RESUMO
BACKGROUNDProteinuria is considered an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear whether all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Gräsbeck syndrome (IGS), which is characterized by intestinal malabsorption of vitamin B12 and in some cases proteinuria. CUBN encodes for cubilin, an intestinal and proximal tubular uptake receptor containing 27 CUB domains for ligand binding.METHODSWe used next-generation sequencing for renal disease genes to genotype cohorts of patients with suspected hereditary renal disease and chronic proteinuria. CUBN variants were analyzed using bioinformatics, structural modeling, and epidemiological methods.RESULTSWe identified 39 patients, in whom biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset. Since the proteinuria in these patients had a high proportion of albuminuria, glomerular diseases such as steroid-resistant nephrotic syndrome or Alport syndrome were often the primary clinical diagnosis, motivating renal biopsies and the use of proteinuria-lowering treatments. However, renal function was normal in all cases. By contrast, we did not found any biallelic CUBN variants in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis. Unlike the more N-terminal IGS mutations, 37 of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain. Finally, we show that 4 C-terminal CUBN variants are associated with albuminuria and slightly increased GFR in meta-analyses of large population-based cohorts.CONCLUSIONCollectively, our data suggest an important role for the C-terminal half of cubilin in renal albumin reabsorption. Albuminuria due to reduced cubilin function could be an unexpectedly common benign condition in humans that may not require any proteinuria-lowering treatment or renal biopsy.FUNDINGATIP-Avenir program, Fondation Bettencourt-Schueller (Liliane Bettencourt Chair of Developmental Biology), Agence Nationale de la Recherche (ANR) Investissements d'avenir program (ANR-10-IAHU-01) and NEPHROFLY (ANR-14-ACHN-0013, to MS), Steno Collaborative Grant 2018 (NNF18OC0052457, to TSA and MS), Heisenberg Professorship of the German Research Foundation (KO 3598/5-1, to AK), Deutsche Forschungsgemeinschaft (DFG) Collaborative Research Centre (SFB) KIDGEM 1140 (project 246781735, to CB), and Federal Ministry of Education and Research (BMB) (01GM1515C, to CB).
Assuntos
Albuminúria , Anemia Megaloblástica , Túbulos Renais Proximais , Síndromes de Malabsorção , Mutação , Proteinúria , Receptores de Superfície Celular , Deficiência de Vitamina B 12 , Albuminúria/epidemiologia , Albuminúria/genética , Albuminúria/metabolismo , Albuminúria/patologia , Anemia Megaloblástica/epidemiologia , Anemia Megaloblástica/genética , Anemia Megaloblástica/metabolismo , Anemia Megaloblástica/patologia , Feminino , Humanos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Síndromes de Malabsorção/epidemiologia , Síndromes de Malabsorção/genética , Síndromes de Malabsorção/metabolismo , Síndromes de Malabsorção/patologia , Masculino , Proteinúria/epidemiologia , Proteinúria/genética , Proteinúria/metabolismo , Proteinúria/patologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Deficiência de Vitamina B 12/epidemiologia , Deficiência de Vitamina B 12/genética , Deficiência de Vitamina B 12/metabolismo , Deficiência de Vitamina B 12/patologiaRESUMO
Damage to and loss of glomerular podocytes has been identified as the culprit lesion in progressive kidney diseases. Here, we combine mass spectrometry-based proteomics with mRNA sequencing, bioinformatics, and hypothesis-driven studies to provide a comprehensive and quantitative map of mammalian podocytes that identifies unanticipated signaling pathways. Comparison of the in vivo datasets with proteomics data from podocyte cell cultures showed a limited value of available cell culture models. Moreover, in vivo stable isotope labeling by amino acids uncovered surprisingly rapid synthesis of mitochondrial proteins under steady-state conditions that was perturbed under autophagy-deficient, disease-susceptible conditions. Integration of acquired omics dimensions suggested FARP1 as a candidate essential for podocyte function, which could be substantiated by genetic analysis in humans and knockdown experiments in zebrafish. This work exemplifies how the integration of multi-omics datasets can identify a framework of cell-type-specific features relevant for organ health and disease.
Assuntos
Regulação da Expressão Gênica , Estudos de Associação Genética , Nefropatias/genética , Podócitos/metabolismo , Animais , Sequência de Bases , Células Cultivadas , Humanos , Camundongos , Proteoma/metabolismo , Transcriptoma/genética , Peixe-ZebraRESUMO
Relata-se uma experiência de grupo com pacientes de cirurgia cardíaca. A atividade realiza-se no Instituto de Cardiologia do Rio Grande do Sul e tem por objetivo proporcionar aos pacientes a oportunidade de verbalizarem suas ansiedades e conversarem sobre suas experiências relacionadas com a cirurgia e anestesia. Os grupos reunem-se duas vezes por semana sendo constituídos por pacientes adultos em pré e pós-operatório imediato. A equipe de saúde é composta por enfermeiros, psicólogo, anestesista, cardiologistas e fisioterapeutas e sua atuaçäo é no sentido de auxiliar na compreensäo dos procedimentos aos quais o paciente vai se submeter, desfazendo fantasias distorcidas da realidade
