caa a22 4500 467932875 CHVBK 20180406152948.0 cr unu---uuuuu 170328e20061201xx s 000 0 eng 10.1007/s10545-006-0403-z doi (NATIONALLICENCE)springer-10.1007/s10545-006-0403-z Molecular characterization of Portuguese patients with mucopolysaccharidosis type II shows evidence that the IDS gene is prone to splicing mutations [Elektronische Daten] [S. Alves, M. Mangas, M. Prata, G. Ribeiro, L. Lopes, H. Ribeiro, J. Pinto-Basto, M. Lima, L. Lacerda] Summary: 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.104−2AG, c.241−2A>G, c.241−1G>A, c.418+1G>A, c.880−8AG and c.1181−1G>C); two exonic splice mutations (c.1006G>lC 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+1G>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. SSIEM and Springer, 2006 Alves S. Institute of Medical Genetics Jacinto Magalhães, Porto, Portugal aut Mangas M. Institute of Medical Genetics Jacinto Magalhães, Porto, Portugal aut Prata M. Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal aut Ribeiro G. Institute of Medical Genetics Jacinto Magalhães, Porto, Portugal aut Lopes L. Institute of Medical Genetics Jacinto Magalhães, Porto, Portugal aut Ribeiro H. Institute of Medical Genetics Jacinto Magalhães, Porto, Portugal aut Pinto-Basto J. Institute of Medical Genetics Jacinto Magalhães, Porto, Portugal aut Lima M. Institute of Medical Genetics Jacinto Magalhães, Porto, Portugal aut Lacerda L. Institute of Medical Genetics Jacinto Magalhães, Porto, Portugal aut Journal of Inherited Metabolic Disease Kluwer Academic Publishers 29/6(2006-12-01), 743-754 0141-8955 29:6<743 2006 29 10545 https://doi.org/10.1007/s10545-006-0403-z text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10545-006-0403-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Alves S. Institute of Medical Genetics Jacinto Magalhães, Porto, Portugal aut NATIONALLICENCE 700 1- Mangas M. Institute of Medical Genetics Jacinto Magalhães, Porto, Portugal aut NATIONALLICENCE 700 1- Prata M. Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal aut NATIONALLICENCE 700 1- Ribeiro G. Institute of Medical Genetics Jacinto Magalhães, Porto, Portugal aut NATIONALLICENCE 700 1- Lopes L. Institute of Medical Genetics Jacinto Magalhães, Porto, Portugal aut NATIONALLICENCE 700 1- Ribeiro H. Institute of Medical Genetics Jacinto Magalhães, Porto, Portugal aut NATIONALLICENCE 700 1- Pinto-Basto J. Institute of Medical Genetics Jacinto Magalhães, Porto, Portugal aut NATIONALLICENCE 700 1- Lima M. Institute of Medical Genetics Jacinto Magalhães, Porto, Portugal aut NATIONALLICENCE 700 1- Lacerda L. Institute of Medical Genetics Jacinto Magalhães, Porto, Portugal aut NATIONALLICENCE 773 0- Journal of Inherited Metabolic Disease Kluwer Academic Publishers 29/6(2006-12-01), 743-754 0141-8955 29:6<743 2006 29 10545 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer