A Novel Functional Missense Mutation p.T219A in Type 1 Gaucher's Disease
- Author:
- No author available
- Journal Title:
- Chinese Medical Journal
- Issue:
- 9
- DOI:
- 10.4103/0366-6999.180523
- Key Word:
- Gaucher's Disease;GCase;Genetics;Novel Missense Mutation
Abstract： Background:Gaucher's disease (GD) is an autosomal recessive disorder caused by a deficiency of acid β-glucosidase (glucocerebrosidase [GBA])that results in the accumulation of glucocerebroside within macrophages.Many mutations have been reported to be associated with this disorder.This study aimed to discover more mutations and provide data for the genetic pattern of the gene,which will help the development of quick and accurate genetic diagnostic tools for this disease.Methods:Genomic DNA was obtained from peripheral blood leukocytes of the patient and Sanger sequencing is used to sequence GBA gene.Sequence alignments of mammalian β-GBA (GCase) and three-dimensional protein structure prediction of the mutation were made.A construct of this mutant and its compound heterozygous counterpart were used to measure GCase in vitro.Results:GCase is relatively conserved at p.T219A.This novel mutation differs from its wild-type in structure.Moreover,it also causes a reduction in GCase enzyme activity.Conclusion:This novel mutation (c.655A＞G,p.T219A) is a pathogenic missense mutation,which contributes to GD.
- [1]Ju-Young, Lee,Beom Hee, Lee,Gu-Hwan, Kim,etc.Clinical and genetic characteristics of Gaucher disease according to phenotypic subgroups.[J].2012,55(2).
- [2]Laura, van Dussen,Marieke, Biegstraaten,Marcel Gw, Dijkgraaf,etc.Modelling Gaucher disease progression: long-term enzyme replacement therapy reduces the incidence of splenectomy and bone complications.[J].2014,9.
- [3]Grabowski GA.Phenotype, diagnosis, and treatment of Gaucher's disease.[J].2008,372(9645).
- [4]Raquel L, Lieberman.A Guided Tour of the Structural Biology of Gaucher Disease: Acid-β-Glucosidase and Saposin C.[J].2011,2011.
- [5]G, Sinclair,F Y, Choy,L, Humphries.A novel complex allele and two new point mutations in type 2 (acute neuronopathic) Gaucher disease.[J].1998,24(4).
- [6]Bendikov-Bar,I.,Horowitz,M..Gaucher disease paradigm: From ERAD to comorbidity[J].2012,33(10).
- [7]M, Reed,R J, Baker,A B, Mehta,etc.Enhanced differentiation of osteoclasts from mononuclear precursors in patients with Gaucher disease.[J].2013,51(3).
- [8]Zhao,H.,Mistry,P.K.,Yang,R.,etc.Genome-wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation[J].2012,87(4).
- [9]M, Horowitz,M, Pasmanik-Chor,Z, Borochowitz,etc.Prevalence of glucocerebrosidase mutations in the Israeli Ashkenazi Jewish population.[J].1998,12(4).
- [10]Wiessner C,Recchia A,Raas Rothschild A,etc.Lysosomal storage disorders and Parkinson's disease: Gaucher disease and beyond.[J].2011,26(9).
- [11]Silman I,Dvir H,McCarthy AA,etc.X-ray structure of human acid-beta-glucosidase, the defective enzyme in Gaucher disease[J].2003,4(7).
- [12]Mansson JE,Enquist IB,Olsson K,etc.Effective cell and gene therapy in a murine model of Gaucher disease[J].2006,103(37).
- [13]Enquist IB,Lo Bianco C,Ooka A,etc.Murine models of acute neuronopathic Gaucher disease[J].2007,104(44).
- [14]Tessa N, Campbell,Francis Y M, Choy.Gaucher disease and the synucleinopathies: refining the relationship.[J].2012,7.
- [15]Tammachote,R.,Tongkobpetch,S.,Srichomthong,C.,etc.A common and two novel GBA mutations in Thai patients with Gaucher disease[J].2013,58(9).
- [16]Gregory A, Grabowski.Gaucher disease and other storage disorders.[J].2012,2012.
- [17]Burrow, Thomas A.,Sun, Ying,Prada, Carlos E.,etc.CNS, lung, and lymph node involvement in Gaucher disease type 3 after 11 years of therapy: Clinical, histopathologic, and biochemical findings[J].2015,114(2).
- [18]Laura, van Dussen,Marieke, Biegstraaten,Carla E M, Hollak,etc.Cost-effectiveness of enzyme replacement therapy for type 1 Gaucher disease.[J].2014,9.
- [19]Liou B,Hegde RS,Zhang M,etc.Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations.[J].2006,281(7).
- [20]J, Kyte,R F, Doolittle.A simple method for displaying the hydropathic character of a protein.[J].1982,157(1).
- [21]Bru Cormand,Lluïsa Vilageliu,José M. Burguera,etc.Gaucher disease in Spanish patients: Analysis of eight mutations[J].1995,5(4).
- [22]S, Tsuji,P V, Choudary,B M, Martin,etc.A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher's disease.[J].1987,316.
- [23]E H Schuchman,R J Desnick.Enzyme replacement therapy for lysosomal diseases: lessons from 20 years of experience and remaining challenges.[J].2012,13.
- [24]Pires RF,Sobreira E,Cizmarik M,etc.Phenotypic and genotypic heterogeneity in Gaucher disease type 1: a comparison between Brazil and the rest of the world.[J].2007,90(1).
- [25]Mingyi, Chen,Jun, Wang.Gaucher disease: review of the literature.[J].2008,132.
- [26]Thomas,A.S.,Mehta,A.B.,Hughes,D.A..Diagnosing Gaucher disease: An on-going need for increased awareness amongst haematologists[J].2013,50(3).