title: 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.
authors.affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Cosma
authors.forename: Stefano
authors.initials: S
authors.lastname: Pepe
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Parenti
authors.forename: Carmine
authors.initials: C
authors.lastname: Settembre
authors.forename: Ida
authors.initials: I
authors.lastname: Annunziata
authors.forename: Richard
authors.initials: R
authors.lastname: Wade-Martins
authors.forename: Carmela
authors.initials: C
authors.lastname: Di Domenico
authors.forename: Paola
authors.initials: P
authors.lastname: Di Natale
authors.forename: Anuj
authors.initials: A
authors.lastname: Mankad
authors.forename: Barbara
authors.initials: B
authors.lastname: Cox
authors.forename: Graziella
authors.initials: G
authors.lastname: Uziel
authors.forename: Grazia M S
authors.initials: GM
authors.lastname: Mancini
authors.forename: Enrico
authors.initials: E
authors.lastname: Zammarchi
authors.forename: Maria Alice
authors.initials: MA
authors.lastname: Donati
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Kleijer
authors.forename: Mirella
authors.initials: M
authors.lastname: Filocamo
authors.forename: Romeo
authors.initials: R
authors.lastname: Carrozzo
authors.forename: Massimo
authors.initials: M
authors.lastname: Carella
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
mesh_terms: D000818:Animals; D019556:COS Cells; D006801:Humans; D009154:Mutation; D050862:Oxidoreductases Acting on Sulfur Group Donors; D013106:Sphingolipidoses / Q000201:enzymology / Q000235:genetics*; D013429:Sulfatases / Q000172:deficiency / Q000235:genetics*
chemical_list: D050862:Oxidoreductases Acting on Sulfur Group Donors; C480483:SUMF1 protein, human; D013429:Sulfatases