The  GBA  p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects

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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-Canadian 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 visceromegaly and skeletal symptoms, exhibited a potential founder effect in Korean GD patients.

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Most cited references 37

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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.

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Phenotype, diagnosis, and treatment of Gaucher's disease.

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Gaucher's disease continues to be a model for applications of molecular medicine to clinical delineation, diagnosis, and treatment. Analyses of several thousand affected individuals have broadened the range of the pan-ethnic disease variants, provided initial genotype and phenotype correlations, and established the effectiveness of enzyme therapy. Large numbers of affected individuals worldwide have provided insight into the effect of disease variation related to ethnic origin, prognosis, and outcome. The ability to safely and effectively use enzyme therapy to inhibit or reverse visceral-disease progression and involvement has provided impetus for design of new enzyme therapies, and creation of substrate depletion and pharmacological chaperone strategies. Such innovations could provide interventions that are effective for neuronopathic variants and, potentially, could be more cost effective than other treatments. These developments are novel, clinically important, advancements for patients with other lysosomal storage diseases and genetic diseases.

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The Gaucher Registry, the largest database of patients with Gaucher disease (GD) worldwide, was initiated to better delineate the progressive nature of the disorder and determine optimal therapy. This report describes the demographic and clinical characteristics of 1698 patients with GD before they received enzyme replacement therapy. Physicians worldwide who treat patients with GD were invited to submit prospective and retrospective data for an ongoing registry, using standardized data collection forms, for central processing and review. Most patients were from the United States (45%) and Israel (17%), but patients are from 38 countries. Most (94%) had type 1 GD, fewer than 1% had type 2, and 5% had type 3. Mutant allele frequency data, available for 45% of patients, showed the most common alleles to be N370S (53%), L444P (18%), 84GG (7%), and IVS2+1 (2%). Twenty-five percent of L444P homozygotes (13 of 52 patients) had type 1 GD phenotype. Mean age at diagnosis in patients with the N370S/N370S genotype was 27.2 years (SD, 19.7 years); in L444P/L444P patients, 2. 3 years (SD, 3.2 years). Histories of bone pain and radiological bone disease were reported by 63% and 94% of patients, respectively; both were more likely in asplenic patients than in patients with spleens. Mean spleen and liver volumes were 19.8 and 2.0 multiples of normal, respectively. Anemia and thrombocytopenia were present in 64% and 56%, respectively. Thrombocytopenia was present in 13% of asplenic patients. The Gaucher Registry permits a comprehensive understanding of the clinical spectrum of GD because of the uniquely large sample size. The Registry will be useful in evaluating the effects of specific therapies in GD and the possible influences of environment, ethnicity, and genotype on the natural history of the disorder.

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Author and article information

Contributors

Han-Wook Yoo:

ORCID: http://orcid.org/0000-0001-8615-186X

hwyoo@amc.seoul.kr

Journal

Journal ID (nlm-ta): Orphanet J Rare Dis

Journal ID (iso-abbrev): Orphanet J Rare Dis

Title: Orphanet Journal of Rare Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1750-1172

Publication date (Electronic): 11 November 2020

Publication date PMC-release: 11 November 2020

Publication date Collection: 2020

Volume: 15

Electronic Location Identifier: 318

Affiliations

[1 ]GRID grid.254230.2, ISNI 0000 0001 0722 6377, Department of Pediatrics, College of Medicine, Chungnam National University, , Chungnam National University Sejong Hospital, ; Sejong, Korea

[2 ]GRID grid.411665.1, ISNI 0000 0004 0647 2279, Department of Pediatrics, College of Medicine, Chungnam National University, , Chungnam National University Hospital, ; Daejeon, Korea

[3 ]GRID grid.267370.7, ISNI 0000 0004 0533 4667, 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

[4 ]GRID grid.267370.7, ISNI 0000 0004 0533 4667, Medical Genetics Center, Asan Medical Center, , University of Ulsan College of Medicine, ; Seoul, Korea

[5 ]GRID grid.411261.1, ISNI 0000 0004 0648 1036, Department of Medical Genetics, Ajou University School of Medicine, , Ajou University Hospital, ; Suwon, Korea

[6 ]GRID grid.412482.9, ISNI 0000 0004 0484 7305, Department of Pediatrics, College of Medicine, , Seoul National University Children’s Hospital, ; Seoul, Korea

[7 ]GRID grid.262229.f, ISNI 0000 0001 0719 8572, Department of Pediatrics, College of Medicine, , Pusan National University Children’s Hospital, ; Yangsan, Korea

Author information

Han-Wook Yoo http://orcid.org/0000-0001-8615-186X

Article

Publisher ID: 1597

DOI: 10.1186/s13023-020-01597-0

PMC ID: 7656680

PubMed ID: 33176831

SO-VID: 2bb55de8-08f2-40d4-9d70-cac69909bd57

License:

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