Mucopolysaccharidosis type I: Identification and characterization of mutations affecting alpha-L-iduronidase activity.
Mucopolysaccharidosis type I (MPS I) is caused by a deficiency of the lysosomal enzyme alpha-L-iduronidase (IDUA). MPS I covers a broad spectrum of clinical severity ranging from severe Hurler syndrome through intermediate Hurler/Scheie syndrome to mild Scheie syndrome. Mutation screening was performed in two unrelated Taiwanese MPS I patients. A Hurler/Scheie patient had A79V (C to T transition in codon 79) in exon 2 and R619G (C to G transversion in codon 619) in exon 14. R619G has been shown to cause disease. Expression of A79V in COS-7 cells showed trace amounts of IDUA activity, demonstrating the deleterious nature of the mutation. A79V mutation did not cause a reduction in IDUA mRNA levels. The reduced level of IDUA protein suggests increased degradation of the mutant enzyme. A Hurler patient had 134del12 (in-frame deletion of codons 16-19 in signal peptide) in exon 1 and Q584X (C to T transition in codon 584) in exon 13. Transfection of COS-7 cells with Q584X did not yield active enzyme. Q584X mutation caused an apparent reduction in the IDUA mRNA level and no IDUA protein was detected. Conversely, 134del12 showed 124.6% of normal activity in transfected cells and a 77-kDa precursor protein was observed on Western blot, suggesting biologic activity of precursor IDUA without posttranslational cleavage. These findings provide further evidence of the molecular heterogeneity in mutations in MPS I.
Lee-Chen
Guey-Jen
GJ
Department of Biology, National Taiwan Normal University, 88 Ting-chow Road, Section 4, Taipei, Taiwan.
Lin
Shuan-Pei
SP
Chen
I-Shen
IS
Chang
Jui-Hung
JH
Yang
Chyau-Wen
CW
Chin
Yi-Wen
YW
D000293:Adolescent; D002648:Child; D006801:Humans; D007068:Iduronidase / Q000235:genetics*; D008059:Mucopolysaccharidosis I / Q000201:enzymology / Q000235:genetics*; D009154:Mutation
D007068:Iduronidase