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Nat Commun. 2019 Feb 15;10(1):797. doi: 10.1038/s41467-019-08548-9.

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

Author information

1
Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-UAM, 28029, Madrid, Spain.
2
CIBER de Enfermedades Raras (CIBERER), ISCIII, 28029, Madrid, Spain.
3
Department of Clinical Genetics, Human Genetics and Genome Research Division, Centre of Excellence of Human Genetics, National Research Centre, Cairo, 12311, Egypt.
4
Departamento de Anatomía Patológica, Hospital Universitario La Paz-IdiPaz-UAM, 28046, Madrid, Spain.
5
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20814, USA.
6
Division of Pathology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, ON, M5G 1X8, Canada.
7
School of Pharmacy and Biomedical Sciences and Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA, 6102, Australia.
8
Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, MA, 02115, USA.
9
Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz-IdiPaz-UAM, 28046, Madrid, Spain.
10
Bone and Joint Research Unit, The Institution of Health Research (IIS)-Fundación Jiménez Díaz, UAM, 28040, Madrid, Spain.
11
Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, 28029, Madrid, Spain.
12
Servicio de Genética, Hospital Ramón y Cajal, 28034, Madrid, Spain.
13
Department of Clinical and Molecular Genetics and Rare Diseases Unit, Hospital Vall d'Hebron, 08035, Barcelona, Spain.
14
Centro Andaluz de Biología del Desarrollo (CSIC-UPO-JA), Universidad Pablo de Olavide, 41013, Sevilla, Spain.
15
Department of Molecular and Human Genetics, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, 1250 Moursund Street, Houston, TX, 77030, USA.
16
Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G 1X8, Canada. grace.yoon@utoronto.ca.
17
Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, M5G 1X8, Canada. grace.yoon@utoronto.ca.
18
Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-UAM, 28029, Madrid, Spain. vlruiz@iib.uam.es.
19
CIBER de Enfermedades Raras (CIBERER), ISCIII, 28029, Madrid, Spain. vlruiz@iib.uam.es.
20
Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz-IdiPaz-UAM, 28046, Madrid, Spain. vlruiz@iib.uam.es.

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.

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