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.

Rapid degradation of an active formylglycine generating enzyme variant leads to a late infantile severe form of multiple sulfatase deficiency

“…The early onset of neurodegeneration in the second year of life and the disease progression due to the manifestation of several additional clinical symptoms throughout her life is comparable to other described late infantile severe cases of MSD. [6][7][8] Two new MSD causing SUMF1 mutations In this patient we identified two so far unknown SUMF1 mutations. c.156delC leads to a frameshift and premature stop codon (p.C52fsX57).…”

“…For patients with a functionally characterized mutation, a prediction of the clinical outcome is possible. [6][7][8][9] Here, we report a patient with two novel SUMF1 mutations, one nonsense and one missense, describe the clinical consequences and correlate this with the molecular defects attributable to the missense mutation.…”

“…10,11 Expression studies Cell culturing of patient skin fibroblasts and HT-1080 fibrosarcoma cells as well as stable transfection with pSB-FGE-His plasmids were described earlier. 6,7 The FGE-E130D mutation was created by site-directed mutagenesis according to the QuikChange Protocol (Stratagene, La Jolla, CA, USA) with Pfu polymerase and complementary primer pairs (coding sequence only: FGE_ E130D-His_c 5 0 -CATGGATGCCTATGATGTCAGTAATACTG-3 0 ).…”

“…More than 30 different SUMF1 mutations are known, most of them missense mutations that affect stability and residual molecular activity of mutant FGE, which both determine MSD disease severity. 6,7 The clinical phenotype includes the neonatal very severe, late infantile (severe and mild) and rare juvenile (mild) form. MSD combines main clinical symptoms of different single sulfatase deficiencies like dysmorphic features, neurodegenerative course of disease and ichthyotic skin rash.…”

Characterization of Riemerella anatipestifer CH-1 gldJ gene and GldJ protein

“…The GldJ protein belongs to the formylglycine-generating sulfatase enzyme (FGE-sulfatase) superfamily. The homologous proteins found in eukaryotes were required for posttranslational sulphatase modification (SUMF1) (Schlotawa et al, 2011). Moreover, the GldJ protein was involved in the gliding motility of bacteria (Braun and McBride, 2005).…”