Abstract

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.

FXR1P is a RNA binding protein involved in muscle development. Here, the authors show that mutations in FXR1 exon 15, which is alternatively spliced in muscle, cause multi-minicore myopathy in humans and in mouse models.

Details

Title
Recessive mutations in muscle-specific isoforms of FXR1 cause congenital multi-minicore myopathy
Author
Estañ, María Cristina 1 ; Fernández-Núñez, Elisa 2 ; Zaki, Maha S 3 ; Esteban, María Isabel 4 ; Donkervoort, Sandra 5 ; Hawkins, Cynthia 6 ; Caparros-Martin, José A 7 ; Saade Dimah 5 ; Hu, Ying 5 ; Bolduc Véronique 5 ; Chao, Katherine Ru-Yui 8 ; Nevado Julián 9 ; Lamuedra Ana 10 ; Largo Raquel 10   VIAFID ORCID Logo  ; Herrero-Beaumont, Gabriel 10   VIAFID ORCID Logo  ; Regadera Javier 11 ; Hernandez-Chico, Concepción 12 ; Tizzano, Eduardo F 13 ; Martinez-Glez, Victor 14   VIAFID ORCID Logo  ; Carvajal, Jaime J 15 ; Zong Ruiting 16 ; Nelson, David L 16 ; Otaify, Ghada A 3 ; Temtamy Samia 3 ; Aglan Mona 3 ; Issa Mahmoud 3   VIAFID ORCID Logo  ; Bönnemann, Carsten G 5 ; Lapunzina Pablo 14 ; Yoon, Grace 17 ; Ruiz-Perez, Victor L 18 

1  Instituto de Investigaciones Biomédicas “Alberto Sols”, CSIC-UAM, Madrid, Spain (GRID:grid.466793.9) (ISNI:0000 0004 1803 1972); CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427) 
2  Instituto de Investigaciones Biomédicas “Alberto Sols”, CSIC-UAM, Madrid, Spain (GRID:grid.466793.9) (ISNI:0000 0004 1803 1972) 
3  National Research Centre, Department of Clinical Genetics, Human Genetics and Genome Research Division, Centre of Excellence of Human Genetics, Cairo, Egypt (GRID:grid.419725.c) (ISNI:0000 0001 2151 8157) 
4  Hospital Universitario La Paz-IdiPaz-UAM, Departamento de Anatomía Patológica, Madrid, Spain (GRID:grid.81821.32) (ISNI:0000 0000 8970 9163) 
5  National Institutes of Health, Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
6  University of Toronto, Division of Pathology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
7  Instituto de Investigaciones Biomédicas “Alberto Sols”, CSIC-UAM, Madrid, Spain (GRID:grid.466793.9) (ISNI:0000 0004 1803 1972); CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Curtin University, School of Pharmacy and Biomedical Sciences and Curtin Health Innovation Research Institute (CHIRI), Perth, Australia (GRID:grid.1032.0) (ISNI:0000 0004 0375 4078) 
8  Broad Institute of MIT and Harvard, Center for Mendelian Genomics, Program in Medical and Population Genetics, Boston, USA (GRID:grid.66859.34) 
9  Hospital Universitario La Paz-IdiPaz-UAM, Instituto de Genética Médica y Molecular (INGEMM), Madrid, Spain (GRID:grid.81821.32) (ISNI:0000 0000 8970 9163) 
10  The Institution of Health Research (IIS)-Fundación Jiménez Díaz, UAM, Bone and Joint Research Unit, Madrid, Spain (GRID:grid.5515.4) (ISNI:0000000119578126) 
11  Universidad Autónoma de Madrid, Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Madrid, Spain (GRID:grid.5515.4) (ISNI:0000000119578126) 
12  CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Servicio de Genética, Hospital Ramón y Cajal, Madrid, Spain (GRID:grid.411347.4) (ISNI:0000 0000 9248 5770) 
13  CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Hospital Vall d’Hebron, Department of Clinical and Molecular Genetics and Rare Diseases Unit, Barcelona, Spain (GRID:grid.411083.f) (ISNI:0000 0001 0675 8654) 
14  CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Hospital Universitario La Paz-IdiPaz-UAM, Instituto de Genética Médica y Molecular (INGEMM), Madrid, Spain (GRID:grid.81821.32) (ISNI:0000 0000 8970 9163) 
15  Universidad Pablo de Olavide, Centro Andaluz de Biología del Desarrollo (CSIC-UPO-JA), Sevilla, Spain (GRID:grid.15449.3d) (ISNI:0000 0001 2200 2355) 
16  Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X) 
17  University of Toronto, Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); University of Toronto, Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
18  Instituto de Investigaciones Biomédicas “Alberto Sols”, CSIC-UAM, Madrid, Spain (GRID:grid.466793.9) (ISNI:0000 0004 1803 1972); CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Hospital Universitario La Paz-IdiPaz-UAM, Instituto de Genética Médica y Molecular (INGEMM), Madrid, Spain (GRID:grid.81821.32) (ISNI:0000 0000 8970 9163) 
Publication year
2019
Publication date
Dec 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-08548-9
ProQuest document ID
2181779658
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.