title: Gaucher disease and parkinsonism: a phenotypic and genotypic characterization.
abstract: Among the many phenotypes associated with Gaucher disease, the inherited deficiency of glucocerebrosidase, are reports of patients with parkinsonian symptoms. The basis for this association is unknown, but could be due to alterations in the gene or gene region. The human glucocerebrosidase gene, located on chromosome 1q21, has a nearby pseudogene that shares 96% identity. Immediately adjacent to the glucocerebrosidase pseudogene is a convergently transcribed gene, metaxin, which has a pseudogene that is located just downstream to the glucocerebrosidase gene. We describe a patient with mild Gaucher disease but impaired horizontal saccadic eye movements who developed a tremor at age 42, followed by rapid deterioration of her gait. A pallidotomy at age 47 was unsuccessful. Her motor and cognitive deterioration progressed despite enzyme replacement therapy. Sequencing of the glucocerebrosidase gene identified mutations L444P and D409H. Southern blot analysis using the enzyme SspI showed that the maternal allele had an additional 17-kb band. PCR amplifications and sequencing of this fragment demonstrated a duplication which included the glucocerebrosidase pseudogene, metaxin gene, and a pseudometaxin/metaxin fusion. Gene alterations associated with this novel rearrangement, resulting from a crossover between the gene for metaxin and its pseudogene, could contribute to the atypical phenotype encountered in this patient.
authors.affiliation: Clinical Neuroscience Branch, NIMH, 49 Convent Drive MSC405, 49/B1EE16, Bethesda, MD 20892-4405, USA.
authors.forename: N
authors.initials: N
authors.lastname: Tayebi
authors.forename: M
authors.initials: M
authors.lastname: Callahan
authors.forename: V
authors.initials: V
authors.lastname: Madike
authors.forename: B K
authors.initials: BK
authors.lastname: Stubblefield
authors.forename: E
authors.initials: E
authors.lastname: Orvisky
authors.forename: D
authors.initials: D
authors.lastname: Krasnewich
authors.forename: J J
authors.initials: JJ
authors.lastname: Fillano
authors.forename: E
authors.initials: E
authors.lastname: Sidransky
mesh_terms: D000483:Alleles; D015139:Blotting, Southern; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D003434:Crossing Over, Genetic / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005776:Gaucher Disease / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D005838:Genotype; D005962:Glucosylceramidase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008025:Ligases / Q000235:genetics; D008297:Male; D008875:Middle Aged; D033681:Mitochondrial Membrane Transport Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics; D010302:Parkinson Disease, Secondary / Q000150:complications* / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D020161:Physical Chromosome Mapping; D011110:Polymorphism, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics; D011544:Pseudogenes / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051843:Synucleins; D044767:Ubiquitin-Protein Ligases
chemical_list: C093550:MTX1 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D012333:RNA, Messenger; D051843:Synucleins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D005962:Glucosylceramidase; D008025:Ligases