Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency
ABSTRACT Multiple sulfatase deficiency (MSD) is a rare disorder characterized by impaired activity of all known sulfatases. The gene mutated in this disease is SUMF1, which encodes a protein involved in a post-translational modification at the catalytic site of all sulfatases that is necessary for their function. SUMF1 strongly enhances the activity of sulfatases when coexpressed with sulfatase in Cos-7 cells. We performed a mutational analysis of SUMF1 in 20 MSD patients of different ethnic origin. The clinical presentation of these patients was variable, ranging from severe neonatal forms to mild phenotypes showing mild neurological involvement. A total of 22 SUMF1 mutations were identified, including missense, nonsense, microdeletion, and splicing mutations. We expressed all missense mutations in culture to study their ability to enhance the activity of sulfatases. Of the predicted amino acid changes, 11 (p.R349W, p.R224W, p.L20F, p.A348P, p.S155P, p.C218Y, p.N259I, p.A279V, p.R349Q, p.C336R, p.A177P) resulted in severely impaired sulfatase-enhancing activity. Two (p.R345C and p.P266L) showed a high residual activity on some, but not all, of the nine sulfatases tested, suggesting that some SUMF1 mutations may have variable effects on the activity of each sulfatase. This study compares, for the first time, clinical, biochemical, and molecular data in MSD patients. Our results show lack of a direct correlation between the type of molecular defect and the severity of phenotype. Hum Mutat 23:576–581, 2004. © 2004 Wiley-Liss, Inc.
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ABSTRACT: Multiple sulfatase deficiency (MSD, OMIM 272200) is an autosomal recessive leukodystrophy associated with the deficiency of several, in total seven, sulfatases. The disorder is clinically and biochemically variable. The clinical picture combines features of mucopolysaccharidosis and metachromatic leukodystrophy (MLD, OMIM 250100) in a variable spectrum. Here we report a 3-year old Iranian girl with an MLD-like presentation of MSD. Arylsulfatase A deficiency and sulfatide excretion were found. Differently from what was previously reported in Multiple sulfatase deficiency (MSD, OMIM 272200) is an autosomal recessive leukodystrophy associated with the deficiency of several, in total seven, sulfatases. The disorder is clinically and biochemically variable. The clinical picture combines features of mucopolysaccharidosis and metachromatic leukodystrophy (MLD, OMIM 250100) in a variable spectrum. Here we report a 3-year old Iranian girl with an MLD-like presentation of MSD. Arylsulfatase A deficiency and sulfatide excretion the literature, this girl never showed abnormal mucopolysaccharide excretion in the urine. There were no additional visceral or skeletal signs. She was originally diagnosed as having MLD. Only when she developed ichthyosis were seven additional sulfatases measured. In leukocytes, arylsulfatase A, steroid sulfatase and N-acetylglucosamine-6 sulfatase were profoundly deficient, while iduronate-2 sulfatase and arylsulfatase B were moderately reduced. In fibroblasts, N-acetylglucosamine-6 sulfatase was deficient, while arylsulfatase A was moderately reduced. This case illustrates the possible pitfalls in the clinical and laboratory diagnosis of MSD.Neuropediatrics 03/2001; 32(1):38-40. · 1.19 Impact Factor
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ABSTRACT: C(alpha)-formylglycine (FGly) is the catalytic residue in the active site of eukaryotic sulfatases. It is posttranslationally generated from a cysteine in the endoplasmic reticulum. The genetic defect of FGly formation causes multiple sulfatase deficiency (MSD), a lysosomal storage disorder. We purified the FGly generating enzyme (FGE) and identified its gene and nine mutations in seven MSD patients. In patient fibroblasts, the activity of sulfatases is partially restored by transduction of FGE encoding cDNA, but not by cDNA carrying an MSD mutation. The gene encoding FGE is highly conserved among pro- and eukaryotes and has a paralog of unknown function in vertebrates. FGE is localized in the endoplasmic reticulum and is predicted to have a tripartite domain structure.Cell 06/2003; 113(4):435-44. · 31.96 Impact Factor
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ABSTRACT: In multiple sulfatase deficiency (MSD), a human inherited disorder, the activities of all sulfatases are impaired due to a defect in posttranslational modification. Here we report the identification, by functional complementation using microcell-mediated chromosome transfer, of a gene that is mutated in MSD and is able to rescue the enzymatic deficiency in patients' cell lines. Functional conservation of this gene was observed among distantly related species, suggesting a critical biological role. Coexpression of SUMF1 with sulfatases results in a strikingly synergistic increase of enzymatic activity, indicating that SUMF1 is both an essential and a limiting factor for sulfatases. These data have profound implications on the feasibility of enzyme replacement therapy for eight distinct inborn errors of metabolism.Cell 06/2003; 113(4):445-56. · 31.96 Impact Factor