Molecular characterization of Portuguese patients with mucopolysaccharidosis type II shows evidence that the IDS gene is prone to splicing mutations

• Type: Article in International Scientific Journal
• Date: 2006

Authors

Alves, S (Author) Other; Mangas, M (Author) Other; Prata, MJ (Author) FCUP; Ribeiro, G (Author) Other; Lopes, L (Author) Other; Ribeiro, H (Author) Other; Pinto Basto, J (Author) Other; Reis R Lima (Author) Other; Lacerda, L (Author) Other

Journal

Title: Journal of Inherited Metabolic Disease

Vol. 29

Pages: 743-754

ISSN: 0141-8955

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 26 Citations

Scopus - 29 Citations

Scientific classification

FOS: Medical and Health sciences > Clinical medicine

Other information

Authenticus ID: P-004-FTV

DOI: 10.1007/s10545-006-0403-z

Abstract (EN): Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal storage disease caused by a defect in the iduronate-2-sulfatase gene (IDS). Alternative splicing of the IDS gene can occur and the underlying regulatory mechanism may be rather complex. Nevertheless, little information is available on the role of variations at the IDS locus in the splicing process. Here we report that splice mutations at the IDS locus are an important source of MPS II pathogenicity, accounting for almost 56% of Portuguese cases. Among 16 unrelated Portuguese MPS II patients, 15 different mutations were identified: six intronic splice mutations (c.104-2A > G, c.241-2A > G, c.241-1G > A, c.418+IG > A, c.880-8A > G and c.1181-IG > C); two exonic splice mutations (c.1006G > C and c.1122C > T); five missense mutations (D269V, D69V, D148N, R88C and P86L); one nonsense mutation (Q465Ter); one total IDS gene deletion; and one rearrangement involving a IDS gene inversion. Furthermore, nine of the 15 detected mutations affected the usual splicing pattern at the locus. Some of them are responsible for dramatic changes in the splicing mechanism. For example, the substitution mutation, c.418+IG > A, revealed the presence of an exonic sequence inside intron 3. Our study provides evidence that the IDS locus is prone to splicing mutations and that such susceptibility is particularly high in exon 3 and neighbouring regions. Consequently, mutation screening of the IDS gene cannot be restricted to gDNA examination. Unless cDNA analysis is also conducted, misclassifications as silent or missense mutations can be produced and even uncharacteristic splice-site mutations can be misinterpreted as classic splicing defects that may generate severe, unconventional splicing alterations.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12