, a lysosomal enzyme that catalyses the hydrolysis of the glycolipid glucocerebroside to ceramide and glucose. Lysosomal storage of the substrate in cells of the reticuloendothelial system leads to multisystemic manifestations, including involvement of the liver, spleen, bone marrow, lungs, and nervous system. Patients with GD have highly variable presentations and symptoms that, in many cases, do not correlate well with specific genotypes. Almost 300 unique mutations have been reported in the glucocerebrosidase gene (GBA), with a distribution that spans the gene. These include 203 missense mutations, 18 nonsense mutations, 36 small insertions or deletions that lead to either frameshifts or in-frame alterations, 14 splice junction mutations, and 13 complex alleles carrying two or more mutations in cis. Recombination events with a highly homologous pseudogene downstream of the GBA locus also have been identified, resulting from gene conversion, fusion, or duplication. In this review we discuss the spectrum of GBA mutations and their distribution in the patient population, evolutionary conservation, clinical presentations, and how they may affect the structure and function of glucocerebrosidase. Hum Mutat 29(5), 567–583, 2008. Published 2008 Wiley-Liss, Inc.

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