RESUMO
Exome sequencing was performed in 2 unrelated families with progressive myoclonus epilepsy. Affected individuals from both families shared a rare, homozygous c.191A > G variant affecting a splice site in SLC7A6OS. Analysis of cDNA from lymphoblastoid cells demonstrated partial splice site abolition and the creation of an abnormal isoform. Quantitative reverse transcriptase polymerase chain reaction and Western blot showed a marked reduction of protein expression. Haplotype analysis identified a ~0.85cM shared genomic region on chromosome 16q encompassing the c.191A > G variant, consistent with a distant ancestor common to both families. Our results suggest that biallelic loss-of-function variants in SLC7A6OS are a novel genetic cause of progressive myoclonus epilepsy. ANN NEUROL 2021;89:402-407.
Assuntos
Epilepsias Mioclônicas Progressivas/genética , Peptídeo Hidrolases/genética , Sítios de Splice de RNA/genética , Adolescente , Ataxia/genética , Ataxia/fisiopatologia , Atrofia , Western Blotting , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , DNA Complementar , Eletroencefalografia , Feminino , Homozigoto , Humanos , Mutação com Perda de Função , Imageamento por Ressonância Magnética , Masculino , Epilepsias Mioclônicas Progressivas/diagnóstico por imagem , Epilepsias Mioclônicas Progressivas/fisiopatologia , Epilepsias Mioclônicas Progressivas/psicologia , Linhagem , Peptídeo Hidrolases/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto JovemRESUMO
Zebrafish (Danio rerio) has proven to be a versatile and reliable in vivo experimental model to study human hematopoiesis and hematological malignancies. As vertebrates, zebrafish has significant anatomical and biological similarities to humans, including the hematopoietic system. The powerful genome editing and genome-wide forward genetic screening tools have generated models that recapitulate human malignant hematopoietic pathologies in zebrafish and unravel cellular mechanisms involved in these diseases. Moreover, the use of zebrafish models in large-scale chemical screens has allowed the identification of new molecular targets and the design of alternative therapies. In this review we summarize the recent achievements in hematological research that highlight the power of the zebrafish model for discovery of new therapeutic molecules. We believe that the model is ready to give an immediate translational impact into the clinic.