Mucopolysaccharidosis type I: molecular characteristics of two novel alpha-L-iduronidase mutations in Tunisian patients
1 Laboratory of Biochemistry, Farhat Hached Hospital, 4000 Sousse - Tunisia
2 Laboratory of Molecular Biology, University of Pharmacy, 5000 Monastir - Tunisia
3 Laboratory of Pediatric LaRabta Hospital Tunis-Tunisia
4 Hereditary Metabolic Diseases Service, Center for Biology and Pathology, Est Hospices Civils Lyon, 69677 BRON CEDEX France
Diagnostic Pathology 2011, 6:47 doi:10.1186/1746-1596-6-47Published: 3 June 2011
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.
Aim of study: This study was carried out on six newly collected MPS I patients recruited from many regions of Tunisia.
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.
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.
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.
The identification of these mutations should facilitate prenatal diagnosis and counseling for MPS I in Tunisia.
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 126.96.36.199). 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) . Isolation of complementary and genomic DNAs encoding human α -L- iduronidase [2,3] 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; http://www.hgmd.org webcite). High prevalence of the common mutations p.W402X and p.Q70X has been described; both of them in the severe clinical forms [4,5]. A high prevalence of common mutation p.P533R has also been described in MPS I patients with various phenotypes [5,6]. In addition, rare mutations including single base substitution, deletion, insertion and splicing site mutation have been identified , indicating a high degree of allelic heterogeneity in IDUA gene.
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 .