Identification of molecular defects in Italian Sanfilippo a patients including 13 novel mutations

Sanfilippo syndrome type A or mucopolysaccharidosis IIIA (MPS IIIA) is a lysosomal storage disorder caused by the deficiency of the enzyme heparin sulfamidase (EC 3.10.1.1), required for the degradation of the mucopolysaccharide heparan sulfate. Patients develop central nervous system degeneration resulting in progressive dementia, developmental delay, hyperactivity, and aggressive behaviour; subjects may present a wide spectrum of clinical severity. Here, we report the results from molecular analysis of 24 Italian MPS Ilia patients diagnosed over the last 15 years in our laboratory. Altogether, we were able to characterize 38 out of the 48 (79%) pathogenic alleles. We identified 16 molecular defects, 13 novel. The majority of alterations were missense mutations: on exon two (Y40N; A44T; S66W; R74C), on exon four (G122R; P128L; L146P; R150Q), on exon five (D179N; R182C), on exon six (P227R) and on exon eight (E369K; R377C). Single base pair deletions: on exon two (A52nt-1) and on exon eight (T360nt-1) and one base pair insertion on exon eight (V361nt+1) were also identified. Restriction enzyme or ARMS analyses were used to confirm each alteration. S66W represents the most common alteration in our patients population accounting for 33% of the total alleles. Interestingly, all six patients from Sardinia present this mutation, and five of them are homozygous for this change, suggesting that these subjects may have been derived from a common founder.