title: Rapid degradation of an active formylglycine generating enzyme variant leads to a late infantile severe form of multiple sulfatase deficiency.
abstract: Multiple sulfatase deficiency (MSD) is a rare inborn error of metabolism affecting posttranslational activation of sulfatases by the formylglycine generating enzyme (FGE). Due to mutations in the encoding SUMF1 gene, FGE's catalytic capacity is impaired resulting in reduced cellular sulfatase activities. Both, FGE protein stability and residual activity determine disease severity and have previously been correlated with the clinical MSD phenotype. Here, we report a patient with a late infantile severe course of disease. The patient is compound heterozygous for two so far undescribed SUMF1 mutations, c.156delC (p.C52fsX57) and c.390A>T (p.E130D). In patient fibroblasts, mRNA of the frameshift allele is undetectable. In contrast, the allele encoding FGE-E130D is expressed. FGE-E130D correctly localizes to the endoplasmic reticulum and has a very high residual molecular activity in vitro (55% of wildtype FGE); however, it is rapidly degraded. Thus, despite substantial residual enzyme activity, protein instability determines disease severity, which highlights that potential MSD treatment approaches should target protein folding and stabilization mechanisms.
authors: Department of Pediatrics and Pediatric Neurology, Georg August University Göttingen, Göttingen, Germany.
authors: Lars
authors: L
authors: Schlotawa
authors: Karthikeyan
authors: K
authors: Radhakrishnan
authors: Matthias
authors: M
authors: Baumgartner
authors: Regula
authors: R
authors: Schmid
authors: Bernhard
authors: B
authors: Schmidt
authors: Thomas
authors: T
authors: Dierks
authors: Jutta
authors: J
authors: Gärtner
mesh_terms: D045744:Cell Line, Tumor; D002675:Child, Preschool; D004795:Enzyme Stability / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D025202:Molecular Diagnostic Techniques; D052517:Multiple Sulfatase Deficiency Disease / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D050862:Oxidoreductases Acting on Sulfur Group Donors; D013429:Sulfatases / Q000235:genetics* / Q000378:metabolism
chemical_list: D050862:Oxidoreductases Acting on Sulfur Group Donors; C480483:SUMF1 protein, human; D013429:Sulfatases