Mucopolysaccharidosis type I: molecular characteristics of two novel alpha-L-iduronidase mutations in Tunisian patients

<p>Abstract</p> <p>Background</p> <p>Mucopolysaccharidosis type I (MPS I) is an autosomal storage disease resulting from defective activity of the enzyme α-L-iduronidase (IDUA). This glycosidase is involved in the degradation of heparan sulfate and dermatan sulfate. MPS I has severe and milder phenotypic subtypes.</p> <p>Aim of study: This study was carried out on six newly collected MPS I patients recruited from many regions of Tunisia.</p> <p>Patients and methods: Mutational analysis of the IDUA gene in unrelated MPS I families was performed by sequencing the exons and intron-exon junctions of IDUA gene.</p> <p>Results</p> <p>Two novel IDUA mutations, p.L530fs (1587_1588 insGC) in exon 11 and p.F177S in exon 5 and two previously reported mutations p.P533R and p.Y581X were detected. The patient in family 1 who has the Hurler phenotype was homozygous for the previously described nonsense mutation p.Y581X.</p> <p>The patient in family 2 who also has the Hurler phenotype was homozygous for the novel missense mutation p.F177S. The three patients in families 3, 5 and 6 were homozygous for the p.P533R mutation. The patient in family 4 was homozygous for the novel small insertion 1587_1588 insGC. In addition, eighteen known and one unknown IDUA polymorphisms were identified.</p> <p>Conclusion</p> <p>The identification of these mutations should facilitate prenatal diagnosis and counseling for MPS I in Tunisia.</p> <p>Background</p> <p>Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by the deficient activity of the enzyme of α-L-iduronidase (IDUA, EC 3.2.1.76). This glycosidase is involved in the degradation of heparan sulfate and dermatan sulfate. The clinical phenotype of MPS I ranges from the very severe in Hurler syndrome (MPS IH) to the relatively benign in Scheie syndrome (MPS IS), with an intermediate phenotype designated Hurler/Scheie (MPS IH/S) <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>. Isolation of complementary and genomic DNAs encoding human α -L- iduronidase <abbrgrp><abbr bid="B2">2</abbr><abbr bid="B3">3</abbr></abbrgrp> have enable the identification of mutations underlying the enzyme defect and resulting in MPS I clinical phenotype. More than 100 mutations have been reported in patients with the MPS I subtypes (Human Gene Mutation Database; <url>http://www.hgmd.org</url>). High prevalence of the common mutations p.W402X and p.Q70X has been described; both of them in the severe clinical forms <abbrgrp><abbr bid="B4">4</abbr><abbr bid="B5">5</abbr></abbrgrp>. A high prevalence of common mutation p.P533R has also been described in MPS I patients with various phenotypes <abbrgrp><abbr bid="B5">5</abbr><abbr bid="B6">6</abbr></abbrgrp>. In addition, rare mutations including single base substitution, deletion, insertion and splicing site mutation have been identified <abbrgrp><abbr bid="B7">7</abbr></abbrgrp>, indicating a high degree of allelic heterogeneity in IDUA gene.</p> <p>Here, we described two novel IDUA mutations in MPS I Tunisian patients. These lesions were homoallelic in all the patients of the six families investigated as consanguineous marriages are still frequent in Tunisia <abbrgrp><abbr bid="B8">8</abbr></abbrgrp>.</p