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

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.

• Authors: María Cristina Estañ, Elisa Fernández-Núñez, Maha S Zaki, María Isabel Esteban, Sandra Donkervoort, Cynthia Hawkins, José A Caparros-Martin, Dimah Saade, Ying Hu, Véronique Bolduc, Katherine Ru-Yui Chao, Julián Nevado, Ana Lamuedra, Raquel Largo, Gabriel Herrero-Beaumont, Javier Regadera, Concepción 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 Bönnemann, Pablo Lapunzina, Grace Yoon, Victor L Ruiz-Perez
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 797 (02 15 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 30770808 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• FXR1 protein, human
• Fxr1h protein, mouse
• RNA-Binding Proteins
• Ryanodine Receptor Calcium Release Channel

Topics

• Animals
• Cells, Cultured
• Exons (genetics)
• Gene Expression
• Genes, Recessive
• Genetic Predisposition to Disease (genetics)
• HEK293 Cells
• HeLa Cells
• Humans
• Mice, Transgenic
• Muscle, Skeletal (metabolism)
• Mutation
• Myopathies, Structural, Congenital (congenital, genetics, metabolism)
• Ophthalmoplegia (congenital, genetics, metabolism)
• RNA-Binding Proteins (genetics, metabolism)
• Ryanodine Receptor Calcium Release Channel (deficiency, genetics, metabolism)