Genetic Analysis of 17 Children with Hunter Syndrome:Identification and Functional Characterization of Four Novel Mutations in the Iduronate-2-Sulfatase Gene

被引：0

作者：

Dimitry A.Chistiakov ^{[1
,2
]}

Lyudmila M.Kuzenkova ^{[3
]}

Kirill V.Savost’anov ^{[2
]}

Anait K.Gevorkyan ^{[4
]}

Alexander A.Pushkov ^{[2
]}

Alexey G.Nikitin ^{[2
]}

Nato D.Vashakmadze ^{[3
]}

Natalia V.Zhurkova ^{[2
]}

Tatiana V.Podkletnova ^{[3
]}

Leila S.Namazova-Baranova ^{[4
]}

Alexander A.Baranove ^{[5
]}

机构：

[1] Department of Medical Nanobiotechnology,Pirogov Russian State Medical University

[2] Department of Molecular and Genetic Diagnostics,Division of Laboratory Medicine,Institute of Pediatrics,Research Center for Children’s Health

[3] Department of Psychoneurology and Psychosomatic Pathology,Institute of Pediatrics,Research Center for Children’s Health

[4] Institute of Preventive Pediatrics and Rehabilitation,Research Center for Children’s Health

[5] Research Center for Children’s Health

来源：

Journal of Genetics and Genomics | 2014年 / 04期

关键词：

Hunter syndrome; Mucopolysaccharidosis type II; Iduronate-2-sulfatase; Mutations; Glycosaminoglycans;

D O I：

暂无

中图分类号：

R596 [遗传性疾病];

学科分类号：

1002 ; 100201 ;

摘要：

Mucopolysaccharidosis type II(MPS II)is a rare X-linked disorder caused by alterations in the iduronate-2-sulfatase(IDS)gene.In this study,IDS activity in peripheral mononuclear blood monocytes(PMBCs)was measured with a fluorimetric enzyme assay.Urinary glycosaminoglycans(GAGs)were quantified using a colorimetric assay.All IDS exons and intronic flanks were bidirectionally sequenced.A total of 15 mutations(all exonic region)were found in 17 MPS II patients.In this cohort of MPS II patients,all alterations in the IDS gene were caused by point nucleotide substitutions or small deletions.Mutations p.Arg88His and p.Arg172*occurred twice.All mutations were inherited except for p.Gly489Alafs*7,a germline mutation.We found four new mutations(p.Ser142Phe,p.Arg233Gly,p.Glu430*,and p.Ile360Tyrfs*31).In Epstein-Barr virus(EBV)-immortalized PMBCs derived from the MPS II patients,no IDS protein was detected in case of the p.Ser142Phe and p.Ile360Tyrfs*31 mutants.For p.Arg233Gly and p.Glu430*,we observed a residual expression of IDS.The p.Arg233Gly and p.Glu430*mutants had a residuary enzymatic activity that was lowered by 14.3 and 76-fold,respectively,compared with healthy controls.This observation may help explain the mild disease phenotype in MPS II patients who had these two mutations whereas the p.Ser142Phe and p.Ile360Tyrfs*31 mutations caused the severe disease manifestation.

引用

页码：197 / 203

页数：7

共 17 条

[1] Christina Lampe,Cinzia Maria Bellettato,Nesrin Karabul,Maurizio Scarpa.Mucopolysaccharidoses and Other Lysosomal Storage Diseases[J].Rheumatic Disease Clinics of North America,2013
[2] Young BaeSohn,Su JinKim,Sung WonPark,Hyung‐DooPark,Chang‐SeokKi,Chi HwaKim,Seung WonHuh,SungheeYeau,Kyung‐HoonPaik,Dong‐KyuJin.A mother and daughter with the p.R443X mutation of mucopolysaccharidosis type II: Genotype and phenotype analysis[J].Am. J. Med. Genet.,2010(12)
[3] J.R.Alonso‐Fernández,J.Fidalgo,C.Colón.Neonatal screening for mucopolysaccharidoses by determination of glycosaminoglycans in the eluate of urine‐impregnated paper: preliminary results of an improved DMB‐based procedure[J].J. Clin. Lab. Anal.,2010(3)
[4] RoselineFroissart,IrèneMaire,GillesMillat,StéphaneCudry,Anne‐MarieBirot,VéroniqueBonnet,OlivierBouton,DominiqueBozon.Identification of iduronate sulfatase gene alterations in 70 unrelated Hunter patients[J].Clinical Genetics,2008(5)
[5] S. Keeratichamroen,J. R. Ketudat Cairns,D. Wattanasirichaigoon,P. Wasant,L. Ngiwsara,P. Suwannarat,S. Pangkanon,J. Kuptanon,P. Tanpaiboon,T. Rujirawat,S. Liammongkolkul,J. Svasti.Molecular analysis of the iduronate-2-sulfatase gene in Thai patients with Hunter syndrome[J].Journal of Inherited Metabolic Disease,2008(2)
[6] K. Sukegawa-Hayasaka,Z. Kato,H. Nakamura,S. Tomatsu,T. Fukao,K. Kuwata,T. Orii,N. Kondo.Effect of Hunter disease (mucopolysaccharidosis type II) mutations on molecular phenotypes of iduronate-2-sulfatase: Enzymatic activity, protein processing and structural analysis[J].Journal of Inherited Metabolic Disease,2006(6)
[7] Shuan-Pei Lin,Jui-Hung Chang,Guey-Jen Lee-Chen,Dar-Shong Lin,Hsiang-Yu Lin,Chih-Kuang Chuang.Detection of hunter syndrome (mucopolysaccharidosis type II) in Taiwanese: Biochemical and linkage studies of the iduronate-2-sulfatase gene defects in MPS II patients and carriers[J].Clinica Chimica Acta,2006(1)
[8] Expression studies of mutations underlying Taiwanese Hunter syndrome (mucopolysaccharidosis type II)
Chang, JH
Lin, SP
Lin, SC
Tseng, KL
Li, CL
Chuang, CK
Lee-Chen, GJ
[J]. HUMAN GENETICS, 2005, 116 (03) : 160 - 166
[9] Emma J Parkinson,Viv Muller,John J Hopwood,Doug A Brooks.Iduronate-2-sulphatase protein detection in plasma from mucopolysaccharidosis type II patients[J].Molecular Genetics and Metabolism,2003(1)
[10] Crystal structure of an enzyme-substrate complex provides insight into the interaction between human arylsulfatase A and its substrates during catalysis
von Bülow, R
Schmidt, B
Dierks, T
von Figura, K
Usón, I
[J]. JOURNAL OF MOLECULAR BIOLOGY, 2001, 305 (02) : 269 - 277

← 1 2 →