Idioma:

Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish

Lin, Sheng-Jia ; Barbalho, Patricia G. ; Kaiyrzhanov, Rauan ; Maroofian, Reza ; Petree, Cassidy ; Severino, Mariasavina ; Stanley, Valentina ; Varshney, Pratishtha ; Bahena, Paulina ; Alzahrani, Fatema ; Alhashem, Amal ; Pagnamenta, Alistair T. ; Aubertin, Gudrun ; Estrada-Veras, Juvianee I. ; Hernández, Héctor Adrián Díaz ; Mazaheri, Neda ; Oza, Andrea ; Thies, Jenny ; Renaud, Deborah L. ; Dugad, Sanmati ; McEvoy, Jennifer ; Sultan, Tipu ; Pais, Lynn S. ; Tabarki, Brahim ; Villalobos-Ramirez, Daniel ; Rad, Aboulfazl ; Ambrose, J.C. ; Arumugam, P. ; Bleda, M. ; Boardman-Pretty, F. ; Boustred, C.R. ; Brittain, H. ; Caulfield, M.J. ; Chan, G.C. ; Fowler, T. ; Giess, A. ; Hamblin, A. ; Henderson, S. ; Hubbard, T.J.P. ; Jackson, R. ; Jones, L.J. ; Kasperaviciute, D. ; Kayikci, M. ; Kousathanas, A. ; Lahnstein, L. ; Leigh, S.E.A. ; Leong, I.U.S. ; Lopez, F.J. ; Maleady-Crowe, F. ; Moutsianas, L. ; Mueller, M. ; Murugaesu, N. ; Need, A.C. ; O‘Donovan, P. ; Odhams, C.A. ; Patch, C. ; Perez-Gil, D. ; Pereira, M.B. ; Pullinger, J. ; Rendon, A. ; Rogers, T. ; Savage, K. ; Sawant, K. ; Scott, R.H. ; Siddiq, A. ; Sieghart, A. ; Smith, S.C. ; Sosinsky, A. ; Stuckey, A. ; Tanguy, M. ; Thomas, E.R.A. ; Thompson, S.R. ; Tucci, A. ; Walsh, E. ; Welland, M.J. ; Williams, E. ; Witkowska, K. ; Wood, S.M. ; Galehdari, Hamid ; Ashrafzadeh, Farah ; Sahebzamani, Afsaneh ; Saeidi, Kolsoum ; Torti, Erin ; Elloumi, Houda Z. ; Mora, Sara ; Palculict, Timothy B. ; Yang, Hui ; Ben Fowler ; Joshi, Manali ; Behra, Martine ; Burgess, Shawn M. ; Nath, Swapan K. ; Kenna, Margaret ; Houlden, Henry ; Karimiani, Ehsan Ghayoor ; Zaki, Maha S. ; Haaf, Thomas ; Alkuraya, Fowzan S. ; Gleeson, Joseph G. ; Varshney, Gaurav K.

Genetics in medicine, 2021-10, Vol.23 (10), p.1933-1943 [Periódico revisado por pares]

United States: Elsevier Inc

Sem texto completo

Citações Citado por

Enviar para

Título:
Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish
Autor: Lin, Sheng-Jia ; Barbalho, Patricia G. ; Kaiyrzhanov, Rauan ; Maroofian, Reza ; Petree, Cassidy ; Severino, Mariasavina ; Stanley, Valentina ; Varshney, Pratishtha ; Bahena, Paulina ; Alzahrani, Fatema ; Alhashem, Amal ; Pagnamenta, Alistair T. ; Aubertin, Gudrun ; Estrada-Veras, Juvianee I. ; Hernández, Héctor Adrián Díaz ; Mazaheri, Neda ; Oza, Andrea ; Thies, Jenny ; Renaud, Deborah L. ; Dugad, Sanmati ; McEvoy, Jennifer ; Sultan, Tipu ; Pais, Lynn S. ; Tabarki, Brahim ; Villalobos-Ramirez, Daniel ; Rad, Aboulfazl ; Ambrose, J.C. ; Arumugam, P. ; Bleda, M. ; Boardman-Pretty, F. ; Boustred, C.R. ; Brittain, H. ; Caulfield, M.J. ; Chan, G.C. ; Fowler, T. ; Giess, A. ; Hamblin, A. ; Henderson, S. ; Hubbard, T.J.P. ; Jackson, R. ; Jones, L.J. ; Kasperaviciute, D. ; Kayikci, M. ; Kousathanas, A. ; Lahnstein, L. ; Leigh, S.E.A. ; Leong, I.U.S. ; Lopez, F.J. ; Maleady-Crowe, F. ; Moutsianas, L. ; Mueller, M. ; Murugaesu, N. ; Need, A.C. ; O‘Donovan, P. ; Odhams, C.A. ; Patch, C. ; Perez-Gil, D. ; Pereira, M.B. ; Pullinger, J. ; Rendon, A. ; Rogers, T. ; Savage, K. ; Sawant, K. ; Scott, R.H. ; Siddiq, A. ; Sieghart, A. ; Smith, S.C. ; Sosinsky, A. ; Stuckey, A. ; Tanguy, M. ; Thomas, E.R.A. ; Thompson, S.R. ; Tucci, A. ; Walsh, E. ; Welland, M.J. ; Williams, E. ; Witkowska, K. ; Wood, S.M. ; Galehdari, Hamid ; Ashrafzadeh, Farah ; Sahebzamani, Afsaneh ; Saeidi, Kolsoum ; Torti, Erin ; Elloumi, Houda Z. ; Mora, Sara ; Palculict, Timothy B. ; Yang, Hui ; Ben Fowler ; Joshi, Manali ; Behra, Martine ; Burgess, Shawn M. ; Nath, Swapan K. ; Kenna, Margaret ; Houlden, Henry ; Karimiani, Ehsan Ghayoor ; Zaki, Maha S. ; Haaf, Thomas ; Alkuraya, Fowzan S. ; Gleeson, Joseph G. ; Varshney, Gaurav K.
Assuntos: Alleles ; Animals ; Disease ; Disease Models, Animal ; Hearing loss ; Hearing Loss - genetics ; Humans ; Lysine-tRNA Ligase - genetics ; Neurodevelopmental Disorders - genetics ; Phenotype ; Zebrafish - genetics
É parte de: Genetics in medicine, 2021-10, Vol.23 (10), p.1933-1943
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Author Contributions
Conceptualization: S.J.L., B.V., R.M., M.S.Z., V.S., F.A., J.G.G., G.K.V. Data curation: B.V., R.K., R.M., M.S., P.B., A.A., A.T.P., G.A., J.I.E.V., H.A.D.H., N.M., A.O., J.T., D.L.R., J.M., T.S., A.R., M.S.Z., G.K.V. Formal Analysis: S.J.L., B.V., P.G.B., R.K., C.P., M.S., V.S., P.V., P.B., F.A.l., A.T.P., N.M., J.M., L.S.P., D.V.R., E.T., H.Z.E., S.M., T.B.P., H.Y., J.D.W., M.B., B.F., S.K.N. Funding acquisition: B.V., J.G.G., G.K.V. Investigation: A.O., J.T., D.L.R., T.S., B.T., H.G., F.A.l., F.A.S., A.S., K.S., M.G.H., M.K., J.L.M., H.H., E.G.K., F.S.A., T.H., M.S.Z., J.G.G. Project administration: G.K.V. Resources: G.E.R.C. Supervision: B.V., M.G.H., M.K., H.H., F.S.A., T.H., J.G.G., G.K.V. Validation: B.V., R.K., R.M., M.S., P.B., G.A., J.I.E.V., H.A.D.H., N.M., A.O., J.T., D.V.R., A.R., E.T., M.S.Z. Visualization S.D., M.J. Writing – original draft: S.J.L., G.V., B.V., M.S.Z., P.G.B., V.S., M.J., and M.S., Writing – review & editing: S.M.B.
These authors contributed equally: Sheng-Jia Lin, Barbara Vona, Patricia G. Barbalho.
Descrição: Pathogenic variants in Lysyl-tRNA synthetase 1 (KARS1) have increasingly been recognized as a cause of early-onset complex neurological phenotypes. To advance the timely diagnosis of KARS1-related disorders, we sought to delineate its phenotype and generate a disease model to understand its function in vivo. Through international collaboration, we identified 22 affected individuals from 16 unrelated families harboring biallelic likely pathogenic or pathogenic in KARS1 variants. Sequencing approaches ranged from disease-specific panels to genome sequencing. We generated loss-of-function alleles in zebrafish. We identify ten new and four known biallelic missense variants in KARS1 presenting with a moderate-to-severe developmental delay, progressive neurological and neurosensory abnormalities, and variable white matter involvement. We describe novel KARS1-associated signs such as autism, hyperactive behavior, pontine hypoplasia, and cerebellar atrophy with prevalent vermian involvement. Loss of kars1 leads to upregulation of p53, tissue-specific apoptosis, and downregulation of neurodevelopmental related genes, recapitulating key tissue-specific disease phenotypes of patients. Inhibition of p53 rescued several defects of kars1−/− knockouts. Our work delineates the clinical spectrum associated with KARS1 defects and provides a novel animal model for KARS1-related human diseases revealing p53 signaling components as potential therapeutic targets.
Editor: United States: Elsevier Inc
Idioma: Inglês

Links

View this record in MEDLINE/PubMed

Voltar para lista de resultados

Realização: Logos de Redes Sociais:

Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish

United States: Elsevier Inc

Buscando em bases de dados remotas. Favor aguardar.