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Title: p.X654R IDUA variant among Thai individuals with intermediate mucopolysaccharidosis type I and its residual activity as demonstrated in COS-7 cells
Authors: Lukana Ngiwsara
James R. Ketudat-Cairns
Phannee Sawangareetrakul
Ratana Charoenwattanasatien
Voraratt Champattanachai
Chulaluck Kuptanon
Suthipong Pangkanon
Thipwimol Tim-Aroon
Duangrurdee Wattanasirichaigoon
Jisnuson Svasti
Suranaree University of Technology
Chulabhorn Research Institute
Faculty of Medicine, Ramathibodi Hospital, Mahidol University
Queen Sirikit National Institute of Child Health
Keywords: Biochemistry, Genetics and Molecular Biology;Medicine
Issue Date: 1-May-2018
Citation: Annals of Human Genetics. Vol.82, No.3 (2018), 150-157
Abstract: © 2017 John Wiley & Sons Ltd/University College London Background: Mucopolysaccharidosis type I (MPS I) is a rare autosomal-recessive disorder caused by defects in alpha-L-iduronidase (IDUA), a lysosomal enzyme encoded by the IDUA gene. Herein, we characterized IDUA mutations underlying mucopolysaccharidosis type I intermediate form (Hurler–Scheie syndrome) and its molecular pathogenic mechanisms. Methods: Clinical data, activity of the IDUA enzyme in leukocytes, and a mutation of the IDUA gene were analyzed. Pathogenesis associated with an IDUA mutation was further investigated by evaluating the mutant cDNA sequence, protein expression and activity in COS-7 cells. Results: Five unrelated patients were identified to have clinical diagnosis of intermediate form of MPS I (Hurler–Scheie) and exhibited low-to-absent levels of leukocyte IDUA activity. Genetic analysis revealed homozygous c.*1T>C (p.X654R) mutation in two patients and compound heterozygosity between the c.*1T>C and another allele including c.265G>A (p.R89Q), c.935G>A (p.W312X), or c.1138 C>T (p.Q380X), each in a single patient. Sequencing the 3′RACE product of the c.*1T>C (p.X654R) allele indicated a 38-amino acids elongation of the mutant protein. COS-7 cells expressing IDUA with the mutations exhibited extremely low levels or complete absence of enzyme activity compared to wild-type IDUA. Western blot analysis detected no protein in p.W312X and p.Q380X samples, while an elevated molecular mass and a different pattern of protein bands were found in p.X654R specimen compared with the wild type IDUA. Conclusions: Mutational spectrum underlying intermediate MPS I is expanded. Our data suggest that the p.X654R is an intermediate IDUA mutant allele with residual enzyme activity. It can lead to intermediate or milder form of MPS I depending on another associated allele.
ISSN: 14691809
Appears in Collections:Scopus 2018

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