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Recessive mutations in muscle-specific isoforms of FXR1 cause congenital multi-minicore myopathy

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posted on 2020-05-14, 11:27 authored by Maria Cristina Estan, Elisa Fernandez-Nunez, Maha S Zaki, Maria Isabel Esteban, Sandra Donkervoort, Cynthia Hawkins, Jose A Caparros-Martin, Dimah Saade, Ying Hu, Veronique Bolduc, Katherine Ru-Yui Chao, Julian Nevado, Ana Lamuedra, Raquel Largo, Gabriel Herrero-Beaumont, Javier Ragavendra, Concepcion Hernandez-Chico, Eduardo F Tizzano, Victor Martinez-Glez, Jaime J Carvajal, Ruiting Zong, David L Nelson, Ghada A Otaify, Samia Temtamy, Mona Aglan, Mahmoud Issa, Carsten G Bonnemann, Pablo Lapunzina, Grace Yoon, Victor L Ruiz-Perez
FXR1 is an alternatively spliced gene that encodes RNA binding proteins (FXR1P) involved in muscle development. In contrast to other tissues, cardiac and skeletal muscle express two FXR1P isoforms that incorporate an additional exon-15. We report that recessive mutations in this particular exon of FXR1 cause congenital multi-minicore myopathy in humans and mice. Additionally, we show that while Myf5-dependent depletion of all FXR1P isoforms is neonatal lethal, mice carrying mutations in exon-15 display non-lethal myopathies which vary in severity depending on the specific effect of each mutation on the protein.


This work was financially supported by the Spanish Ministry of Economy and Competitiveness (SAF2013-43365-R/SAF2016-75434-R) and CIBERER (ACCI 2017). The work performed at the NIH was supported by intramural funds from the NIH National Institute of Neurological Disorders and Stroke. Sequencing analysis was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics and was funded by the National Human Genome Research Institute, the National Eye Institute and the National Heart, Lung and Blood Institute grant UM1 HG008900 to Daniel MacArthur and Heidi Rehm. The Broad Center for Mendelian Genomics (UM1 HG008900) is funded by the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute. We also would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at about. This Article resulted in part from a successful GeneMatcher match.



Nature Communications 10, 797 (2019)

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