RESUMO
Dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) cause diverse and largely distinct channelopathies, including inherited forms of neuromuscular disease, skeletal dysplasias, and arthropathy. Pathogenic TRPV4 mutations cause gain of ion channel function and toxicity that can be rescued by small molecule TRPV4 antagonists in cellular and animal models, suggesting that TRPV4 antagonism could be therapeutic for patients. Numerous variants in TRPV4 have been detected with targeted and whole exome/genome sequencing, but for the vast majority, their pathogenicity remains unclear. Here, we used a combination of clinical information and experimental structure-function analyses to evaluate 30 TRPV4 variants across various functional protein domains. We report clinical features of seven patients with TRPV4 variants of unknown significance and provide extensive functional characterization of these and an additional 17 variants, including structural position, ion channel function, subcellular localization, expression level, cytotoxicity, and protein-protein interactions. We find that gain-of-function mutations within the TRPV4 intracellular ankyrin repeat domain target charged amino acid residues important for RhoA interaction, whereas ankyrin repeat domain residues outside of the RhoA interface have normal or reduced ion channel activity. We further identify a cluster of gain-of-function variants within the intracellular intrinsically disordered region that may cause toxicity via altered interactions with membrane lipids. In contrast, assessed variants in the transmembrane domain and other regions of the intrinsically disordered region do not cause gain of function and are likely benign. Clinical features associated with gain of function and cytotoxicity include congenital onset of disease, vocal cord weakness, and motor predominant disease, whereas patients with likely benign variants often demonstrated late-onset and sensory-predominant disease. These results provide a framework for assessing additional TRPV4 variants with respect to likely pathogenicity, which will yield critical information to inform patient selection for future clinical trials for TRPV4 channelopathies.
Assuntos
Alemtuzumab/uso terapêutico , Fatores Imunológicos/uso terapêutico , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/efeitos adversos , Rituximab/uso terapêutico , Etanercepte/uso terapêutico , Feminino , Humanos , Imunossupressores/uso terapêutico , Troca PlasmáticaAssuntos
Crotonatos/uso terapêutico , Hidroxibutiratos/uso terapêutico , Fatores Imunológicos/efeitos adversos , Imunossupressores/uso terapêutico , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/efeitos adversos , Nitrilas/uso terapêutico , Toluidinas/uso terapêutico , Adulto , Feminino , Humanos , Leucoencefalopatia Multifocal Progressiva/diagnósticoAssuntos
Cerebelo/patologia , Fatores Imunológicos/efeitos adversos , Vírus JC/patogenicidade , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Natalizumab/efeitos adversos , Infecções por Polyomavirus/diagnóstico , Evolução Fatal , Humanos , Leucoencefalopatia Multifocal Progressiva/etiologia , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/etiologiaAssuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico , Doenças dos Nervos Cranianos/diagnóstico , Encefalite/diagnóstico , Alucinações/diagnóstico , Adolescente , Encefalite Antirreceptor de N-Metil-D-Aspartato/complicações , Encefalite Antirreceptor de N-Metil-D-Aspartato/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Congressos como Assunto , Doenças dos Nervos Cranianos/complicações , Doenças dos Nervos Cranianos/patologia , Diagnóstico Diferencial , Encefalite/complicações , Alucinações/complicações , Humanos , MasculinoRESUMO
Hypercalcemia from tumors has been associated with Posterior Reversible Encephalopathy Syndrome (PRES) but the mechanism remains unclear. In this article, we describe a case of PRES caused by hypercalcemia from lymphoma. We summarize the available scientific evidence linking hypercalcemia to failure of cerebral autoregulation and potentially PRES. A major link is the hypomagnesemia induced by hypercalcemia. While this concept requires further clinical testing and validation, it is clinically significant for the management of PRES, even when not directly caused by hypercalcemia.