Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion

Ehsan, Mehroz; Kelly, Matthew; Hooper, Charlotte; Yavari, Arash; Beglov, Julia; Bellahcene, Mohamed; Ghataorhe, Kirandeep; Poloni, Giulia; Goel, Anuj; Kyriakou, Theodosios; Fleischanderl, Karin; Ehler, Elisabeth; Makeyev, Eugene V.; Lange, Stephan; Ashrafian, Houman; Redwood, Charles; Davies, Benjamin; Watkins, Hugh; Gehmlich, Katja

doi:10.1016/j.yjmcc.2018.07.248

Cited by 28 publications

(41 citation statements)

References 44 publications

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“…28 Indeed, the heterozygous mice for CSRP3 pathogenic variants do not display an overt cardiac phenotype (except for an increase in anterior wall thickness), while the homozygous mutated mouse shows a clear cardiomyopathy phenotype. 28 The "non -core HCM genes" with mutations in the present HCM cohort were GYG1, GUSB, PMM2 and SCO2. Cases 64, 161, 211, and 218 were indeed identified as heterozygous carriers of autosomal recessive alterations associated with PMM2, SCO2, GUSB, and GYG1 deficiency, respectively (TABLE 4).…”

Section: Statistical Assessment Of Genotype-phenotype Cor-mentioning

confidence: 72%

Identification of a variant hotspot in MYBPC3 and of a novel CSRP3 autosomal recessive alteration in a cohort of Polish cases affected by hypertrophic cardiomyopathy

Lipari¹,

Wypasek²,

Karpiński³

et al. 2020

Polish Archives of Internal Medicine

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INTRODUCTION Hypertrophic cardiomyopathy (HCM) is a heart disorder caused by autosomal dominant alterations affecting both sarcomeric genes and other nonsarcomeric loci in a minority of cases. However, in some patients, the occurrence of the causal pathogenic variant or variants in homozygosity, compound heterozygosity, or double heterozygosity has also been described. Most of the HCM pathogenic variants are missense and unique, but truncating mutations of the MYBPC3 gene have been reported as founder pathogenic variants in populations from Finland, France, Japan, Iceland, Italy, and the Netherlands. OBJECTIVES This study aimed to assess the genetic background of HCM in a cohort of Polish patients. PATIENTS AND METHODS Twenty-nine Polish patients were analyzed by a next-generation sequencing panel including 404 cardiovascular genes. RESULTS Pathogenic variants were found in 41% of the patients, with ultra-rare MYBPC3 c.2541C>G (p.Tyr847Ter) mutation standing for a variant hotspot and correlating with a lower age at HCM diagnosis. Among the nonsarcomeric genes, the CSRP3 mutation was found in a single case carrying the novel c.364C>T (p.Arg122Ter) variant in homozygosity. With this finding, the total number of known HCM cases with human CSRP3 knockout cases has reached 3. CONCLUSIONS This report expands the mutational spectrum and the inheritance pattern of HCM.

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Section: Statistical Assessment Of Genotype-phenotype Cor-mentioning

confidence: 72%

Identification of a variant hotspot in MYBPC3 and of a novel CSRP3 autosomal recessive alteration in a cohort of Polish cases affected by hypertrophic cardiomyopathy

Lipari¹,

Wypasek²,

Karpiński³

et al. 2020

Polish Archives of Internal Medicine

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“…However, despite the DCM phenotype, the gross performance of titin seemed to be unaffected by the missense variant: the titin protein has unchanged abundance and isoform composition and is normally incorporated into sarcomeres. Given the mild phenotype of our mouse model, it is no surprise that RNAseq identified only a modest number of differently expressed genes compared to other mouse models of cardiomyopathy [ 4 , 10 ]. Likewise, the proteomics approach identified only 6 differentially expressed proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Cardiac-specific loss of Bag3 results in cardiomyopathy in mice [ 11 ], and myofibrillar disruption in human induced pluripotent stem cell derived cardiomyocytes [ 26 ]. Moreover, the contribution of a proteo-toxic response to cardiomyopathy has been documented for pathogenic variants in CSRP3 and MYBPC3 through in vitro experiments and mouse models [ 10 , 57 ].…”

Section: Discussionmentioning

confidence: 99%

Functional analysis of a gene-edited mouse model to gain insights into the disease mechanisms of a titin missense variant

et al. 2021

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Titin truncating variants are a well-established cause of cardiomyopathy; however, the role of titin missense variants is less well understood. Here we describe the generation of a mouse model to investigate the underlying disease mechanism of a previously reported titin A178D missense variant identified in a family with non-compaction and dilated cardiomyopathy. Heterozygous and homozygous mice carrying the titin A178D missense variant were characterised in vivo by echocardiography. Heterozygous mice had no detectable phenotype at any time point investigated (up to 1 year). By contrast, homozygous mice developed dilated cardiomyopathy from 3 months. Chronic adrenergic stimulation aggravated the phenotype. Targeted transcript profiling revealed induction of the foetal gene programme and hypertrophic signalling pathways in homozygous mice, and these were confirmed at the protein level. Unsupervised proteomics identified downregulation of telethonin and four-and-a-half LIM domain 2, as well as the upregulation of heat shock proteins and myeloid leukaemia factor 1. Loss of telethonin from the cardiac Z-disc was accompanied by proteasomal degradation; however, unfolded telethonin accumulated in the cytoplasm, leading to a proteo-toxic response in the mice.We show that the titin A178D missense variant is pathogenic in homozygous mice, resulting in cardiomyopathy. We also provide evidence of the disease mechanism: because the titin A178D variant abolishes binding of telethonin, this leads to its abnormal cytoplasmic accumulation. Subsequent degradation of telethonin by the proteasome results in proteasomal overload, and activation of a proteo-toxic response. The latter appears to be a driving factor for the cardiomyopathy observed in the mouse model.

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“…(codificador de CRP3) são fonte de cardiomiopatia dilatada e hipertrófica familiar, fenótipo observado em humanos que carregam tais mutações (59,97). Estes achados corroboram as evidências deste trabalho, que fornecem os pilares para a solidificação do papel de CRP3 como mecanossensor no sistema cardiovascular.…”

Section: Modulação Da Rigidez Celular Em Resposta Ao Nocaute De Crp3unclassified

Papel da proteína rica em cisteína e glicina 3 (CRP3) na mecanotransdução de células musculares lisas aórticas

Ribeiro-Silva¹

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Agradeço àquele de quem toda sabedoria e conhecimento emanam-Deus que, apesar de Sua infinita grandeza e mesmo eu não sendo merecedor, me lapidou dia após dia desde o meu nascimento de forma que este trabalho fosse desenvolvido. Faltam-me palavras para expressar a minha gratidão. Às pessoas mais nobres que já conhecimeus pais, por incansavelmente suportarem o fardo representado pela criação de alguém como eu, por entenderem os momentos de ausência (que foram muitos) e por fornecerem o suporte necessário para que eu fosse capaz de desenvolver este trabalho. É uma honra ser filho de vocês. Às minhas irmãs, Ester e Nicole, por todo o carinho e compreensão, em especial à Nicole, por ser colírio para os olhos e conforto ao coração sempre, por me entender melhor do que ninguém e sempre buscar fazer o seu melhor para me agradar: palavras falham na tarefa de expressar meu carinho por vocês. Aos meus familiares maternos, especialmente aos meus tios Edilson, Edvaldo, Silvia, Valmir e à minha avó Letícia, por me apoiarem e acreditarem em mim mesmo quando eu estive em dúvida. Este trabalho não existiria se não fosse por vocês, muito obrigado! Ao meu orientador, Prof. Dr. José Eduardo Krieger, por me conceder o privilégio de ser parte do seu time no Laboratório de Genética e Cardiologia Molecular, pelos desafios e pela contribuição à edificação da minha carreira científica. À minha mãe (versão científica), Dra. Ayumi Aurea Miyakawa, por confiar a mim o projeto do qual este trabalho deriva, por acreditar no meu potencial, por me compreender e pela paciência em todos os dias me ensinar a lidar com as nuances que fogem ao nosso controle no meio científico. Ser seu pupilo e parte de sua equipe tem sido enriquecedor desde o princípio. À Renata Carmona, por me receber de braços abertos no Laboratório de Genética e Cardiologia Molecular, pela paciência, pelo apoio nos momentos difíceis e pela receptividade constante às minhas críticas e sugestões. À Dra. Miriam Alaniz, por me compreender nas horas de desespero, por compartilhar sua experiência comigo nos momentos oportunos e pela ajuda incansável na bancada. Ao querido Dr. Mário Costa Cruz da Central de Facilidades para Pesquisa (CEFAP, USP), por todo o tempo dedicado à otimização dos meus ensaios, pelo auxílio na obtenção das imagens, pelos conselhos e por dividir comigo sua vasta experiência científica e de vida. Você simplesmente não existe, Mário!

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Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion

Cited by 28 publications

References 44 publications

Identification of a variant hotspot in MYBPC3 and of a novel CSRP3 autosomal recessive alteration in a cohort of Polish cases affected by hypertrophic cardiomyopathy

Identification of a variant hotspot in MYBPC3 and of a novel CSRP3 autosomal recessive alteration in a cohort of Polish cases affected by hypertrophic cardiomyopathy

Functional analysis of a gene-edited mouse model to gain insights into the disease mechanisms of a titin missense variant

Papel da proteína rica em cisteína e glicina 3 (CRP3) na mecanotransdução de células musculares lisas aórticas

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