{"id":{"repo_id":"the-open-u","oai_identifier":"oai:oro.open.ac.uk:56060"},"canonical_url":"https://search.dev.ndltd.org/etd/the-open-u/oai:oro.open.ac.uk:56060","repository":{"repo_id":"the-open-u","name":"The Open University","base_url":"https://oro.open.ac.uk/cgi/oai2"},"display":{"title":"Nephrotic Syndrome and Glomerular Basement Membrane: Genetic Defect of the Laminin α5 Chain","abstract":"Nephrotic syndrome is a heterogeneous group of disorders characterised by renal and extra-renal manifestations. Classic symptoms of nephrotic syndrome include severe proteinuria, hypoalbumiaemia, oedema and hyperlipidaemia. <br></br><br></br> Genetic studies of hereditary forms of nephrotic syndrome have led to the identification of proteins playing a crucial role in slit diaphragm signalling, regulation of actin cytoskeleton dynamics and cell-matrix interactions. <br></br><br></br> The laminin α5 chain is a 404 kDa protein essential for embryonic development and, in association with laminin β2 and laminin γ1, it is a major component of the glomerular basement membrane. Mutations in <i>LAMB2</i> are associated with Pierson’s syndrome and mutations in <i>LAMA5</i> have recently been identified in paediatric patients affected by nephrotic syndrome. <br></br><br></br> As part of the MRC Harwell Ageing Screen, a large-scale ENU mutagenesis screen, a novel missense mutation (E884G) was identified in the gene Lama5. Homozygous mice showed a nephrotic phenotype including a severe proteinuria that preceded histological and ultrastructural changes. Further investigation using <i>in vitro</i> studies, extensive proteomics analysis and investigation of integrin activation, revealed a possible impact of the causative mutation on protein folding. Data suggest that changes in protein structure lead to a reduced secretion, integrin β1 activation, and agrin expression ultimately resulting in possible instability of the podocyte actin cytoskeleton.","abstract_html":"Nephrotic syndrome is a heterogeneous group of disorders characterised by renal and extra-renal manifestations. Classic symptoms of nephrotic syndrome include severe proteinuria, hypoalbumiaemia, oedema and hyperlipidaemia. &lt;br&gt;&lt;/br&gt;&lt;br&gt;&lt;/br&gt; Genetic studies of hereditary forms of nephrotic syndrome have led to the identification of proteins playing a crucial role in slit diaphragm signalling, regulation of actin cytoskeleton dynamics and cell-matrix interactions. &lt;br&gt;&lt;/br&gt;&lt;br&gt;&lt;/br&gt; The laminin α5 chain is a 404 kDa protein essential for embryonic development and, in association with laminin β2 and laminin γ1, it is a major component of the glomerular basement membrane. Mutations in &lt;i&gt;LAMB2&lt;/i&gt; are associated with Pierson’s syndrome and mutations in &lt;i&gt;LAMA5&lt;/i&gt; have recently been identified in paediatric patients affected by nephrotic syndrome. &lt;br&gt;&lt;/br&gt;&lt;br&gt;&lt;/br&gt; As part of the MRC Harwell Ageing Screen, a large-scale ENU mutagenesis screen, a novel missense mutation (E884G) was identified in the gene Lama5. Homozygous mice showed a nephrotic phenotype including a severe proteinuria that preceded histological and ultrastructural changes. Further investigation using &lt;i&gt;in vitro&lt;/i&gt; studies, extensive proteomics analysis and investigation of integrin activation, revealed a possible impact of the causative mutation on protein folding. Data suggest that changes in protein structure lead to a reduced secretion, integrin β1 activation, and agrin expression ultimately resulting in possible instability of the podocyte actin cytoskeleton.","abstract_has_math":false,"creators":["Falcone, Sara"],"institution":"The Open University","degree_name":"phd","degree_level":"doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-07","date_published":"2018-07","updated_at":"2026-07-24T05:02:52Z","subjects":[],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Falcone, Sara"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2018-07-10"]},{"key":"dc:date.issued","label":"Date","values":["2018-07"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["ARRAY(0x7ffb9a1762f8)"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["The Open University"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://oro.open.ac.uk/56060/"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["phd"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://oro.open.ac.uk/56060/1/SF%20corrected%20thesis%20PDF.pdf","https://oro.open.ac.uk/56060/8/__HULSE_RAS-StudentData_STEM_Active%20Students_FALCONE%20Sara%20C8105567_Exam_Corrections%20%2B%20Completion_Completion_Thesis%20deposition%20form.pdf","https://oro.open.ac.uk/56060/9/__HULSE_RAS-StudentData_STEM_Active%20Students_FALCONE%20Sara%20C8105567_Exam_Corrections%20%2B%20Completion_Completion_GRADPROG%20memo-%20ARC.docx","https://oro.open.ac.uk/56060/16/Falcone%20-%20Library%20deposition%20memo.doc"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Nephrotic syndrome is a heterogeneous group of disorders characterised by renal and extra-renal manifestations. Classic symptoms of nephrotic syndrome include severe proteinuria, hypoalbumiaemia, oedema and hyperlipidaemia. <br></br><br></br> Genetic studies of hereditary forms of nephrotic syndrome have led to the identification of proteins playing a crucial role in slit diaphragm signalling, regulation of actin cytoskeleton dynamics and cell-matrix interactions. <br></br><br></br> The laminin α5 chain is a 404 kDa protein essential for embryonic development and, in association with laminin β2 and laminin γ1, it is a major component of the glomerular basement membrane. Mutations in <i>LAMB2</i> are associated with Pierson’s syndrome and mutations in <i>LAMA5</i> have recently been identified in paediatric patients affected by nephrotic syndrome. <br></br><br></br> As part of the MRC Harwell Ageing Screen, a large-scale ENU mutagenesis screen, a novel missense mutation (E884G) was identified in the gene Lama5. Homozygous mice showed a nephrotic phenotype including a severe proteinuria that preceded histological and ultrastructural changes. Further investigation using <i>in vitro</i> studies, extensive proteomics analysis and investigation of integrin activation, revealed a possible impact of the causative mutation on protein folding. Data suggest that changes in protein structure lead to a reduced secretion, integrin β1 activation, and agrin expression ultimately resulting in possible instability of the podocyte actin cytoskeleton."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf","application/vnd.openxmlformats-officedocument.wordprocessingml.document","application/msword"]},{"key":"dc:title","label":"Title","values":["Nephrotic Syndrome and Glomerular Basement Membrane: Genetic Defect of the Laminin α5 Chain"]}]}],"canonical_facts":{"dc:creator":["Falcone, Sara"],"dc:date":["2018-07-10"],"dc:date.issued":["2018-07"],"dc:description.abstract":["Nephrotic syndrome is a heterogeneous group of disorders characterised by renal and extra-renal manifestations. Classic symptoms of nephrotic syndrome include severe proteinuria, hypoalbumiaemia, oedema and hyperlipidaemia. <br></br><br></br> Genetic studies of hereditary forms of nephrotic syndrome have led to the identification of proteins playing a crucial role in slit diaphragm signalling, regulation of actin cytoskeleton dynamics and cell-matrix interactions. <br></br><br></br> The laminin α5 chain is a 404 kDa protein essential for embryonic development and, in association with laminin β2 and laminin γ1, it is a major component of the glomerular basement membrane. Mutations in <i>LAMB2</i> are associated with Pierson’s syndrome and mutations in <i>LAMA5</i> have recently been identified in paediatric patients affected by nephrotic syndrome. <br></br><br></br> As part of the MRC Harwell Ageing Screen, a large-scale ENU mutagenesis screen, a novel missense mutation (E884G) was identified in the gene Lama5. Homozygous mice showed a nephrotic phenotype including a severe proteinuria that preceded histological and ultrastructural changes. Further investigation using <i>in vitro</i> studies, extensive proteomics analysis and investigation of integrin activation, revealed a possible impact of the causative mutation on protein folding. 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