Molecular analysis of 30 mucopolysaccharidosis type I patients: evaluation of the mutational spectrum in Italian population and identification of 13 novel mutations.
Mucopolysaccharidosis type I (MPS-I orMPS1) is an autosomal recessive condition characterized by a broad range of clinical symptoms. Molecular diagnosis of MPS-I is important 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.
Centro Ricerca Fondazione M. Tettamanti and BMT-Unit, Università di Milano-Bicocca, Ospedale San Gerardo, Monza, Italy.
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N
Venturi
A
A
Rovelli
R
R
Parini
F
F
Menni
F
F
Brambillasca
F
F
Bertagnolio
G
G
Uziel
R
R
Gatti
M
M
Filocamo
M A
MA
Donati
A
A
Biondi
S
S
Goldwurm
D000483:Alleles; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007068:Iduronidase / Q000235:genetics*; D007558:Italy; D008059:Mucopolysaccharidosis I / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D010641:Phenotype
D004247:DNA; D007068:Iduronidase