title: p.L18P: a novel IDUA mutation that causes a distinct attenuated phenotype in mucopolysaccharidosis type I patients.
abstract: Mucopolysaccharidosis type I is a rare autosomal recessive disorder caused by deficiency of α-l-iduronidase (IDUA) which leads to a wide spectrum of clinical severity. Here, we describe the case of four male patients who present the previously undescribed p.L18P mutation. Patient 1 (p.L18P/p.L18P) presents, despite multiple joint contractures, an attenuated phenotype. Patient 2 (p.L18P/p.W402X) was diagnosed at 4 years of age with bone dysplasia, coarse facies, limited mobility, claw hands and underwent bilateral carpal tunnel surgery at 6 years of age. Patients 3 and 4 (both p.L18P/p.L18P) are brothers. Patient 3 was diagnosed at 4 years of age, when presented claw hands, lower limb and shoulder pain, restricted articular movement and bilateral carpal tunnel syndrome. Patient 4 was diagnosed at 17 months of age when presented lower limb pain at night, respiratory allergy and repeated upper airways infections. Bioinformatics analysis indicates that p.L18P mutation reduces the signal peptide to 25 amino acids and alters its secondary structure. In conclusion, we report a new IDUA variant that alters the structure of the signal peptide, which likely impairs transport to lysosomes. Moreover, it leads to a distinct attenuated phenotype with mainly bone and cartilage symptoms, without visceromegalies, heart disease, or cognitive impairment.
authors.affiliation: Post-Graduate Program on Genetics and Molecular Biology, UFRGS, Porto Alegre, Brazil.|Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
authors.forename: G
authors.initials: G
authors.lastname: Pasqualim
authors.affiliation: Instituto de Puericultura e Pediatria Martagão Gesteira, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, Brazil.
authors.forename: M G
authors.initials: MG
authors.lastname: Ribeiro
authors.affiliation: Instituto de Puericultura e Pediatria Martagão Gesteira, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, Brazil.
authors.forename: G G G
authors.initials: GG
authors.lastname: da Fonseca
authors.affiliation: Fundación para el Estudio de las Enfermedades metabólicas (FESEN), Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Szlago
authors.affiliation: Fundación para el Estudio de las Enfermedades metabólicas (FESEN), Buenos Aires, Argentina.
authors.forename: A
authors.initials: A
authors.lastname: Schenone
authors.affiliation: Instituto de Genética Médica, Hospital Italiano, Montevideo, Uruguay.
authors.forename: A
authors.initials: A
authors.lastname: Lemes
authors.affiliation: Genzyme, Genzyme Latin America - A Sanofi Company, Rio de Janeiro, Brazil.
authors.forename: M V M
authors.initials: MV
authors.lastname: Rojas
authors.affiliation: Post-Graduate Program on Genetics and Molecular Biology, UFRGS, Porto Alegre, Brazil.|Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.|Department of Genetics, UFRGS, Porto Alegre, Brazil.|INAGEMP, Porto Alegre, Brazil.
authors.forename: U
authors.initials: U
authors.lastname: Matte
authors.affiliation: Post-Graduate Program on Genetics and Molecular Biology, UFRGS, Porto Alegre, Brazil.|Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.|Department of Genetics, UFRGS, Porto Alegre, Brazil.|INAGEMP, Porto Alegre, Brazil.|Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil.
authors.forename: R
authors.initials: R
authors.lastname: Giugliani
mesh_terms: D056947:Enzyme Replacement Therapy; D056726:Genetic Association Studies; D006801:Humans; D007068:Iduronidase / Q000235:genetics*; D008297:Male; D008059:Mucopolysaccharidosis I / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation
chemical_list: D007068:Iduronidase
keywords: Scheie syndrome; lysosomal storage disorders; mucopolysaccharidosis type I; signal peptide mutation