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Related Experiment Videos

NAGLU mutations underlying Sanfilippo syndrome type B

A Schmidtchen1, D Greenberg, H G Zhao

  • 1Department of Biological Chemistry, UCLA School of Medicine, Los Angeles, CA 90095-1737, USA.

American Journal of Human Genetics
|March 7, 1998
PubMed
Summary

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Sanfilippo syndrome type B, a rare genetic disorder, results from a deficient enzyme (alpha-N-acetylglucosaminidase) crucial for cellular waste removal. Researchers identified 10 new mutations in the NAGLU gene, highlighting significant molecular diversity in the disease.

Area of Science:

  • Biochemistry
  • Genetics
  • Molecular Biology

Background:

  • Sanfilippo syndrome type B (mucopolysaccharidosis III B) is a rare autosomal recessive lysosomal storage disease.
  • It stems from a deficiency in alpha-N-acetylglucosaminidase, an enzyme vital for heparan sulfate degradation.
  • The NAGLU gene, encoding this enzyme, was recently isolated, paving the way for mutation analysis.

Purpose of the Study:

  • To identify novel mutations in the NAGLU gene in patients with Sanfilippo syndrome type B.
  • To investigate the functional impact of identified missense mutations on alpha-N-acetylglucosaminidase activity.

Main Methods:

  • DNA was extracted from fibroblast cell lines of nine Sanfilippo syndrome type B patients.
  • Exons of the NAGLU gene were amplified and sequenced to identify mutations.

Related Experiment Videos

  • Chinese hamster ovary cells were stably transfected with mutagenized NAGLU cDNA to assess enzyme activity.

    • Main Results:

    • Ten new mutations in the NAGLU gene were identified: Y92H, P115S, Y140C, E153K, R203X, 650insC, 901delAA, P358L, A664V, and L682R.
    • Four mutations were homozygous, and two were found in multiple patients, indicating molecular heterogeneity.
    • Transfection experiments showed that missense mutations rendered the alpha-N-acetylglucosaminidase enzyme inactive.
    • Most identified substitutions are located near the enzyme's amino or carboxyl termini.

    Conclusions:

    • Sanfilippo syndrome type B exhibits significant molecular heterogeneity with numerous identified NAGLU gene mutations.
    • The identified mutations are largely deleterious, leading to inactive alpha-N-acetylglucosaminidase.
    • The clustering of mutations suggests critical roles for the enzyme's terminal regions in its transport and function.