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Linda M. Hendershot - One of the best experts on this subject based on the ideXlab platform.
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Role of the HSP70 Co-Chaperone SIL1 in Health and Disease
International journal of molecular sciences, 2021Co-Authors: Viraj P. Ichhaporia, Linda M. HendershotAbstract:Cell surface and secreted proteins provide essential functions for multicellular life. They enter the endoplasmic reticulum (ER) lumen co-translationally, where they mature and fold into their complex three-dimensional structures. The ER is populated with a host of molecular chaperones, associated co-factors, and enzymes that assist and stabilize folded states. Together, they ensure that nascent proteins mature properly or, if this process fails, target them for degradation. BiP, the ER HSP70 chaperone, interacts with unfolded client proteins in a nucleotide-dependent manner, which is tightly regulated by eight DnaJ-type proteins and two nucleotide exchange factors (NEFs), SIL1 and GRP170. Loss of SIL1′s function is the leading cause of Marinesco-Sjogren syndrome (MSS), an autosomal recessive, multisystem disorder. The development of animal models has provided insights into SIL1′s functions and MSS-associated pathologies. This review provides an in-depth update on the current understanding of the molecular mechanisms underlying SIL1′s NEF activity and its role in maintaining ER homeostasis and normal physiology. A precise understanding of the underlying molecular mechanisms associated with the loss of SIL1 may allow for the development of new pharmacological approaches to treat MSS.
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SIL1, the endoplasmic-reticulum-localized BiP co-chaperone, plays a crucial role in maintaining skeletal muscle proteostasis and physiology.
Disease models & mechanisms, 2018Co-Authors: Viraj P. Ichhaporia, Jieun Kim, Kanisha Kavdia, Peter Vogel, Linda Horner, Sharon Frase, Linda M. HendershotAbstract:Mutations in SIL1, a cofactor for the endoplasmic reticulum (ER)-localized Hsp70 chaperone, BiP, cause Marinesco-Sjogren syndrome (MSS), an autosomal recessive disorder. Using a mouse model, we characterized molecular aspects of the progressive myopathy associated with MSS. Proteomic profiling of quadriceps at the onset of myopathy revealed that SIL1 deficiency affected multiple pathways critical to muscle physiology. We observed an increase in ER chaperones prior to the onset of muscle weakness, which was complemented by upregulation of multiple components of cellular protein degradation pathways. These responses were inadequate to maintain normal expression of secretory pathway proteins, including insulin and IGF-1 receptors. There was a paradoxical enhancement of downstream PI3K-AKT-mTOR signaling and glucose uptake in SIL1-disrupted skeletal muscles, all of which were insufficient to maintain skeletal muscle mass. Together, these data reveal a disruption in ER homeostasis upon SIL1 loss, which is countered by multiple compensatory responses that are ultimately unsuccessful, leading to trans-organellar proteostasis collapse and myopathy.
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SIL1, a nucleotide exchange factor for BiP, is not required for antibody assembly or secretion
Molecular biology of the cell, 2014Co-Authors: Viraj P. Ichhaporia, Tyler Sanford, Jenny Howes, Tony N. Marion, Linda M. HendershotAbstract:SIL1 is a nucleotide exchange factor for the endoplasmic reticulum chaperone BiP, and mutations in this gene lead to Marinesco-Sjögren syndrome (MSS), a debilitating autosomal recessive disease characterized by multisystem defects. A mouse model for MSS was previously produced by disrupting SIL1 using gene-trap methodology. The resulting SIL1Gt mouse phenocopies several pathologies associated with MSS, although its ability to assemble and secrete antibodies, the best-characterized substrate of BiP, has not been investigated. In vivo antigen-specific immunizations and ex vivo LPS stimulation of splenic B cells revealed that the SIL1Gt mouse was indistinguishable from wild-type age-matched controls in terms of both the kinetics and magnitude of antigen-specific antibody responses. There was no significant accumulation of BiP-associated Ig assembly intermediates or evidence that another molecular chaperone system was used for antibody production in the LPS-stimulated splenic B cells from SIL1Gt mice. ER chaperones were expressed at the same level in SIL1WT and SIL1Gt mice, indicating that there was no evident compensation for the disruption of SIL1. Finally, these results were confirmed and extended in three human EBV-transformed lymphoblastoid cell lines from individuals with MSS, leading us to conclude that the BiP cofactor SIL1 is dispensable for antibody production.
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c terminal mutations destabilize SIL1 bap and can cause marinesco sjogren syndrome
Journal of Biological Chemistry, 2012Co-Authors: Jennifer E. Howes, Yuichiro Shimizu, Matthias J. Feige, Linda M. HendershotAbstract:Marinesco-Sjogren syndrome (MSS) is an autosomal recessive, neurodegenerative, multisystem disorder characterized by severe phenotypes developing in infancy. Recently, mutations in the endoplasmic reticulum (ER)-associated co-chaperone SIL1/BAP were identified to be the major cause of MSS. SIL1 acts as a nucleotide exchange factor for BiP, the ER Hsp70 orthologue, which plays an essential role in the folding and assembly of nascent polypeptide chains in the ER. SIL1 facilitates the release of BiP from unfolded protein substrates, enabling the subsequent folding and transport of the protein. Although most mutations leading to MSS result in deletion of the majority of the protein, three separate mutations have been identified that disrupt only the last five or six amino acids of the protein, which were assumed to encode a divergent ER retention motif. This study presents an in depth analysis of two of these mutants and reveals that the phenotype in the affected individuals is not likely to be due to depletion of SIL1 from the ER via secretion. Instead, our analyses show that the mutant proteins are particularly unstable and either form large aggregates in the ER or are rapidly degraded via the proteasome. In agreement with our findings, homology modeling suggests that the very C-terminal residues of SIL1 play a role in its structural integrity rather than its localization. These new insights might be a first step toward a possible pharmacological treatment of certain types of MSS by specifically stabilizing the mutant SIL1 protein.
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C-terminal mutations destabilize SIL1/BAP and can cause Marinesco-Sjögren syndrome.
The Journal of biological chemistry, 2012Co-Authors: Jennifer E. Howes, Yuichiro Shimizu, Matthias J. Feige, Linda M. HendershotAbstract:Marinesco-Sjögren syndrome (MSS) is an autosomal recessive, neurodegenerative, multisystem disorder characterized by severe phenotypes developing in infancy. Recently, mutations in the endoplasmic reticulum (ER)-associated co-chaperone SIL1/BAP were identified to be the major cause of MSS. SIL1 acts as a nucleotide exchange factor for BiP, the ER Hsp70 orthologue, which plays an essential role in the folding and assembly of nascent polypeptide chains in the ER. SIL1 facilitates the release of BiP from unfolded protein substrates, enabling the subsequent folding and transport of the protein. Although most mutations leading to MSS result in deletion of the majority of the protein, three separate mutations have been identified that disrupt only the last five or six amino acids of the protein, which were assumed to encode a divergent ER retention motif. This study presents an in depth analysis of two of these mutants and reveals that the phenotype in the affected individuals is not likely to be due to depletion of SIL1 from the ER via secretion. Instead, our analyses show that the mutant proteins are particularly unstable and either form large aggregates in the ER or are rapidly degraded via the proteasome. In agreement with our findings, homology modeling suggests that the very C-terminal residues of SIL1 play a role in its structural integrity rather than its localization. These new insights might be a first step toward a possible pharmacological treatment of certain types of MSS by specifically stabilizing the mutant SIL1 protein.
Claudio Airoldi - One of the best experts on this subject based on the ideXlab platform.
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Anchored fibrous chrysotile silica and its ability in using nitrogen basic centers on cation complexing from aqueous solution
Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2003Co-Authors: Maria G Fonseca, Edson Cavalcanti Da Silva Filho, Ricardo S. De A. Machado Junior, Luiza N.h. Arakaki, José G.p. Espínola, Severino F. De Oliveira, Claudio AiroldiAbstract:Abstract Amorphous silica gel obtained through natural chrysotile was lixiviated with hydrochloric acid, which was chemically modified with organosilanes (H3CO)3SiR, where R corresponds to the organic moieties CH2CH2CH2NH2 and CH2CH2CH2NHCH2CH2NH2, yielding solids named SIL1 and SIL2. These anchored silicas showed 2.14±0.05 and 1.90±0.04 mmol g−1 of attached amino groups on surfaces SIL1 and SIL2, respectively. The isotherms of adsorption data were obtained by batchwise process, whose values were adjusted to a modified Langmuir equation. The maximum adsorption capacity showed the sequence for copper and cobalt as 1.02, 0.35 mmol g−1 on SIL2 and 0.71, 0.26 mmol g−1 on SIL1, respectively. By using calorimetric titration, the enthalpy change of the adsorption process was 18.77±0.75 and −43.29±1.08 kJ mol−1 for copper, 12.70±0.57 and −169.3±1.23 kJ mol−1 for cobalt on SIL1 and SIL2, respectively. Negative Gibbs free energy values are in agreement with the spontaneity of the proposed reactions involving both divalent cations, when complexed by basic amino groups attached to pendant chain covalently bonded to the inorganic surface.
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silylating agents grafted onto silica derived from leached chrysotile
Journal of Colloid and Interface Science, 2001Co-Authors: Maria G Fonseca, Andrea S Oliveira, Claudio AiroldiAbstract:Silica from leached chrysotile fibers (SILO) was silanized with trialkoxyaminosilanes to yield inorganic–organic hybrids designated SILx (x=1–3). The greatest amounts of the immobilized agents were quantified as 2.14, 1.90, and 2.18 mmol g−1 on SIL1, SIL2, and SIL3 for –(CH2)3NH2,–(CH2)3NH(CH2)2NH2, and –(CH2)3NH(CH2)2NH(CH2)2NH2 groups attached to the inorganic support. The infrared spectra for all modified silicas showed the absence of the Si–OH deformation mode, originally found at 950 cm−1, and the appearance of asymmetric and symmetric C–H stretching bands at 2950 and 2840 cm−1. Other important bands associated with the organic moieties were assigned to νas(NH) at 3478 and νsym(NH) at 3418 cm−1. The NMR spectrum of the solid precursor material suggested two different kinds of silicon atoms: silanol and siloxane groups, between −90 and 110 ppm; however, additional species of silicon that contain the organic moieties bonded to silicon at −58 and −66 ppm appeared after chemical modification. These modified silicas showed a high adsorption capacity for cobalt and copper cations in aqueous solution, in contrast to the original SILO matrix, confirming the unequivocal anchoring of silylating agents on the silica surface.
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Silylating agents grafted onto silica derived from leached chrysotile
Journal of colloid and interface science, 2001Co-Authors: Maria G Fonseca, Andrea Oliveira, Claudio AiroldiAbstract:Silica from leached chrysotile fibers (SILO) was silanized with trialkoxyaminosilanes to yield inorganic-organic hybrids designated SILx (x=1-3). The greatest amounts of the immobilized agents were quantified as 2.14, 1.90, and 2.18 mmol g(-1) on SIL1, SIL2, and SIL3 for -(CH(2))(3)NH(2),-(CH(2))(3)NH(CH(2))(2)NH(2), and -(CH(2))(3)NH(CH(2))(2)NH(CH(2))(2)NH(2) groups attached to the inorganic support. The infrared spectra for all modified silicas showed the absence of the Si-OH deformation mode, originally found at 950 cm(-1), and the appearance of asymmetric and symmetric C-H stretching bands at 2950 and 2840 cm(-1). Other important bands associated with the organic moieties were assigned to nu(as)(NH) at 3478 and nu(sym)(NH) at 3418 cm(-1). The NMR spectrum of the solid precursor material suggested two different kinds of silicon atoms: silanol and siloxane groups, between -90 and 110 ppm; however, additional species of silicon that contain the organic moieties bonded to silicon at -58 and -66 ppm appeared after chemical modification. These modified silicas showed a high adsorption capacity for cobalt and copper cations in aqueous solution, in contrast to the original SILO matrix, confirming the unequivocal anchoring of silylating agents on the silica surface. Copyright 2001 Academic Press.
Andreas Roos - One of the best experts on this subject based on the ideXlab platform.
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Identification of Cellular Pathogenicity Markers for SIL1 Mutations Linked to Marinesco-Sjögren Syndrome.
Frontiers in neurology, 2019Co-Authors: Christian Gatz, Thomas Labisch, Stephan Buchkremer, Joachim Weis, Denisa Hathazi, Ute Münchberg, Ben Munro, Rita Horvath, Ana Töpf, Andreas RoosAbstract:Background and objective: Recessive mutations in the SIL1 gene cause Marinesco-Sjogren syndrome (MSS), a rare neuropediatric disorder. MSS-patients typically present with congenital cataracts, intellectual disability, cerebellar ataxia and progressive vacuolar myopathy. However, atypical clinical presentations associated with SIL1 mutations have been described over the last years; compound heterozygosity of SIL1 missense mutations even resulted in a phenotype not fulfilling the clinical diagnostic criteria of MSS. Thus, a read-out system to evaluate reliably the pathogenicity of amino acid changes in SIL1 is needed. Here, we aim to provide suitable cellular biomarkers enabling the robust evaluation of pathogenicity of SIL1 mutations. Methods: Five SIL1 variants including one polymorphism (p.K132Q), three known pathogenic mutations (p.V231_I232del, p.G312R, and p.L457P) and one ambiguous missense variant (p.R92W) were studied along with the wild-type proteins in Hek293 in vitro models by cell biological assays, immunoprecipitation, immunoblotting, and immunofluorescence as well as electron microscopy. Moreover, the SIL1-interactomes were interrogated by tandem-affinity-purification and subsequent mass spectrometry. Results: Our combined studies confirmed the pathogenicity of p.V231_I232del, p.G312R, and p.L457P by showing instability of the proteins as well as tendency to form aggregates. This observation is in line with altered structure of the ER-Golgi system and vacuole formation upon expression of these pathogenic SIL1-mutants as well as the presence of oxidative or ER-stress. Reduced cellular fitness along with abnormal mitochondrial architecture could also be observed. Notably, both the polymorphic p.K132Q and the ambiguous p.R92W variants did not elicit such alterations. Study of the SIL1-interactome identified POC1A as a novel binding partner of wild-type SIL1; the interaction is disrupted upon the presence of pathogenic mutants but not influenced by the presence of benign variants. Disrupted SIL1-POC1A interaction is associated with centrosome disintegration. Conclusions: We developed a combination of cellular outcome measures to evaluate the pathogenicity of SIL1 variants in suitable in vitro models and demonstrated that the p. R92W missense variant is a polymorphism rather than a pathogenic mutation leading to MSS.
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In-depth phenotyping of lymphoblastoid cells suggests selective cellular vulnerability in Marinesco-Sjögren syndrome.
Oncotarget, 2017Co-Authors: Laxmikanth Kollipara, Stephan Buchkremer, José Andrés González Coraspe, Joachim Weis, René P. Zahedi, Denisa Hathazi, Jan Senderek, Andreas RoosAbstract:// Laxmikanth Kollipara 1, * , Stephan Buchkremer 2, * , Jose Andres Gonzalez Coraspe 2 , Denisa Hathazi 1 , Jan Senderek 3 , Joachim Weis 2 , Rene P. Zahedi 1, ** and Andreas Roos 1, 2, 4, ** 1 Leibniz-Institut fur Analytische Wissenschaften–ISAS –e.V., 44227 Dortmund, Germany 2 Institute of Neuropathology, University Hospital Aachen, RWTH Aachen, 5274 Aachen, Germany 3 Friedrich-Baur-Institute, Medical Faculty, Ludwig-Maximilians-University, 80336 Munich, Germany 4 The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK * First authors contributed equally to this work ** Senior authors contributed equally to this work Correspondence to: Andreas Roos, email: andreas.roos@ncl.ac.uk , andreas.roos@isas.de Keywords: Marinesco-Sjogren syndrome, woozy mouse, SIL1, ataxin-10, chaperonopathy Received: May 03, 2016 Accepted: May 28, 2017 Published: July 28, 2017 ABSTRACT SIL1 is a ubiquitous protein of the Endoplasmic Reticulum (ER) acting as a co-chaperone for the ER-resident chaperone, BiP. Recessive mutations of the corresponding gene lead to vulnerability of skeletal muscle and central nervous system in man (Marinesco-Sjogren syndrome; MSS) and mouse. However, it is still unclear how loss of ubiquitous SIL1 leads to selective vulnerability of the nervous system and skeletal muscle whereas other cells and organs are protected from clinical manifestations. In this study we aimed to disentangle proteins participating in selective vulnerability of SIL1-deficient cells and tissues: morphological examination of MSS patient-derived lymphoblastoid cells revealed altered organelle structures (ER, nucleus and mitochondria) thus showing subclinical vulnerability. To correlate structural perturbations with biochemical changes and to identify proteins potentially preventing phenotypical manifestation, proteomic studies have been carried out. Results of proteomic profiling are in line with the morphological findings and show affection of nuclear, mitochondrial and cytoskeletal proteins as well as of such responsible for cellular viability. Moreover, expression patterns of proteins known to be involved in neuromuscular disorders or in development and function of the nervous system were altered. Paradigmatic findings were confirmed by immunohistochemistry of splenic lymphocytes and the cerebellum of SIL1-deficient mice. Ataxin-10, identified with increased abundance in our proteome profile, is necessary for the neuronal survival but also controls muscle fiber apoptosis, thus declaring this protein as a plausible candidate for selective tissue vulnerability. Our combined results provide first insights into the molecular causes of selective cell and tissue vulnerability defining the MSS phenotype.
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SIL1-Mutant Mice Elucidate Chaperone Function in Neurological Disorders
Journal of neuromuscular diseases, 2016Co-Authors: Stephan Buchkremer, José Andrés González Coraspe, Joachim Weis, Andreas RoosAbstract:Chaperone dysfunction leading to the build-up of misfolded proteins could frequently be linked to clinical manifestations also affecting the nervous system and the skeletal muscle. In addition, increase in chaperone function is beneficial to antagonize protein aggregation and thus represents a promising target for therapeutic concepts for many genetic and acquired chaperonopathies. However, little is known on the precise molecular mechanisms defining the cell and tissue abnormalities in the case of impaired chaperone function as well as on underlying effects in the case of compensatory up-regulation of chaperones. This scarcity of knowledge often arises from a lack of appropriate animal models that mimic closely the human molecular, cellular, and histological characteristics. Here, we introduce the SIL1-mutant woozy mouse as a suitable model to investigate molecular and cellular mechanisms of impaired ER-chaperone function affecting the integrity of nervous system and skeletal muscle. The overlapping clinical findings in man and mouse indicate that woozy is a good copy of a human phenotype called Marinesco-Sjögren syndrome. We confirm the presence of ER-stress and expand the biochemical knowledge of altered nuclear envelope in muscle, a hallmark of SIL1-disease. In addition, our data suggest that impaired excitation-contraction coupling might be part of the SIL1-pathophysiology. Our results moreover indicate that divergent expression of pro- and anti-survival proteins is decisive for Purkinje cell survival. By summarizing the current knowledge of woozy, we focus on the suitability of this animal model to study neuroprotective co-chaperone function and to investigate the involvement of co-chaperones in the predisposition of other disorders such as diabetic neuropathy.
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Cellular Signature of SIL1 Depletion: Disease Pathogenesis due to Alterations in Protein Composition Beyond the ER Machinery.
Molecular neurobiology, 2015Co-Authors: Andreas Roos, Thomas Labisch, Stephan Buchkremer, Laxmikanth Kollipara, Christian Gatz, Chris Lentz, Eva Brauers, Jose Gerardo-nava, Joachim Weis, René P. ZahediAbstract:SIL1 acts as nucleotide exchange factor for the endoplasmic reticulum chaperone BiP. Mutations of SIL1 cause Marinesco-Sjögren syndrome (MSS), a neurodegenerative disorder. Moreover, a particular function of SIL1 for etiopathology of amyotrophic lateral sclerosis (ALS) was highlighted, thus declaring the functional SIL1-BiP complex as a modifier for neurodegenerative disorders. Thereby, depletion of SIL1 was associated with an earlier manifestation and in strengthened disease progression in ALS. Owing to the absence of appropriate in vitro models, the precise cellular pathophysiological mechanisms leading to neurodegeneration in MSS and triggering the same in further disorders like ALS are still elusive. We found that SIL1 depletion in human embryonic kidney 293 (HEK293) cells led to structural changes of the endoplasmic reticulum (ER) including the nuclear envelope and mitochondrial degeneration that closely mimic pathological alterations in MSS and ALS. Functional studies revealed disturbed protein transport, cytotoxicity with reduced proliferation and viability, accompanied by activation of cellular defense mechanisms including the unfolded protein response, ER-associated degradation pathway, proteolysis, and expression of apoptotic and survival factors. Our data moreover indicated that proteins involved in cytoskeletal organization, vesicular transport, mitochondrial function, and neurological processes contribute to SIL1 pathophysiology. Altered protein expression upon SIL1 depletion in vitro could be confirmed in SIL1-deficient motoneurones for paradigmatic proteins belonging to different functional classes. Our results demonstrate that SIL1-depleted HEK293 cells are an appropriate model to identify proteins modulated by SIL1 expression level and contributing to neurodegeneration in MSS and further disorders like ALS. Thereby, our combined results point out that proteins beyond such involved ER-related protein processing are affected by SIL1 depletion.
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Search for cryptic subtelomeric aberrations in patients with non-classical Marinesco-Sjögren phenotype
Journal of pediatric neurology, 2015Co-Authors: Andreas Roos, Gesa Schwanitz, Irmgard Diepolder, Jan Senderek, Katja EggermannAbstract:Marinesco-Sjogren syndrome (MSS) is a multiorgan disorder firstly described in 1931 by Gheorge Marinescu. During the last seven decades, research into the clinical picture of MSS has led to the description of varying MSS phenotypes and since 2005, it is known that mutations within the SIL1 gene cause MSS in a part of these patients. Among these “SIL1-related MSS cases”, “classical and non-classical phenotypes” are distinguished. All “SIL1-related MSS cases” show at least an ataxia due to cerebellar atrophy, congenital or infantile cataracts and a progressive myopathy as well as mental impairment (“classical MSS phenotype”). Additional clinical features are for example in some cases short stature, hypogonadism, scoliosis, nystagmus and strabismus (“non-classical MSS phenotype”). However, the primary pathology has remained unknown in non-SIL1-related MSS cases. As the clinical features detected in “classical MSS phenotype” and “non-classical MSS phenotype” may also be associated with cryptic subtelomeric rearrangements and as a frequent localization of for example cataract-related genes/loci within these regions is proven, we performed subtelomere screening in a series of 23 patients with “non-SIL1-related non-classical MSS phenotypes” presenting with at least three features like early cataracts, mental retardation, brain malformations, muscular hypotonia, growth retardation and skeletal abnormalities. Karyotype and the SIL1 coding sequence were normal in all cases. Subtelomere screening by multiplex ligation-dependent probe amplification did not identify any subtelomeric imbalances. Therefore, a causative role of these regions in manifesting "non-SIL1-related non-classical MSS phenotypes" seems to be unlikely.
Anna-kaisa Anttonen - One of the best experts on this subject based on the ideXlab platform.
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marinesco sjogren syndrome due to SIL1 mutations with a comment on the clinical phenotype
European Journal of Paediatric Neurology, 2013Co-Authors: M. Horvers, Anna-kaisa Anttonen, Anna-elina Lehesjoki, Eva Morava, Saskia B. Wortmann, Sascha Vermeer, B.p.c. Van De Warrenburg, Michèl A.a.p. WillemsenAbstract:Abstract Background Marinesco-Sjogren syndrome is an autosomal recessive cerebellar ataxia, characterised by cerebellar ataxia, myopathy, cataracts and intellectual disability, due to mutations in the SIL1 gene. Methods The clinical features and two novel SIL1 mutations of four Dutch patients with Marinesco-Sjogren syndrome are described and compared to the literature on genetically proven Marinesco-Sjogren patients. Results The core phenotype of this syndrome appears homogeneous, but: [1] cataract can develop later than the motor and cognitive signs; [2] myopathy is an early feature that seems progressive during the course of the disease; [3] serum creatine kinase is normal or only mildly elevated; [4] peripheral neuropathy is absent; and [5] a variable degree of intellectual disability is present in most Marinesco-Sjogren patients. Conclusions Because the late appearance of some hallmarks and the uncertainty as to whether incomplete phenotypes occur, SIL1 mutation analysis is helpful early in the diagnostic work-up of children with suspected inherited ataxias.
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Marinesco-Sjögren syndrome due to SIL1 mutations with a comment on the clinical phenotype.
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 2012Co-Authors: M. Horvers, Anna-kaisa Anttonen, Anna-elina Lehesjoki, Eva Morava, Saskia B. Wortmann, Sascha Vermeer, B.p.c. Van De Warrenburg, Michèl A.a.p. WillemsenAbstract:Marinesco-Sjögren syndrome is an autosomal recessive cerebellar ataxia, characterised by cerebellar ataxia, myopathy, cataracts and intellectual disability, due to mutations in the SIL1 gene. The clinical features and two novel SIL1 mutations of four Dutch patients with Marinesco-Sjögren syndrome are described and compared to the literature on genetically proven Marinesco-Sjögren patients. The core phenotype of this syndrome appears homogeneous, but: [1] cataract can develop later than the motor and cognitive signs; [2] myopathy is an early feature that seems progressive during the course of the disease; [3] serum creatine kinase is normal or only mildly elevated; [4] peripheral neuropathy is absent; and [5] a variable degree of intellectual disability is present in most Marinesco-Sjögren patients. Because the late appearance of some hallmarks and the uncertainty as to whether incomplete phenotypes occur, SIL1 mutation analysis is helpful early in the diagnostic work-up of children with suspected inherited ataxias. Copyright © 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
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Marinesco-Sjögren Syndrome
Encyclopedia of Movement Disorders, 2010Co-Authors: Anna-kaisa Anttonen, Anna-elina LehesjokiAbstract:Marinesco–Sjogren syndrome (MSS) is a rare autosomal recessively inherited neurodegenerative disorder characterized by cerebellar ataxia with cerebellar atrophy, early-onset cataracts, mild to severe mental retardation, hypotonia, and muscle weakness. Additional features include strabismus, hypergonadotropic hypogonadism, short stature, and orthopedic manifestations. The diagnosis is usually based on evaluation of clinical, neuroimaging, and muscle biopsy data combined with molecular genetic testing. Mutations in the SIL1 gene, which encodes an endoplasmic reticulum (ER) resident cochaperone, were recently identified as a major cause of MSS. SIL1 is so far the only gene associated with MSS and mutations can be found in 50–60% of patients.
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Novel SIL1 mutations and exclusion of functional candidate genes in Marinesco-Sjögren syndrome.
European journal of human genetics : EJHG, 2008Co-Authors: Anna-kaisa Anttonen, Outi Kopra, Eija Siintola, Lisbeth Tranebjærg, Nobue K. Iwata, Emilia K. Bijlsma, Hiroyuki Meguro, Yaeko Ichikawa, Jun Goto, Anna-elina LehesjokiAbstract:Marinesco-Sjogren syndrome (MSS) is a rare autosomal recessively inherited neurodegenerative disorder characterized by cerebellar ataxia, cataracts, mental retardation, and progressive myopathy. Recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum (ER) resident cochaperone, were identified as a major cause of MSS. We here report four novel mutations in SIL1, including the first missense substitution p.Leu457Pro described in MSS. In addition, we excluded three functional candidate genes, HSPA5, HYOU1, and AARS, as causative genes in SIL1 mutation-negative patients. To understand the mechanisms of disturbed SIL1 function, we studied the subcellular localization of the missense mutant Leu457Pro protein in COS-1 cells. Moreover, we studied a mutant protein lacking the putative C-terminal ER retrieval signal. In contrast to the wild-type protein's localization to ER and Golgi apparatus, both mutant proteins formed aggregates within the ER depending on the expression level. These data imply that aggregation of mutant proteins may contribute to MSS pathogenesis. The genetic background of a subgroup of patients with MSS remains uncovered.
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The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone
Nature Genetics, 2005Co-Authors: Anna-kaisa Anttonen, Ibrahim Mahjneh, Riikka H Hämäläinen, Clotilde Lagier-tourenne, Outi Kopra, Laura Waris, Mikko Anttonen, Tarja Joensuu, Hannu Kalimo, Anders PaetauAbstract:We identified the gene underlying Marinesco-Sjögren syndrome, which is characterized by cerebellar ataxia, progressive myopathy and cataracts. We identified four disease-associated, predicted loss-of-function mutations in SIL1 , which encodes a nucleotide exchange factor for the heat-shock protein 70 (HSP70) chaperone HSPA5. These data, together with the similar spatial and temporal patterns of tissue expression of SIL1 and Hspa5, suggest that disturbed SIL1-HSPA5 interaction and protein folding is the primary pathology in Marinesco-Sjögren syndrome.
Maria G Fonseca - One of the best experts on this subject based on the ideXlab platform.
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Anchored fibrous chrysotile silica and its ability in using nitrogen basic centers on cation complexing from aqueous solution
Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2003Co-Authors: Maria G Fonseca, Edson Cavalcanti Da Silva Filho, Ricardo S. De A. Machado Junior, Luiza N.h. Arakaki, José G.p. Espínola, Severino F. De Oliveira, Claudio AiroldiAbstract:Abstract Amorphous silica gel obtained through natural chrysotile was lixiviated with hydrochloric acid, which was chemically modified with organosilanes (H3CO)3SiR, where R corresponds to the organic moieties CH2CH2CH2NH2 and CH2CH2CH2NHCH2CH2NH2, yielding solids named SIL1 and SIL2. These anchored silicas showed 2.14±0.05 and 1.90±0.04 mmol g−1 of attached amino groups on surfaces SIL1 and SIL2, respectively. The isotherms of adsorption data were obtained by batchwise process, whose values were adjusted to a modified Langmuir equation. The maximum adsorption capacity showed the sequence for copper and cobalt as 1.02, 0.35 mmol g−1 on SIL2 and 0.71, 0.26 mmol g−1 on SIL1, respectively. By using calorimetric titration, the enthalpy change of the adsorption process was 18.77±0.75 and −43.29±1.08 kJ mol−1 for copper, 12.70±0.57 and −169.3±1.23 kJ mol−1 for cobalt on SIL1 and SIL2, respectively. Negative Gibbs free energy values are in agreement with the spontaneity of the proposed reactions involving both divalent cations, when complexed by basic amino groups attached to pendant chain covalently bonded to the inorganic surface.
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silylating agents grafted onto silica derived from leached chrysotile
Journal of Colloid and Interface Science, 2001Co-Authors: Maria G Fonseca, Andrea S Oliveira, Claudio AiroldiAbstract:Silica from leached chrysotile fibers (SILO) was silanized with trialkoxyaminosilanes to yield inorganic–organic hybrids designated SILx (x=1–3). The greatest amounts of the immobilized agents were quantified as 2.14, 1.90, and 2.18 mmol g−1 on SIL1, SIL2, and SIL3 for –(CH2)3NH2,–(CH2)3NH(CH2)2NH2, and –(CH2)3NH(CH2)2NH(CH2)2NH2 groups attached to the inorganic support. The infrared spectra for all modified silicas showed the absence of the Si–OH deformation mode, originally found at 950 cm−1, and the appearance of asymmetric and symmetric C–H stretching bands at 2950 and 2840 cm−1. Other important bands associated with the organic moieties were assigned to νas(NH) at 3478 and νsym(NH) at 3418 cm−1. The NMR spectrum of the solid precursor material suggested two different kinds of silicon atoms: silanol and siloxane groups, between −90 and 110 ppm; however, additional species of silicon that contain the organic moieties bonded to silicon at −58 and −66 ppm appeared after chemical modification. These modified silicas showed a high adsorption capacity for cobalt and copper cations in aqueous solution, in contrast to the original SILO matrix, confirming the unequivocal anchoring of silylating agents on the silica surface.
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Silylating agents grafted onto silica derived from leached chrysotile
Journal of colloid and interface science, 2001Co-Authors: Maria G Fonseca, Andrea Oliveira, Claudio AiroldiAbstract:Silica from leached chrysotile fibers (SILO) was silanized with trialkoxyaminosilanes to yield inorganic-organic hybrids designated SILx (x=1-3). The greatest amounts of the immobilized agents were quantified as 2.14, 1.90, and 2.18 mmol g(-1) on SIL1, SIL2, and SIL3 for -(CH(2))(3)NH(2),-(CH(2))(3)NH(CH(2))(2)NH(2), and -(CH(2))(3)NH(CH(2))(2)NH(CH(2))(2)NH(2) groups attached to the inorganic support. The infrared spectra for all modified silicas showed the absence of the Si-OH deformation mode, originally found at 950 cm(-1), and the appearance of asymmetric and symmetric C-H stretching bands at 2950 and 2840 cm(-1). Other important bands associated with the organic moieties were assigned to nu(as)(NH) at 3478 and nu(sym)(NH) at 3418 cm(-1). The NMR spectrum of the solid precursor material suggested two different kinds of silicon atoms: silanol and siloxane groups, between -90 and 110 ppm; however, additional species of silicon that contain the organic moieties bonded to silicon at -58 and -66 ppm appeared after chemical modification. These modified silicas showed a high adsorption capacity for cobalt and copper cations in aqueous solution, in contrast to the original SILO matrix, confirming the unequivocal anchoring of silylating agents on the silica surface. Copyright 2001 Academic Press.