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Thomas Dierks - One of the best experts on this subject based on the ideXlab platform.
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a homozygous missense variant of sumf1 in the bedouin population extends the clinical spectrum in ultrarare neonatal Multiple Sulfatase Deficiency
Molecular Genetics & Genomic Medicine, 2020Co-Authors: Orna Staretzchacham, Lars Schlotawa, Thomas Dierks, Ohad Wormser, Inbal Golantripto, Ohad S Birk, Carlos Ferreira, Karthikeyan RadhakrishnanAbstract:Background Multiple Sulfatase Deficiency (MSD, MIM #272200) is an ultrarare congenital disorder caused by SUMF1 mutation and often misdiagnosed due to its complex clinical presentation. Impeded by a lack of natural history, knowledge gained from individual case studies forms the source for a reliable diagnosis and consultation of patients and parents. Methods We collected clinical records as well as genetic and metabolic test results from two MSD patients. The functional properties of a novel SUMF1 variant were analyzed after expression in a cell culture model. Results We report on two MSD patients-the first neonatal type reported in Israel-both presenting with this most severe manifestation of MSD. Our patients showed uniform clinical symptoms with persistent pulmonary hypertension, hypotonia, and dysmorphism at birth. Both patients were homozygous for the same novel SUMF1 mutation (c.1043C>T, p.A348V). Functional analysis revealed that the SUMF1-encoded variant of formylglycine-generating enzyme is highly instable and lacks catalytic function. Conclusion The obtained results confirm genotype-phenotype correlation in MSD, expand the spectrum of clinical presentation and are relevant for diagnosis including the extremely rare neonatal severe type of MSD.
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severe neonatal Multiple Sulfatase Deficiency presenting with hydrops fetalis in a preterm birth patient
JIMD reports, 2019Co-Authors: Lars Schlotawa, Thomas Dierks, Andreas Ohlenbusch, Sophie Christoph, Eva Cloppenburg, Christoph G Korenke, Jutta GartnerAbstract:Multiple Sulfatase Deficiency (MSD) is an ultra-rare lysosomal storage disorder (LSD). Mutations in the SUMF1 gene encoding the formylglycine generating enzyme (FGE) result in an unstable FGE protein with reduced enzymatic activity, thereby affecting the posttranslational activation of newly synthesized Sulfatases. Complete absence of FGE function results in the most severe clinical form of MSD with neonatal onset and rapid deterioration. We report on a preterm infant presenting with hydrops fetalis, lung hypoplasia, and dysmorphism as major clinical signs. The patient died after 6 days from an intraventricular hemorrhage followed by multi-organ failure. MSD was caused by a homozygous SUMF1 stop mutation (c.191C>A, p.Ser64Ter). FGE protein and Sulfatase activities were absent in patient fibroblasts. Hydrops fetalis is a rare symptom of LSDs and should be considered in the differential diagnosis in combination with dysmorphism. The diagnostic set up should include measurements of glycosaminoglycan excretion and lysosomal enzyme activities, among them at least two Sulfatases, and molecular confirmation.
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Recognition and ER Quality Control of Misfolded Formylglycine-Generating Enzyme by Protein Disulfide Isomerase
'Elsevier BV', 2018Co-Authors: Lars Schlotawa, Thomas Dierks, Bernhard Schmidt, Michaela Wachs, Olaf Bernhard, Franz J. Mayer, Karthikeyan RadhakrishnanAbstract:Summary: Multiple Sulfatase Deficiency (MSD) is a fatal, inherited lysosomal storage disorder characterized by reduced activities of all Sulfatases in patients. Sulfatases require a unique post-translational modification of an active-site cysteine to formylglycine that is catalyzed by the formylglycine-generating enzyme (FGE). FGE mutations that affect intracellular protein stability determine residual enzyme activity and disease severity in MSD patients. Here, we show that protein disulfide isomerase (PDI) plays a pivotal role in the recognition and quality control of MSD-causing FGE variants. Overexpression of PDI reduces the residual activity of unstable FGE variants, whereas inhibition of PDI function rescues the residual activity of Sulfatases in MSD fibroblasts. Mass spectrometric analysis of a PDI+FGE variant covalent complex allowed determination of the molecular signature for FGE recognition by PDI. Our findings highlight the role of PDI as a disease modifier in MSD, which may also be relevant for other ER-associated protein folding pathologies. : Impaired activity of misfolded formylglycine-generating enzyme (FGE) results in Multiple Sulfatase Deficiency (MSD) in humans. Schlotawa et al. show that recognition and quality control of misfolded FGE by protein disulfide isomerase (PDI) play a crucial role in the manifestation of MSD as a severe disease. Keywords: endoplasmic reticulum, protein disulfide isomerase, protein folding, quality control, formylglycine, Sulfatases, Multiple Sulfatase Deficiency, lysosomal storage disorders, formylglycine generating enzyme, SUMF
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expanding the genetic cause of Multiple Sulfatase Deficiency a novel sumf1 variant in a patient displaying a severe late infantile form of the disease
Molecular Genetics and Metabolism, 2017Co-Authors: Ilona Jaszczuk, Lars Schlotawa, Thomas Dierks, Karthikeyan Radhakrishnan, Andreas Ohlenbusch, Dominique Koppenhofer, Mariusz Babicz, Monika Lejman, Agnieszka ługowskaAbstract:Abstract Multiple Sulfatase Deficiency (MSD) is a rare inherited metabolic disease caused by defective cellular Sulfatases. Activity of Sulfatases depends on post-translational modification catalyzed by formylglycine-generating enzyme (FGE), encoded by the SUMF1 gene. SUMF1 pathologic variants cause MSD, a syndrome presenting with a complex phenotype. We describe the first Polish patient with MSD caused by a yet undescribed pathologic variant c.337G > A [p.Glu113Lys] (i.e. p.E113K) in heterozygous combination with the known deletion allele c.519 + 5_519 + 8del [p.Ala149_Ala173del]. The clinical picture of the patient initially suggested late infantile metachromatic leukodystrophy, with developmental delay followed by regression of visual, hearing and motor abilities as the most apparent clinical symptoms. Transient signs of ichthyosis and minor dysmorphic features guided the laboratory workup towards MSD. Since MSD is a rare disease and there is a variable clinical spectrum, we thoroughly describe the clinical outcome of our patient. The FGE-E113K variant, expressed in cell culture, correctly localized to the endoplasmic reticulum but was retained intracellularly in contrast to the wild type FGE. Analysis of FGE-mediated activation of steroid Sulfatase in immortalized MSD cells revealed that FGE-E113K exhibited only approx. 15% of the activity of wild type FGE. Based on the crystal structure we predict that the exchange of glutamate-113 against lysine should induce a strong destabilization of the secondary structure, possibly affecting the folding for correct disulfide bridging between C235-C346 as well as distortion of the active site groove that could affect both the intracellular stability as well as the activity of FGE. Thus, the novel variant of the SUMF1 gene obviously results in functionally impaired FGE protein leading to a severe late infantile type of MSD.
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rapid degradation of an active formylglycine generating enzyme variant leads to a late infantile severe form of Multiple Sulfatase Deficiency
European Journal of Human Genetics, 2013Co-Authors: Lars Schlotawa, Thomas Dierks, Bernhard Schmidt, Karthikeyan Radhakrishnan, Matthias R Baumgartner, Regula Schmid, Jutta GartnerAbstract: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.
Lars Schlotawa - One of the best experts on this subject based on the ideXlab platform.
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a systematic review and meta analysis of published cases reveals the natural disease history in Multiple Sulfatase Deficiency
Journal of Inherited Metabolic Disease, 2020Co-Authors: Lars Schlotawa, Jutta Gartner, Laura Adang, Rebecca C Ahrensnicklas, Joana Preiskorn, Stina Schiller, Tim FriedeAbstract:Multiple Sulfatase Deficiency (MSD, MIM#272200) is an ultra-rare lysosomal storage disorder arising from mutations in the SUMF1 gene, which encodes the formylglycine-generating enzyme (FGE). FGE is necessary for the activation of Sulfatases, a family of enzymes that are involved in the degradation of sulfated substrates such as glycosaminoglycans and sulfolipids. SUMF1 mutations lead to functionally impaired FGE and individuals with MSD demonstrate clinical signs of single Sulfatase deficiencies, including metachromatic leukodystrophy (MLD) and several mucopolysaccharidosis (MPS) subtypes. Comprehensive information related to the natural history of MSD is missing. We completed a systematic literature review and a meta-analysis on data from published cases reporting on MSD. As available from these reports, we extracted clinical, genetic, biochemical, and brain imaging information. We identified 75 publications with data on 143 MSD patients with a total of 53 unique SUMF1 mutations. The mean survival was 13 years (95% CI 9.8-16.2 years). Seventy-five clinical signs and 11 key clusters of signs were identified. The most frequently affected organs systems were the nervous, skeletal, and integumentary systems. The most frequent MRI features were abnormal myelination and cerebral atrophy. Individuals with later onset MSD signs and survived longer than those with signs at birth. Less severe mutations, low disease burden and achievement of independent walking positively correlated with longer survival. Despite the limitations of our approach, we were able to define clinical characteristics and disease outcomes in MSD. This work will provide the foundation of natural disease history data needed for future clinical trial design.
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natural history of Multiple Sulfatase Deficiency retrospective phenotyping and functional variant analysis to characterize an ultra rare disease
Journal of Inherited Metabolic Disease, 2020Co-Authors: Laura Adang, Lars Schlotawa, Jutta Gartner, Ida Vanessa Doederlein Schwartz, Orna Staretzchacham, Samuel Groeschel, Christiane Kehrer, Klaus Harzer, Thiago Oliveira Silva, Mauricio De CastroAbstract:Multiple Sulfatase Deficiency (MSD) is an ultra-rare neurodegenerative disorder caused by pathogenic variants in SUMF1. This gene encodes formylglycine-generating enzyme (FGE), a protein required for Sulfatase activation. The clinical course of MSD results from additive effect of each Sulfatase Deficiency, including metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IIIE, IVA, VI), chondrodysplasia punctata, and X-linked ichthyosis. While it is known that affected individuals demonstrate a complex and severe phenotype, the genotype-phenotype relationship and detailed clinical course is unknown. We report on 35 cases enrolled in our retrospective natural history study, n = 32 with detailed histories. Neurologic function was longitudinally assessed with retrospective scales. Biochemical and computational modeling of novel SUMF1 variants was performed. Genotypes were classified based on predicted functional change, and each individual was assigned a genotype severity score. The median age at symptom onset was 0.25 years; median age at diagnosis was 2.7 years; and median age at death was 13 years. All individuals demonstrated developmental delay, and only a subset of individuals attained ambulation and verbal communication. All subjects experienced an accumulating systemic symptom burden. Earlier age at symptom onset and severe variant pathogenicity correlated with poor neurologic outcomes. Using retrospective deep phenotyping and detailed variant analysis, we defined the natural history of MSD. We found that attenuated cases can be distinguished from severe cases by age of onset, attainment of ambulation, and genotype. Results from this study can help inform prognosis and facilitate future study design.
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Multiple Sulfatase Deficiency a disease comprising mucopolysaccharidosis sphingolipidosis and more caused by a defect in posttranslational modification
International Journal of Molecular Sciences, 2020Co-Authors: Lars Schlotawa, Karthikeyan Radhakrishnan, Laura Adang, Rebecca C AhrensnicklasAbstract:Multiple Sulfatase Deficiency (MSD, MIM #272200) is an ultra-rare disease comprising pathophysiology and clinical features of mucopolysaccharidosis, sphingolipidosis and other Sulfatase deficiencies. MSD is caused by impaired posttranslational activation of Sulfatases through the formylglycine generating enzyme (FGE) encoded by the Sulfatase modifying factor 1 (SUMF1) gene, which is mutated in MSD. FGE is a highly conserved, non-redundant ER protein that activates all cellular Sulfatases by oxidizing a conserved cysteine in the active site of Sulfatases that is necessary for full catalytic activity. SUMF1 mutations result in unstable, degradation-prone FGE that demonstrates reduced or absent catalytic activity, leading to decreased activity of all Sulfatases. As the majority of Sulfatases are localized to the lysosome, loss of Sulfatase activity induces lysosomal storage of glycosaminoglycans and sulfatides and subsequent cellular pathology. MSD patients combine clinical features of all single Sulfatase deficiencies in a systemic disease. Disease severity classifications distinguish cases based on age of onset and disease progression. A genotype- phenotype correlation has been proposed, biomarkers like excreted storage material and residual Sulfatase activities do not correlate well with disease severity. The diagnosis of MSD is based on reduced Sulfatase activities and detection of mutations in SUMF1. No therapy exists for MSD yet. This review summarizes the unique FGE/ Sulfatase physiology, pathophysiology and clinical aspects in patients and their care and outlines future perspectives in MSD.
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a homozygous missense variant of sumf1 in the bedouin population extends the clinical spectrum in ultrarare neonatal Multiple Sulfatase Deficiency
Molecular Genetics & Genomic Medicine, 2020Co-Authors: Orna Staretzchacham, Lars Schlotawa, Thomas Dierks, Ohad Wormser, Inbal Golantripto, Ohad S Birk, Carlos Ferreira, Karthikeyan RadhakrishnanAbstract:Background Multiple Sulfatase Deficiency (MSD, MIM #272200) is an ultrarare congenital disorder caused by SUMF1 mutation and often misdiagnosed due to its complex clinical presentation. Impeded by a lack of natural history, knowledge gained from individual case studies forms the source for a reliable diagnosis and consultation of patients and parents. Methods We collected clinical records as well as genetic and metabolic test results from two MSD patients. The functional properties of a novel SUMF1 variant were analyzed after expression in a cell culture model. Results We report on two MSD patients-the first neonatal type reported in Israel-both presenting with this most severe manifestation of MSD. Our patients showed uniform clinical symptoms with persistent pulmonary hypertension, hypotonia, and dysmorphism at birth. Both patients were homozygous for the same novel SUMF1 mutation (c.1043C>T, p.A348V). Functional analysis revealed that the SUMF1-encoded variant of formylglycine-generating enzyme is highly instable and lacks catalytic function. Conclusion The obtained results confirm genotype-phenotype correlation in MSD, expand the spectrum of clinical presentation and are relevant for diagnosis including the extremely rare neonatal severe type of MSD.
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severe neonatal Multiple Sulfatase Deficiency presenting with hydrops fetalis in a preterm birth patient
JIMD reports, 2019Co-Authors: Lars Schlotawa, Thomas Dierks, Andreas Ohlenbusch, Sophie Christoph, Eva Cloppenburg, Christoph G Korenke, Jutta GartnerAbstract:Multiple Sulfatase Deficiency (MSD) is an ultra-rare lysosomal storage disorder (LSD). Mutations in the SUMF1 gene encoding the formylglycine generating enzyme (FGE) result in an unstable FGE protein with reduced enzymatic activity, thereby affecting the posttranslational activation of newly synthesized Sulfatases. Complete absence of FGE function results in the most severe clinical form of MSD with neonatal onset and rapid deterioration. We report on a preterm infant presenting with hydrops fetalis, lung hypoplasia, and dysmorphism as major clinical signs. The patient died after 6 days from an intraventricular hemorrhage followed by multi-organ failure. MSD was caused by a homozygous SUMF1 stop mutation (c.191C>A, p.Ser64Ter). FGE protein and Sulfatase activities were absent in patient fibroblasts. Hydrops fetalis is a rare symptom of LSDs and should be considered in the differential diagnosis in combination with dysmorphism. The diagnostic set up should include measurements of glycosaminoglycan excretion and lysosomal enzyme activities, among them at least two Sulfatases, and molecular confirmation.
Bernhard Schmidt - One of the best experts on this subject based on the ideXlab platform.
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Recognition and ER Quality Control of Misfolded Formylglycine-Generating Enzyme by Protein Disulfide Isomerase
'Elsevier BV', 2018Co-Authors: Lars Schlotawa, Thomas Dierks, Bernhard Schmidt, Michaela Wachs, Olaf Bernhard, Franz J. Mayer, Karthikeyan RadhakrishnanAbstract:Summary: Multiple Sulfatase Deficiency (MSD) is a fatal, inherited lysosomal storage disorder characterized by reduced activities of all Sulfatases in patients. Sulfatases require a unique post-translational modification of an active-site cysteine to formylglycine that is catalyzed by the formylglycine-generating enzyme (FGE). FGE mutations that affect intracellular protein stability determine residual enzyme activity and disease severity in MSD patients. Here, we show that protein disulfide isomerase (PDI) plays a pivotal role in the recognition and quality control of MSD-causing FGE variants. Overexpression of PDI reduces the residual activity of unstable FGE variants, whereas inhibition of PDI function rescues the residual activity of Sulfatases in MSD fibroblasts. Mass spectrometric analysis of a PDI+FGE variant covalent complex allowed determination of the molecular signature for FGE recognition by PDI. Our findings highlight the role of PDI as a disease modifier in MSD, which may also be relevant for other ER-associated protein folding pathologies. : Impaired activity of misfolded formylglycine-generating enzyme (FGE) results in Multiple Sulfatase Deficiency (MSD) in humans. Schlotawa et al. show that recognition and quality control of misfolded FGE by protein disulfide isomerase (PDI) play a crucial role in the manifestation of MSD as a severe disease. Keywords: endoplasmic reticulum, protein disulfide isomerase, protein folding, quality control, formylglycine, Sulfatases, Multiple Sulfatase Deficiency, lysosomal storage disorders, formylglycine generating enzyme, SUMF
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rapid degradation of an active formylglycine generating enzyme variant leads to a late infantile severe form of Multiple Sulfatase Deficiency
European Journal of Human Genetics, 2013Co-Authors: Lars Schlotawa, Thomas Dierks, Bernhard Schmidt, Karthikeyan Radhakrishnan, Matthias R Baumgartner, Regula Schmid, Jutta GartnerAbstract: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.
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sumf1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in Multiple Sulfatase Deficiency
European Journal of Human Genetics, 2011Co-Authors: Lars Schlotawa, Thomas Dierks, Bernhard Schmidt, Hugo W. Moser, Karthikeyan Radhakrishnan, Eva C Ennemann, Anupam Chakrapani, Hansjurgen Christen, Beat Steinmann, Jutta GartnerAbstract: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.
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molecular basis of Multiple Sulfatase Deficiency mucolipidosis ii iii and niemann pick c1 disease lysosomal storage disorders caused by defects of non lysosomal proteins
Biochimica et Biophysica Acta, 2009Co-Authors: Thomas Dierks, Marc André Frese, Lars Schlotawa, Kurt Von Figura, Karthikeyan Radhakrishnan, Bernhard SchmidtAbstract:Multiple Sulfatase Deficiency (MSD), mucolipidosis (ML) II/III and Niemann-Pick type C1 (NPC1) disease are rare but fatal lysosomal storage disorders caused by the genetic defect of non-lysosomal proteins. The NPC1 protein mainly localizes to late endosomes and is essential for cholesterol redistribution from endocytosed LDL to cellular membranes. NPC1 Deficiency leads to lysosomal accumulation of a broad range of lipids. The precise functional mechanism of this membrane protein, however, remains puzzling. ML II, also termed I cell disease, and the less severe ML III result from deficiencies of the Golgi enzyme N-acetylglucosamine 1-phosphotransferase leading to a global defect of lysosome biogenesis. In patient cells, newly synthesized lysosomal proteins are not equipped with the critical lysosomal trafficking marker mannose 6-phosphate, thus escaping from lysosomal sorting at the trans Golgi network. MSD affects the entire Sulfatase family, at least seven members of which are lysosomal enzymes that are specifically involved in the degradation of sulfated glycosaminoglycans, sulfolipids or other sulfated molecules. The combined deficiencies of all Sulfatases result from a defective post-translational modification by the ER-localized formylglycine-generating enzyme (FGE), which oxidizes a specific cysteine residue to formylglycine, the catalytic residue enabling a unique mechanism of sulfate ester hydrolysis. This review gives an update on the molecular bases of these enigmatic diseases, which have been challenging researchers since many decades and so far led to a number of surprising findings that give deeper insight into both the cell biology and the pathobiochemistry underlying these complex disorders. In case of MSD, considerable progress has been made in recent years towards an understanding of disease-causing FGE mutations. First approaches to link molecular parameters with clinical manifestation have been described and even therapeutical options have been addressed. Further, the discovery of FGE as an essential Sulfatase activating enzyme has considerable impact on enzyme replacement or gene therapy of lysosomal storage disorders caused by single Sulfatase deficiencies.
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Molecular basis of Multiple Sulfatase Deficiency, mucolipidosis II/III and Niemann-Pick C1 disease - Lysosomal storage disorders caused by defects of non-lysosomal proteins
Biochimica et Biophysica Acta - Molecular Cell Research, 2009Co-Authors: Thomas Dierks, Marc André Frese, Lars Schlotawa, Krishnan Radhakrishnan, Kurt Von Figura, Bernhard SchmidtAbstract:Multiple Sulfatase Deficiency (MSD), mucolipidosis (ML) II/III and Niemann-Pick type C1 (NPC1) disease are rare but fatal lysosomal storage disorders caused by the genetic defect of non-lysosomal proteins. The NPC1 protein mainly localizes to late endosomes and is essential for cholesterol redistribution from endocytosed LDL to cellular membranes. NPC1 Deficiency leads to lysosomal accumulation of a broad range of lipids. The precise functional mechanism of this membrane protein, however, remains puzzling. ML II, also termed I cell disease, and the less severe ML III result from deficiencies of the Golgi enzyme N-acetylglucosamine 1-phosphotransferase leading to a global defect of lysosome biogenesis. In patient cells, newly synthesized lysosomal proteins are not equipped with the critical lysosomal trafficking marker mannose 6-phosphate, thus escaping from lysosomal sorting at the trans Golgi network. MSD affects the entire Sulfatase family, at least seven members of which are lysosomal enzymes that are specifically involved in the degradation of sulfated glycosaminoglycans, sulfolipids or other sulfated molecules. The combined deficiencies of all Sulfatases result from a defective post-translational modification by the ER-localized formylglycine-generating enzyme (FGE), which oxidizes a specific cysteine residue to formylglycine, the catalytic residue enabling a unique mechanism of sulfate ester hydrolysis. This review gives an update on the molecular bases of these enigmatic diseases, which have been challenging researchers since many decades and so far led to a number of surprising findings that give deeper insight into both the cell biology and the pathobiochemistry underlying these complex disorders. In case of MSD, considerable progress has been made in recent years towards an understanding of disease-causing FGE mutations. First approaches to link molecular parameters with clinical manifestation have been described and even therapeutical options have been addressed. Further, the discovery of FGE as an essential Sulfatase activating enzyme has considerable impact on enzyme replacement or gene therapy of lysosomal storage disorders caused by single Sulfatase deficiencies. © 2008 Elsevier B.V. All rights reserved.
Kurt Von Figura - One of the best experts on this subject based on the ideXlab platform.
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molecular basis of Multiple Sulfatase Deficiency mucolipidosis ii iii and niemann pick c1 disease lysosomal storage disorders caused by defects of non lysosomal proteins
Biochimica et Biophysica Acta, 2009Co-Authors: Thomas Dierks, Marc André Frese, Lars Schlotawa, Kurt Von Figura, Karthikeyan Radhakrishnan, Bernhard SchmidtAbstract:Multiple Sulfatase Deficiency (MSD), mucolipidosis (ML) II/III and Niemann-Pick type C1 (NPC1) disease are rare but fatal lysosomal storage disorders caused by the genetic defect of non-lysosomal proteins. The NPC1 protein mainly localizes to late endosomes and is essential for cholesterol redistribution from endocytosed LDL to cellular membranes. NPC1 Deficiency leads to lysosomal accumulation of a broad range of lipids. The precise functional mechanism of this membrane protein, however, remains puzzling. ML II, also termed I cell disease, and the less severe ML III result from deficiencies of the Golgi enzyme N-acetylglucosamine 1-phosphotransferase leading to a global defect of lysosome biogenesis. In patient cells, newly synthesized lysosomal proteins are not equipped with the critical lysosomal trafficking marker mannose 6-phosphate, thus escaping from lysosomal sorting at the trans Golgi network. MSD affects the entire Sulfatase family, at least seven members of which are lysosomal enzymes that are specifically involved in the degradation of sulfated glycosaminoglycans, sulfolipids or other sulfated molecules. The combined deficiencies of all Sulfatases result from a defective post-translational modification by the ER-localized formylglycine-generating enzyme (FGE), which oxidizes a specific cysteine residue to formylglycine, the catalytic residue enabling a unique mechanism of sulfate ester hydrolysis. This review gives an update on the molecular bases of these enigmatic diseases, which have been challenging researchers since many decades and so far led to a number of surprising findings that give deeper insight into both the cell biology and the pathobiochemistry underlying these complex disorders. In case of MSD, considerable progress has been made in recent years towards an understanding of disease-causing FGE mutations. First approaches to link molecular parameters with clinical manifestation have been described and even therapeutical options have been addressed. Further, the discovery of FGE as an essential Sulfatase activating enzyme has considerable impact on enzyme replacement or gene therapy of lysosomal storage disorders caused by single Sulfatase deficiencies.
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Molecular basis of Multiple Sulfatase Deficiency, mucolipidosis II/III and Niemann-Pick C1 disease - Lysosomal storage disorders caused by defects of non-lysosomal proteins
Biochimica et Biophysica Acta - Molecular Cell Research, 2009Co-Authors: Thomas Dierks, Marc André Frese, Lars Schlotawa, Krishnan Radhakrishnan, Kurt Von Figura, Bernhard SchmidtAbstract:Multiple Sulfatase Deficiency (MSD), mucolipidosis (ML) II/III and Niemann-Pick type C1 (NPC1) disease are rare but fatal lysosomal storage disorders caused by the genetic defect of non-lysosomal proteins. The NPC1 protein mainly localizes to late endosomes and is essential for cholesterol redistribution from endocytosed LDL to cellular membranes. NPC1 Deficiency leads to lysosomal accumulation of a broad range of lipids. The precise functional mechanism of this membrane protein, however, remains puzzling. ML II, also termed I cell disease, and the less severe ML III result from deficiencies of the Golgi enzyme N-acetylglucosamine 1-phosphotransferase leading to a global defect of lysosome biogenesis. In patient cells, newly synthesized lysosomal proteins are not equipped with the critical lysosomal trafficking marker mannose 6-phosphate, thus escaping from lysosomal sorting at the trans Golgi network. MSD affects the entire Sulfatase family, at least seven members of which are lysosomal enzymes that are specifically involved in the degradation of sulfated glycosaminoglycans, sulfolipids or other sulfated molecules. The combined deficiencies of all Sulfatases result from a defective post-translational modification by the ER-localized formylglycine-generating enzyme (FGE), which oxidizes a specific cysteine residue to formylglycine, the catalytic residue enabling a unique mechanism of sulfate ester hydrolysis. This review gives an update on the molecular bases of these enigmatic diseases, which have been challenging researchers since many decades and so far led to a number of surprising findings that give deeper insight into both the cell biology and the pathobiochemistry underlying these complex disorders. In case of MSD, considerable progress has been made in recent years towards an understanding of disease-causing FGE mutations. First approaches to link molecular parameters with clinical manifestation have been described and even therapeutical options have been addressed. Further, the discovery of FGE as an essential Sulfatase activating enzyme has considerable impact on enzyme replacement or gene therapy of lysosomal storage disorders caused by single Sulfatase deficiencies. © 2008 Elsevier B.V. All rights reserved.
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molecular analysis of sumf1 mutations stability and residual activity of mutant formylglycine generating enzyme determine disease severity in Multiple Sulfatase Deficiency
Human Mutation, 2008Co-Authors: Lars Schlotawa, Thomas Dierks, Kurt Von Figura, Robert Steinfeld, Jutta GartnerAbstract:Multiple Sulfatase Deficiency (MSD) is a rare inborn autosomal-recessive disorder, which mainly combines clinical features of metachromatic leukodystrophy, mucopolysaccharidosis and X-linked ichthyosis. The clinical course ranges from neonatal severe to mild juvenile cases. MSD is caused by mutations in the SUMF1 gene encoding the formylglycine-generating enzyme (FGE). FGE posttranslationally activates Sulfatases by generating formylglycine in their catalytic sites. We analyzed the functional consequences of missense mutations p.A177P, p.W179S, p.A279V and p.R349W with regard to FGE's subcellular localization, enzymatic activity, protein stability, intracellular retention and resulting Sulfatase activities. All four mutations did not affect localization of FGE in the endoplasmic reticulum of MSD fibroblasts. However, they decreased its specific enzymatic activity to less than 1% (p.A177P and p.R349W), 3% (p.W179S) or 23% (p.A279V). Protein stability was severely decreased for p.A279V and p.R349W, and almost comparable to wild type for p.A177P and p.W179S. The patient with the mildest clinical phenotype carries the mutation p.A279V leading to decreased FGE protein stability, but high residual enzymatic activity and only slightly reduced Sulfatase activities. In contrast, the most severely affected patient carries the mutation p.R349W leading to drastically decreased protein stability, very low residual enzymatic activity and considerably reduced Sulfatase activities. Our functional studies provide novel insight into the molecular defect underlying MSD and reveal that both residual enzyme activity and protein stability of FGE contribute to the clinical phenotype. The application of improved functional assays to determine these two molecular parameters of FGE mutants may enable the prediction of the clinical outcome in the future. © 2007 Wiley-Liss, Inc.
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a general binding mechanism for all human Sulfatases by the formylglycine generating enzyme
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Dirk Roeser, Thomas Dierks, Bernhard Schmidt, Kurt Von Figura, Andrea Preusserkunze, Kathrin Gasow, Julia G Wittmann, Markus G RudolphAbstract:The formylglycine (FGly)-generating enzyme (FGE) uses molecular oxygen to oxidize a conserved cysteine residue in all eukaryotic Sulfatases to the catalytically active FGly. Sulfatases degrade and remodel sulfate esters, and inactivity of FGE results in Multiple Sulfatase Deficiency, a fatal disease. The previously determined FGE crystal structure revealed two crucial cysteine residues in the active site, one of which was thought to be implicated in substrate binding. The other cysteine residue partakes in a novel oxygenase mechanism that does not rely on any cofactors. Here, we present crystal structures of the individual FGE cysteine mutants and employ chemical probing of wild-type FGE, which defined the cysteines to differ strongly in their reactivity. This striking difference in reactivity is explained by the distinct roles of these cysteine residues in the catalytic mechanism. Hitherto, an enzyme-substrate complex as an essential cornerstone for the structural evaluation of the FGly formation mechanism has remained elusive. We also present two FGE-substrate complexes with pentamer and heptamer peptides that mimic Sulfatases. The peptides isolate a small cavity that is a likely binding site for molecular oxygen and could host reactive oxygen intermediates during cysteine oxidation. Importantly, these FGE-peptide complexes directly unveil the molecular bases of FGE substrate binding and specificity. Because of the conserved nature of FGE sequences in other organisms, this binding mechanism is of general validity. Furthermore, several disease-causing mutations in both FGE and Sulfatases are explained by this binding mechanism.
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molecular basis for Multiple Sulfatase Deficiency and mechanism for formylglycine generation of the human formylglycine generating enzyme
Cell, 2005Co-Authors: Thomas Dierks, Bernhard Schmidt, Kurt Von Figura, Malaiyalam Mariappan, Achim Dickmanns, Andrea Preusserkunze, Ralf Ficner, Markus G RudolphAbstract:Sulfatases are enzymes essential for degradation and remodeling of sulfate esters. Formylglycine (FGly), the key catalytic residue in the active site, is unique to Sulfatases. In higher eukaryotes, FGly is generated from a cysteine precursor by the FGly-generating enzyme (FGE). Inactivity of FGE results in Multiple Sulfatase Deficiency (MSD), a fatal autosomal recessive syndrome. Based on the crystal structure, we report that FGE is a single-domain monomer with a surprising paucity of secondary structure and adopts a unique fold. The effect of all 18 missense mutations found in MSD patients is explained by the FGE structure, providing a molecular basis of MSD. The catalytic mechanism of FGly generation was elucidated by six high-resolution structures of FGE in different redox environments. The structures allow formulation of a novel oxygenase mechanism whereby FGE utilizes molecular oxygen to generate FGly via a cysteine sulfenic acid intermediate.
Karthikeyan Radhakrishnan - One of the best experts on this subject based on the ideXlab platform.
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Multiple Sulfatase Deficiency a disease comprising mucopolysaccharidosis sphingolipidosis and more caused by a defect in posttranslational modification
International Journal of Molecular Sciences, 2020Co-Authors: Lars Schlotawa, Karthikeyan Radhakrishnan, Laura Adang, Rebecca C AhrensnicklasAbstract:Multiple Sulfatase Deficiency (MSD, MIM #272200) is an ultra-rare disease comprising pathophysiology and clinical features of mucopolysaccharidosis, sphingolipidosis and other Sulfatase deficiencies. MSD is caused by impaired posttranslational activation of Sulfatases through the formylglycine generating enzyme (FGE) encoded by the Sulfatase modifying factor 1 (SUMF1) gene, which is mutated in MSD. FGE is a highly conserved, non-redundant ER protein that activates all cellular Sulfatases by oxidizing a conserved cysteine in the active site of Sulfatases that is necessary for full catalytic activity. SUMF1 mutations result in unstable, degradation-prone FGE that demonstrates reduced or absent catalytic activity, leading to decreased activity of all Sulfatases. As the majority of Sulfatases are localized to the lysosome, loss of Sulfatase activity induces lysosomal storage of glycosaminoglycans and sulfatides and subsequent cellular pathology. MSD patients combine clinical features of all single Sulfatase deficiencies in a systemic disease. Disease severity classifications distinguish cases based on age of onset and disease progression. A genotype- phenotype correlation has been proposed, biomarkers like excreted storage material and residual Sulfatase activities do not correlate well with disease severity. The diagnosis of MSD is based on reduced Sulfatase activities and detection of mutations in SUMF1. No therapy exists for MSD yet. This review summarizes the unique FGE/ Sulfatase physiology, pathophysiology and clinical aspects in patients and their care and outlines future perspectives in MSD.
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a homozygous missense variant of sumf1 in the bedouin population extends the clinical spectrum in ultrarare neonatal Multiple Sulfatase Deficiency
Molecular Genetics & Genomic Medicine, 2020Co-Authors: Orna Staretzchacham, Lars Schlotawa, Thomas Dierks, Ohad Wormser, Inbal Golantripto, Ohad S Birk, Carlos Ferreira, Karthikeyan RadhakrishnanAbstract:Background Multiple Sulfatase Deficiency (MSD, MIM #272200) is an ultrarare congenital disorder caused by SUMF1 mutation and often misdiagnosed due to its complex clinical presentation. Impeded by a lack of natural history, knowledge gained from individual case studies forms the source for a reliable diagnosis and consultation of patients and parents. Methods We collected clinical records as well as genetic and metabolic test results from two MSD patients. The functional properties of a novel SUMF1 variant were analyzed after expression in a cell culture model. Results We report on two MSD patients-the first neonatal type reported in Israel-both presenting with this most severe manifestation of MSD. Our patients showed uniform clinical symptoms with persistent pulmonary hypertension, hypotonia, and dysmorphism at birth. Both patients were homozygous for the same novel SUMF1 mutation (c.1043C>T, p.A348V). Functional analysis revealed that the SUMF1-encoded variant of formylglycine-generating enzyme is highly instable and lacks catalytic function. Conclusion The obtained results confirm genotype-phenotype correlation in MSD, expand the spectrum of clinical presentation and are relevant for diagnosis including the extremely rare neonatal severe type of MSD.
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Recognition and ER Quality Control of Misfolded Formylglycine-Generating Enzyme by Protein Disulfide Isomerase
'Elsevier BV', 2018Co-Authors: Lars Schlotawa, Thomas Dierks, Bernhard Schmidt, Michaela Wachs, Olaf Bernhard, Franz J. Mayer, Karthikeyan RadhakrishnanAbstract:Summary: Multiple Sulfatase Deficiency (MSD) is a fatal, inherited lysosomal storage disorder characterized by reduced activities of all Sulfatases in patients. Sulfatases require a unique post-translational modification of an active-site cysteine to formylglycine that is catalyzed by the formylglycine-generating enzyme (FGE). FGE mutations that affect intracellular protein stability determine residual enzyme activity and disease severity in MSD patients. Here, we show that protein disulfide isomerase (PDI) plays a pivotal role in the recognition and quality control of MSD-causing FGE variants. Overexpression of PDI reduces the residual activity of unstable FGE variants, whereas inhibition of PDI function rescues the residual activity of Sulfatases in MSD fibroblasts. Mass spectrometric analysis of a PDI+FGE variant covalent complex allowed determination of the molecular signature for FGE recognition by PDI. Our findings highlight the role of PDI as a disease modifier in MSD, which may also be relevant for other ER-associated protein folding pathologies. : Impaired activity of misfolded formylglycine-generating enzyme (FGE) results in Multiple Sulfatase Deficiency (MSD) in humans. Schlotawa et al. show that recognition and quality control of misfolded FGE by protein disulfide isomerase (PDI) play a crucial role in the manifestation of MSD as a severe disease. Keywords: endoplasmic reticulum, protein disulfide isomerase, protein folding, quality control, formylglycine, Sulfatases, Multiple Sulfatase Deficiency, lysosomal storage disorders, formylglycine generating enzyme, SUMF
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expanding the genetic cause of Multiple Sulfatase Deficiency a novel sumf1 variant in a patient displaying a severe late infantile form of the disease
Molecular Genetics and Metabolism, 2017Co-Authors: Ilona Jaszczuk, Lars Schlotawa, Thomas Dierks, Karthikeyan Radhakrishnan, Andreas Ohlenbusch, Dominique Koppenhofer, Mariusz Babicz, Monika Lejman, Agnieszka ługowskaAbstract:Abstract Multiple Sulfatase Deficiency (MSD) is a rare inherited metabolic disease caused by defective cellular Sulfatases. Activity of Sulfatases depends on post-translational modification catalyzed by formylglycine-generating enzyme (FGE), encoded by the SUMF1 gene. SUMF1 pathologic variants cause MSD, a syndrome presenting with a complex phenotype. We describe the first Polish patient with MSD caused by a yet undescribed pathologic variant c.337G > A [p.Glu113Lys] (i.e. p.E113K) in heterozygous combination with the known deletion allele c.519 + 5_519 + 8del [p.Ala149_Ala173del]. The clinical picture of the patient initially suggested late infantile metachromatic leukodystrophy, with developmental delay followed by regression of visual, hearing and motor abilities as the most apparent clinical symptoms. Transient signs of ichthyosis and minor dysmorphic features guided the laboratory workup towards MSD. Since MSD is a rare disease and there is a variable clinical spectrum, we thoroughly describe the clinical outcome of our patient. The FGE-E113K variant, expressed in cell culture, correctly localized to the endoplasmic reticulum but was retained intracellularly in contrast to the wild type FGE. Analysis of FGE-mediated activation of steroid Sulfatase in immortalized MSD cells revealed that FGE-E113K exhibited only approx. 15% of the activity of wild type FGE. Based on the crystal structure we predict that the exchange of glutamate-113 against lysine should induce a strong destabilization of the secondary structure, possibly affecting the folding for correct disulfide bridging between C235-C346 as well as distortion of the active site groove that could affect both the intracellular stability as well as the activity of FGE. Thus, the novel variant of the SUMF1 gene obviously results in functionally impaired FGE protein leading to a severe late infantile type of MSD.
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rapid degradation of an active formylglycine generating enzyme variant leads to a late infantile severe form of Multiple Sulfatase Deficiency
European Journal of Human Genetics, 2013Co-Authors: Lars Schlotawa, Thomas Dierks, Bernhard Schmidt, Karthikeyan Radhakrishnan, Matthias R Baumgartner, Regula Schmid, Jutta GartnerAbstract: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.
