title: SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency.
abstract: Multiple Sulfatase Deficiency (MSD) is caused by mutations in the sulfatase-modifying factor 1 gene encoding the formylglycine-generating enzyme (FGE). FGE post translationally activates all newly synthesized sulfatases by generating the catalytic residue formylglycine. Impaired FGE function leads to reduced sulfatase activities. Patients display combined clinical symptoms of single sulfatase deficiencies. For ten MSD patients, we determined the clinical phenotype, FGE expression, localization and stability, as well as residual FGE and sulfatase activities. A neonatal, very severe clinical phenotype resulted from a combination of two nonsense mutations leading to almost fully abrogated FGE activity, highly unstable FGE protein and nearly undetectable sulfatase activities. A late infantile mild phenotype resulted from FGE G263V leading to unstable protein but high residual FGE activity. Other missense mutations resulted in a late infantile severe phenotype because of unstable protein with low residual FGE activity. Patients with identical mutations displayed comparable clinical phenotypes. These data confirm the hypothesis that the phenotypic outcome in MSD depends on both residual FGE activity as well as protein stability. Predicting the clinical course in case of molecularly characterized mutations seems feasible, which will be helpful for genetic counseling and developing therapeutic strategies aiming at enhancement of FGE.
authors.affiliation: Department of Pediatrics and Pediatric Neurology, Georg August University Göttingen, Göttingen, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Schlotawa
authors.forename: Eva Charlotte
authors.initials: EC
authors.lastname: Ennemann
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Radhakrishnan
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schmidt
authors.forename: Anupam
authors.initials: A
authors.lastname: Chakrapani
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Christen
authors.forename: Hugo
authors.initials: H
authors.lastname: Moser
authors.forename: Beat
authors.initials: B
authors.lastname: Steinmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Dierks
authors.forename: Jutta
authors.initials: J
authors.lastname: Gärtner
mesh_terms: D017668:Age of Onset; D020134:Catalytic Domain; D002675:Child, Preschool; D018389:Codon, Nonsense; D005347:Fibroblasts / Q000378:metabolism; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016464:Lysosomal Storage Diseases / Q000235:genetics; D052517:Multiple Sulfatase Deficiency Disease / Q000235:genetics*; D020125:Mutation, Missense; D050862:Oxidoreductases Acting on Sulfur Group Donors; D010641:Phenotype; D013429:Sulfatases / Q000172:deficiency / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D050862:Oxidoreductases Acting on Sulfur Group Donors; C480483:SUMF1 protein, human; D013429:Sulfatases