Abstract
BackgroundThe mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease resulting from the defective activity of the enzyme α-L-iduronidase (IDUA). The disease has three major clinical subtypes (severe Hurler syndrome, intermediate Hurler–Scheie syndrome and attenuated Scheie syndrome). We aim to identify the genetic variants in MPS I patients and to investigate the effect of the novel splice site mutation on splicing of IDUA- mRNA variability using bioinformatics tools.MethodsThe IDUA mutations were determined in four MPS I patients from four families from Northern Tunisia, by amplifying and sequencing each of the IDUA exons and intron–exon junctions.ResultsOne novel splice site IDUA mutation, c.1650 + 1G > T in intron 11 and two previously reported mutations, p.A75T and p.R555H, were detected. The patients in families 1 and 2 who have the Hurler phenotype were homozygotes for the novel splice site mutation c.1650 + 1G > T. The patient in family 3, who also had the Hurler phenotype, was a compound heterozygote for the novel splice site mutation c.1650 + 1G > T and for the previously reported missense mutation p.A75T. The patient in family 4 who had the Hurler–Scheie phenotype was a compound heterozygote for the novel splice site mutation c.1650 + 1G > T and for the previously reported missense mutation p.R555H. In addition, four known IDUA polymorphisms were identified. Bioinformatics tools allowed us to associate the variant c.1650 + 1G > T with the severe clinical phenotype of MPS I. This variant affects the essential nucleotide + 1 (G to T) of the donor splice site of IDUA intron 11. The G > T in intron 11 leads to wild type donor site broken with minus 19.97% value compared to normal value with 0%, hence the new splice site acceptor has plus 5.59%.ConclusionsThe present findings indicate that the identified mutations facilitate the accurate carrier detection (genetic counseling of at-risk relatives) and the molecular prenatal diagnosis in Tunisia.
Highlights
The mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease resulting from the defective activity of the enzyme α-L-iduronidase (IDUA)
Phenotypic analysis confirmed the diagnosis of all the MPS Mucopolysaccharidosis type IH (IH) studied patients
For all the studied patients, the electrophoresis on cellulose acetate plate of GAGs showed the presence of heparan sulphate (HS) and dermatan sulphate (DS), an abnormal band, compared to the control case, in addition to an abnormal band of HS in MPSIII patient (Fig. 1)
Summary
The mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease resulting from the defective activity of the enzyme α-L-iduronidase (IDUA). Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by the deficient activity of the enzyme α-L-iduronidase (IDUA, EC 3.2.1.76). This glycosidase is required for the hydrolysis of αL-iduronide residues of dermatan sulphate and heparan sulphate [1]. The IDUA gene has 19 kb in length, containing 14 exons and 13 introns It is mapped on the short arm of chromosome 4 at region p16.3 [2] being transcribed into a 2.3 kb cDNA, which encodes a 653-residue glycopeptide [3].
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