The GBA p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects
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The GBA p.G85E mutation in Korean patients with non‑neuronopathic Gaucher disease: founder and neuroprotective effects Yoo‑Mi Kim1,2, Jin‑Ho Choi3, Gu‑Hwan Kim4, Young Bae Sohn5, Jung Min Ko6, Beom Hee Lee3,4, Chong Kun Cheon7, Han Hyuk Lim2, Sun‑Hee Heo4 and Han‑Wook Yoo3,4*
Abstract Background: Gaucher disease (GD) is caused by a deficiency of β-glucocerebrosidase, encoded by GBA. Haplotype analyses previously demonstrated founder effects for particular GBA mutations in Ashkenazi Jewish and French-Cana‑ dian populations. This study aimed to investigate the clinical characteristics and mutation spectrum of GBA in Korean GD patients and to identify founder effect of GBA p.G85E in non-neuronopathic GD patients. Results: The study cohort included 62 GD patients from 58 unrelated families. Among them, 18 patients from 17 families harbored the p.G85E mutation. Haplotype analysis was performed for 9 probands and their parents for whom DNA samples were available. In 58 unrelated probands, the GBA mutation p.L483P was the most common (30/116 alleles, 26%), followed by p.G85E (16%), p.F252I (13%), and p.R296Q (9%). The median age at diagnosis of the 18 patients harboring the p.G85E mutation was 3.8 (range 1.2–57) years. No patients developed neurological symptoms during follow-up periods of 2.2–20.3 (median 13.9) years. The size of the shared haplotype containing GBA p.G85E was 732 kbp, leading to an estimated age of 3075 years. Conclusion: The GBA p.G85E mutation, which appears to be neuroprotective despite producing distinctive viscero‑ megaly and skeletal symptoms, exhibited a potential founder effect in Korean GD patients. Keywords: Gaucher disease, Founder effect, GBA, β-Glucocerebrosidase Background Gaucher disease (GD [MIM: 230,800, 230,900, and 231,000]) is caused by the deficiency of β-glucocerebrosidase (GBA), encoded by GBA [1]. Progressive glycolipid accumulation in the reticuloendothelial system leads to anemia, thrombocytopenia, hepatomegaly, splenomegaly, and skeletal manifestations, such as bone pain, avascular necrosis, and osteoporosis [1, 2]. GD is categorized into non-neuronopathic (type *Correspondence: [email protected] 3 Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, 88 Olympic‑ro 43‑gil, Songpa‑Gu, Seoul 05505, Korea Full list of author information is available at the end of the article
1), acute neuronopathic (type 2), and chronic neuronopathic (type 3) types, in accordance with the degree of central nervous system involvement [1]. Adult-onset Parkinsonism may occur in patients with type 1 GD [1, 2]. However, Parkinsonism is not considered as a feature of neuronopathic GD; rather, GBA mutations are one of the risk factors of Parkinsonism [3]. Mutation spectra differ among ethnicities [4, 5], and genotype–phenotype correlations have been noted in some mutations. According to the International Collaborative Gaucher Group’s Gaucher Registry (clinicaltrials.gov NCT00358943), ~ 94% of patients in Western countries
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