Raquel Duran1, Niccolo E Mencacci1,2, Aikaterini V Angeli3, Maryam Shoai1, Emma Deas1, Henry Houlden1, Atul Mehta4, Derralynn Hughes4, Timothy M Cox5, Patrick Deegan5, Anthony H Schapira6, Andrew J Lees1, Patricia Limousin3, Paul R Jarman3, Kailash P Bhatia3, Nicholas W Wood1, John Hardy1, Tom Foltynie3. 1. Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK. 2. Department of Neurology and Laboratory of Neuroscience, "Dino Ferrari" Center, Universitá degli Studi di Milano, IRCCS Istituto Auxologico Italiano, Milan, Italy. 3. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK. 4. Lysosomal Storage Disorders Unit, Department of Haematology, UCL Medical School, Royal Free Hospital, London, UK. 5. Lysosomal Diseases Unit, Addenbrookes Hospital, and Department of Medicine, University of Cambridge, Cambridge, UK. 6. Department of Clinical Neurosciences, Institute of Neurology, UCL Medical School, Royal Free Hospital, London, UK.
Abstract
BACKGROUND: Heterozygous loss-of-function mutations in the acid beta-glucocerebrosidase (GBA1) gene, responsible for the recessive lysosomal storage disorder, Gaucher's disease (GD), are the strongest known risk factor for Parkinson's disease (PD). Our aim was to assess the contribution of GBA1 mutations in a series of early-onset PD. METHODS: One hundred and eighty-five PD patients (with an onset age of ≤50) and 283 age-matched controls were screened for GBA1 mutations by Sanger sequencing. RESULTS: We show that the frequency of GBA1 mutations is much higher in this patient series than in typical late-onset patient cohorts. Furthermore, our results reveal that the most prevalent PD-associated GBA1 mutation is E326K, a variant that does not, when homozygous, cause GD. CONCLUSIONS: Our results confirm recent reports that the mutation, E326K, predisposes to PD and suggest that, in addition to reduced GBA1 activity, other molecular mechanisms may contribute to the development of the disease.
BACKGROUND: Heterozygous loss-of-function mutations in the acid beta-glucocerebrosidase (GBA1) gene, responsible for the recessive lysosomal storage disorder, Gaucher's disease (GD), are the strongest known risk factor for Parkinson's disease (PD). Our aim was to assess the contribution of GBA1 mutations in a series of early-onset PD. METHODS: One hundred and eighty-five PD patients (with an onset age of ≤50) and 283 age-matched controls were screened for GBA1 mutations by Sanger sequencing. RESULTS: We show that the frequency of GBA1 mutations is much higher in this patient series than in typical late-onset patient cohorts. Furthermore, our results reveal that the most prevalent PD-associated GBA1 mutation is E326K, a variant that does not, when homozygous, cause GD. CONCLUSIONS: Our results confirm recent reports that the mutation, E326K, predisposes to PD and suggest that, in addition to reduced GBA1 activity, other molecular mechanisms may contribute to the development of the disease.
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