Human Molecular Genetics, Vol 6, 787-791, Copyright © 1997 by Oxford University Press
L Blanch, B Weber, XH Guo, HS Scott and JJ Hopwood
Sanfilippo A syndrome (mucopolysaccharidosis type IIIA, MPS-IIIA) is an
autosomal recessive neurodegenerative disorder due to an enzymatic defect
of the lysosomal enzyme sulphamidase (EC 3.10.1.1) required for the
degradation of heparan sulphate. In this study, molecular defects in the
sulphamidase gene of MPS-IIIA patients were investigated in a group of 10
patients of Australian and American origin. The entire coding region of the
sulphamidase gene was RT-PCR amplified and one polymorphism (R456H), four
novel mutations (S66W, R245H, E447K, 1307 del 9) and one previously
described mutation (1284 del 11) were identified by direct PCR sequencing.
R245H was present in six patients including one severely affected
homozygote. In three of the other patients with R245H, second mutant
alleles were identified as S66W, 1284 del 11 and E447K, respectively. S66W
was also detected in another patient where the other mutant allele remains
undefined. In addition, 1307 del 9 was also detected in a patient with the
other mutant allele remaining undefined. Allele specific oligonucleotide
hybridisation was used to determine the incidence of these in a population
of 26 MPS-IIIA patients (Australian and American) and 60 normal controls
(Australian). R245H represented 27% (14/52 alleles) in this total patient
population, while the other three changes ranged from 1.9 to 9.6% (1-5 of
52 alleles). The sequence variant, R456H, was shown to be polymorphic as it
was present in 55% of normal and 38% of patient alleles. The total combined
incidence of these five is 46% of alleles. This is the first study of the
molecular defects in MPS-IIIA patients and will greatly assist the
development of molecular analysis for MPS-IIIA patients and studies
concerned with genotype to phenotype relationships.
ARTICLES
Molecular defects in Sanfilippo syndrome type A
Department of Chemical Pathology, Women's and Children's Hospital, North Adelaide, Australia.
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