Human Molecular Genetics, Vol 6, 1573-1579, Copyright © 1997 by Oxford University Press
B Weber, XH Guo, JE Wraith, A Cooper, WJ Kleijer, S Bunge and JJ Hopwood
Sanfilippo syndrome type A or mucopolysaccharidosis IIIA (MPS IIIA) is an
autosomal recessive lysosomal storage disorder caused by the deficiency of
sulfamidase. The resulting lysosomal storage of heparan sulfate may lead to
severe neurodegeneration preceded by progressive dementia, often combined
with aggressive and hyperactive behaviour. A total of 109 patients from
four different geographic areas were screened for the common mutation R245H
and two other previously identified mutations. SSCP analysis of exons was
used to characterize the unknown alleles. We identified 16 novel sequence
variants, 12 of them likely to be pathogenic. The majority of the
pathogenic variants were single base pair changes leading to missense
mutations. Several single base pair deletions/insertions and one nonsense
mutation were also identified. Altogether, we were able to characterize 55%
of the pathogenic alleles. Sequence homology between sulfamidase and N-
acetylgalactosamine 4-sulfatase, the first sulfatase to have its tertiary
structure defined, suggests that amino acid residues R74 and T79, which
were found to be mutated, are likely to be involved in the formation of the
active site of sulfamidase. R245H accounts for 31% of the Sanfilippo A
alleles in Australasia, for 19.2% of the alleles in patients from the UK
and has a high frequency of 57.8% in patients from The Netherlands. The
identification of mutations common in certain geographic regions or ethnic
groups will help in the diagnosis of MPS IIIA and allow carrier testing and
improved genetic counselling.
ARTICLES
Novel mutations in Sanfilippo A syndrome: implications for enzyme function
Department of Chemical Pathology, Women's and Children's Hospital, North Adelaide, Australia. weberb@wch.sa.gov.au
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