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Identification of the gene encoding the enzyme deficient in mucopolysaccharidosis IIIC (Sanfilippo disease type C)

Xiaolian Fan1, Huiwen Zhang, Sunqu Zhang

  • 1Research Institute, Metabolism Program, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.

American Journal of Human Genetics
|September 9, 2006
PubMed

Insights

Researchers identified the gene responsible for Mucopolysaccharidosis IIIC (MPS IIIC), a rare genetic disorder. The HGSNAT gene

Area of Science:

  • Genetics
  • Biochemistry
  • Molecular Biology

Background:

  • Mucopolysaccharidosis IIIC (MPS IIIC), also known as Sanfilippo C, is a lysosomal storage disorder.
  • The specific gene responsible for MPS IIIC remained unidentified, although localized to chromosome 8.

Purpose of the Study:

  • To identify the gene responsible for Mucopolysaccharidosis IIIC.
  • To characterize the function and localization of the identified gene product.

Main Methods:

  • Proteomics analysis of mouse lysosomal membrane proteins.
  • Gene expression in human MPS IIIC fibroblasts.
  • Sequence analysis and mutation detection in MPS IIIC cell lines.

Main Results:

  • An unknown protein's human homolog, TMEM76, was identified, mapping to chromosome 8p11.1.
  • Expression of a mouse sequence corrected the enzymatic defect in MPS IIIC fibroblasts, localizing to lysosomes.
  • The human homolog, HGSNAT, was identified and found to be highly conserved.
  • Mutational analyses revealed splice-junction and insertion mutations in MPS IIIC cell lines.

Conclusions:

  • The HGSNAT gene is identified as the gene responsible for Mucopolysaccharidosis IIIC.
  • The HGSNAT protein localizes to lysosomes and corrects the enzymatic defect in MPS IIIC.
  • Mutations in HGSNAT cause MPS IIIC, providing a target for future diagnostics and therapies.

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