Volume 113, Issue 4, Pages (May 2003)

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Volume 113, Issue 4, Pages 445-456 (May 2003) The Multiple Sulfatase Deficiency Gene Encodes an Essential and Limiting Factor for the Activity of Sulfatases Maria Pia Cosma, Stefano Pepe, Ida Annunziata, Robert F Newbold, Markus Grompe, Giancarlo Parenti, Andrea Ballabio Cell Volume 113, Issue 4, Pages 445-456 (May 2003) DOI: 10.1016/S0092-8674(03)00348-9

Figure 1 Mapping of the MSD Gene by Microcell-Mediated Chromosome Transfer (A) Sulfatase activities of clones selected after microcell-mediated chromosome transfer. Each of the 22 autosomes was serially transferred into the immortalized MSD cell line obtained from case 1 in Table 1. ARSA, ARSB, and ARSC activities were assayed in 25 independent clones picked after selection with HAT and hygromycin. Average sulfatase activities are expressed in enzymatic units × mg total protein−1 × 3 hr−1. Chromosome 3 clones complement the MSD defect. (B) Sulfatase activities of individual clones from chromosome 3 transfer. ARSA, ARSB, and ARSC activities of 20 independent clones selected after chromosome 3 transfer are shown. Results of microsatellite analysis performed on each independent clone are represented with + and −, indicating the presence or absence of the donor chromosome 3, respectively. Wt and −/− indicate sulfatase activities from control and MSD cell lines, respectively. Only clones retaining the donor chromosome 3 complement the defect. (C) Minimal chromosome 3 complementing region. D3S3630 and D3S2397 polymorphic microsatellite markers include the minimal complementing region narrowed after microsatellite analysis performed on clones generated through irradiation microcell-mediated chromosome transfer. The genes that map within the complementing region are shown. Cell 2003 113, 445-456DOI: (10.1016/S0092-8674(03)00348-9)

Figure 2 Mutations of SUMF1 in MSD Patients (A) Chromatograms of selected mutations. Case 1: homozygous C > T transition causing a missense mutation; Case 8: heterozygous T > C transition causing a missense mutation; Case 2: heterozygous deletion of a G causing a frameshift mutation (see Table 1). Arrows indicate the mutation sites. (B) Splicing mutations. RT-PCR was performed on the mRNAs from cases 6 and 9. An additional aberrant lower band was detected in both cases. Sequence analysis showed skipping of exon 3. (C) Localization of the mutations associated with MSD. SUMF1 exon-intron structure and the locations of all the mutations found are schematically represented. Cell 2003 113, 445-456DOI: (10.1016/S0092-8674(03)00348-9)

Figure 3 SUMF1 Homologs and Evolutionary Conservation (A) Protein alignment. Shadowed boxes indicate amino acids that are represented in more than 50% of the protein sequences shown. Stars indicate missense mutations found in SUMF1. (B) Phylogenetic tree of SUMF1 homologs in selected species. SUMF1 and SUMF2 homologs appear to have evolved independently after vertebrate speciation. Cell 2003 113, 445-456DOI: (10.1016/S0092-8674(03)00348-9)

Figure 4 SUMF1 Expression and Protein Localization (A) Northern blot analysis of SUMF1 mRNA. SUMF1 expression was investigated in the indicated tissues. Hybridization of the β-ACTIN control probe is also shown. SUMF1 is expressed ubiquitously with higher levels in kidney and liver. (B) SUMF1-Myc immunofluorescence analysis. Cos7 cells were transfected with SUMF1-Myc cDNA. Anti-Myc and Anti-ER antibodies were used for detection. The merged picture demonstrates ER localization of the SUMF1-Myc encoded protein. Cell 2003 113, 445-456DOI: (10.1016/S0092-8674(03)00348-9)

Figure 5 SUMF1 Enhances ARSA, ARSC, and ARSE Activities (A) Cotransfection of SUMF1 with ARSA, ARSC, and ARSE cDNAs in Cos-7 cells. Single transfections were performed with either SUMF1, ARSA, ARSC, or ARSE cDNAs, or with an empty vector. Double transfections were performed with either SUMF1 + ARSA, SUMF1 + ARSC, or SUMF1 + ARSE cDNAs at 1:1 ratio. Double transfections showed a 20- to 50-fold increase of enzymatic activities. (B) Cotransfection of SUMF1 and ARSA cDNAs in different cell lines. HEPG-2, HEK293, and U2OS cell lines were single transfected with either SUMF1 or ARSA cDNAs. Double transfections were performed with SUMF1 + ARSA cDNAs at 1:1 ratio. Increase of ARSA activity was observed in double compared to single transfections. (C) Time-course analysis of SUMF1 enhancing effect on sulfatase activities. Cos-7 cells were cotransfected with SUMF1 + ARSA cDNAs at 1:1 ratio. Cells were harvested at 24, 48, and 72 hr after transfection. A linear increase of ARSA activity was observed. (D) Saturation of SUMF1 enhancing effect. ARSA activity was tested after cotransfection of Cos-7 cells with different SUMF1/ARSA ratios. A plateau of sulfatase activity is reached at high ratios, suggesting that ARSA is completely activated. (E) Competition among sulfatases for SUMF1 enhancing effect. Cos-7 cells were single transfected with either SUMF1, ARSA, or ARSC cDNAs, double transfected with either ARSA + ARSC, ARSA + ARSE, ARSC + ARSA, or ARSC + ARSE cDNAs, and triple transfected with ARSA + ARSC + ARSE cDNAs. The ratio of the cotransfected plasmids was 1:1 and 1:1:1, respectively. Each of the previously described combinations of plasmids was also cotransfected together with a constant amount of SUMF1 cDNA. Reduced enhancement by SUMF1 of each individual sulfatase activity in double and triple transfected cells compared to single transfected cells suggests the presence of competition among sulfatases. (F) Murine SUMF1, Drosophila SUMF1, and human SUMF2 enhance human sulfatase activities. Cos-7 cells were cotransfected with either SUMF1 + ARSA, mSUMF1 + ARSA, dSUMF1 + ARSA, or SUMF2 + ARSA cDNAs at 1:1 ratio. Cos-7 cells were also single transfected with ARSA cDNA or with the empty vector. Similarly, cotransfections were performed using either ARSC or ARSE cDNAs instead of ARSA. Enhancing effects on human ARSA, ARSC, and ARSE enzymatic activities were observed with both the murine and Drosophila SUMF1 genes. A much lower enhancing effect was also detected with SUMF2. Cell 2003 113, 445-456DOI: (10.1016/S0092-8674(03)00348-9)

Figure 6 SUMF1 Is Both an Essential and a Limiting Factor for the Activity of Sulfatases (A) In physiological conditions endogenous SUMF1 is able to activate all endogenous sulfatases. (B) In MSD, loss of function mutations in SUMF1, represented by a star, result in impaired activation of all sulfatases. (C) Overexpression of a sulfatase results in an increased amount of protein (larger circle) but partial enzymatic activity (smaller circle), resulting from incomplete activation due to limited availability of SUMF1-encoded protein. (D) A complete activation of the sulfatase occurs only when both a sulfatase and SUMF1 are simultaneously overexpressed (larger circles). Cell 2003 113, 445-456DOI: (10.1016/S0092-8674(03)00348-9)