Publication: p.X654R IDUA variant among Thai individuals with intermediate mucopolysaccharidosis type I and its residual activity as demonstrated in COS-7 cells
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2018-05-01
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14691809
00034800
00034800
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2-s2.0-85039173561
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Mahidol University
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SCOPUS
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Annals of Human Genetics. Vol.82, No.3 (2018), 150-157
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Lukana Ngiwsara, James R. Ketudat-Cairns, Phannee Sawangareetrakul, Ratana Charoenwattanasatien, Voraratt Champattanachai, Chulaluck Kuptanon, Suthipong Pangkanon, Thipwimol Tim-Aroon, Duangrurdee Wattanasirichaigoon, Jisnuson Svasti p.X654R IDUA variant among Thai individuals with intermediate mucopolysaccharidosis type I and its residual activity as demonstrated in COS-7 cells. Annals of Human Genetics. Vol.82, No.3 (2018), 150-157. doi:10.1111/ahg.12236 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/45181
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p.X654R IDUA variant among Thai individuals with intermediate mucopolysaccharidosis type I and its residual activity as demonstrated in COS-7 cells
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© 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.