Molecular analysis of 30 mucopolysaccharidosis type I patients: evaluation of the mutational spectrum in Italian population and identification of 13 novel mutations

Abstract

Mucopolysaccharidosis type I (MPS-I orMPS1) is an autosomal recessive condition characterized by a broad range of clinical symptoms. Molecular diagnosis of MPS-I isimportant for analyzing genotype-phenotype correlation and for selecting patients for innovative therapies. In this study we analyzed 30 Italian MPS-I patients with different phenotypes (20 severe, 6 intermediate, 4 mild) in an attempt to recognize the mutational spectrum in our population and to identify major DNA alterations specific to our country. We identified 93% of mutated alleles (56 out of 60) with the reconstruction of the complete genotype in 26 patients out of 30. Twenty-three different mutations were found, 13 of which are novel while the remaining 10 have been already described. Among the novel mutations we found 5 non conservative missense mutations (A160D, E178K, P183R, G197D, D349Y), one nonsense mutation (C53X), 6 deletions (468-470del3, 486-491del6, 755-759del5, 1251delC, 1839-1867del29, 1902-1903del2), and one splice site mutation (IVS11+5G>A). No common mutation for MPS-I is present in our country. Frequently (40% of the alleles), mutations were found in just one or two patients. However, Q70X, P533R, G51D, and W402X mutations were present in several patients (15%, 13.3%, 13.3%, and 11.6% of the alleles respectively) suggesting a Mediterranean origin of the P533R and G51D mutations. In most cases the patients' genotypes were unique combinations of mutations. The great heterogeneity found in our MPS-I population hampers mutation detection and hinders the genotype-phenotype correlation.

Gene Therapy for a Mucopolysaccharidosis Type I Murine Model with Lentiviral-IDUA Vector

“…Several mutations have been characterized in the Italian population (Gatti et al, 1997;Venturi et al, 2002). In some situations the DNA analysis helps to predict prognosis, but in the majority of patients the distinction between the various subtypes is made on clinical grounds.…”

Evaluation and identification of IDUA gene mutations in Turkishpatients with mucopolysaccharidosis type I

“…For Hurler-Scheie syndrome, the onset of the disease is between 1 and 6 years, survival is variable, and mental retardation is absent or mild, but is not present before 3 years of age. Scheie syndrome manifests itself after 5 years of age, survival is normal, and mental retardation is absent (4).…”

“…Hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) can effectively treat (10)(11)(12), and Spain (13). However, it appears less frequently in Russia (4%) (14), Italy (11%) (4,15), and Brazil (20%) (16). The frequency of p.Q70X is 50% in Russia and Scandinavia; it appears less often in other countries (14,17).…”

“…p.G51D is a common mutation in Italy, with a frequency of 13% (4). It was reported that p.P533R originated in North Africa and is common in Mediterranean countries, appearing at a frequency of 13% in Italy and 10% in Spain (4,14,18). These findings clearly demonstrate that the distribution of IDUA gene mutations is varied among populations.…”

Research Article Clinical features of Mexican patients with Mucopolysaccharidosis type I.

“…Recently, the term severe MPS-I has been suggested to describe patients with early onset and rapid progression, whereas attenuated MPS-I is the suggested term for the milder phenotype and longer life span during the disease course (Wraith, 1995;Neufeld and Muenzer, 2001). Phenotypic heterogeneity is thought to be caused by various combinations of mutations of the IDUA gene (OMIM 252800), but other possible explanations are nonpathogenic polymorphism, residual enzymatic activity, the presence of alternative substrates, modifying genes, and environmental factors that can contribute to difficulty in understanding genotypephenotype correlation (Scott et al, 1993;Venturi et al, 2002;Pereira et al, 2008).…”