A Pseudodeficiency Allele ( DI 52 N ) of the Human ß-Glucuronidase Gene (original) (raw)

We present evidence that a 480G")-A transition in the coding region of the P-glucuronidase gene, which results in an aspartic-acid-to-asparagine substitution at amino acid position 152 (D152N), produces a pseudodefi ciency allele (GUSBp) that leads to greatly reduced levels of P-glucuronidase activity without apparent deleterious consequences. The 480G~>A mutation was found ini tially in the pseudodeficient mother of a child with mu copolysaccharidosis VII (MPSVII), but it was not on her disease-causing allele, which carried the L176F muta tion. The 480G-+A change was also present in an unre lated individual with another MPSYII allele who had unusually low P~glucuronidase activity, but whose clini cal symptoms were probably unrelated to P-glucuroni dase deficiency. This individual also had an R357X mu tation, probably on his second allele. We screened 100 unrelated normal individuals for the 480G-*A mutation with a PCR method and detected one carrier. Reduced p-glucuronidase activity following transfection of COS cells with the D152N cDNA supported the causal rela tionship between the D152N allele and pseudo defi ciency. The mutation reduced the fraction of expressed enzyme that was secreted. Puls e-chase experiments indi cated that the reduced activity in COS cells was due to accelerated intracellular turnover of the D152N enzyme. They also suggested that a potential glycosylation site created by the mutation is utilized in ~5 0 % of the en zyme expressed.

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