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

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

doi:10.1038/s41467-019-08548-9

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

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. CarvajalRuiting Zong, David L. Nelson, Ghada A. Otaify, Samia Temtamy, Mona Aglan, Mahmoud Issa, Carsten G. Bönnemann, Pablo Lapunzina, Grace Yoon, Victor L. Ruiz-Perez^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

20 Citations (Scopus)

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.

Original language	English
Article number	797
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-08548-9
Publication status	Published - Dec 1 2019
Externally published	Yes

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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10.1038/s41467-019-08548-9

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Estañ, M. C., Fernández-Núñez, E., Zaki, M. S., Esteban, M. I., Donkervoort, S., Hawkins, C., Caparros-Martin, J. A., Saade, D., Hu, Y., Bolduc, V., Chao, K. R. Y., Nevado, J., Lamuedra, A., Largo, R., Herrero-Beaumont, G., Regadera, J., Hernandez-Chico, C., Tizzano, E. F., Martinez-Glez, V., ... Ruiz-Perez, V. L. (2019). Recessive mutations in muscle-specific isoforms of FXR1 cause congenital multi-minicore myopathy. Nature Communications, 10(1), Article 797. https://doi.org/10.1038/s41467-019-08548-9

Estañ, MC, Fernández-Núñez, E, Zaki, MS, Esteban, MI, Donkervoort, S, Hawkins, C, Caparros-Martin, JA, Saade, D, Hu, Y, Bolduc, V, Chao, KRY, Nevado, J, Lamuedra, A, Largo, R, Herrero-Beaumont, G, Regadera, J, Hernandez-Chico, C, Tizzano, EF, Martinez-Glez, V, Carvajal, JJ, Zong, R, Nelson, DL, Otaify, GA, Temtamy, S, Aglan, M, Issa, M, Bönnemann, CG, Lapunzina, P, Yoon, G & Ruiz-Perez, VL 2019, 'Recessive mutations in muscle-specific isoforms of FXR1 cause congenital multi-minicore myopathy', Nature Communications, vol. 10, no. 1, 797. https://doi.org/10.1038/s41467-019-08548-9

@article{12a23cf28bc64113a5b756a0692df68a,

title = "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.",

author = "Esta{\~n}, {Mar{\'i}a Cristina} and Elisa Fern{\'a}ndez-N{\'u}{\~n}ez and Zaki, {Maha S.} and Esteban, {Mar{\'i}a Isabel} and Sandra Donkervoort and Cynthia Hawkins and Caparros-Martin, {Jos{\'e} A.} and Dimah Saade and Ying Hu and V{\'e}ronique Bolduc and Chao, {Katherine Ru Yui} and Juli{\'a}n Nevado and Ana Lamuedra and Raquel Largo and Gabriel Herrero-Beaumont and Javier Regadera and Concepci{\'o}n Hernandez-Chico and Tizzano, {Eduardo F.} and Victor Martinez-Glez and Carvajal, {Jaime J.} and Ruiting Zong and Nelson, {David L.} and Otaify, {Ghada A.} and Samia Temtamy and Mona Aglan and Mahmoud Issa and B{\"o}nnemann, {Carsten G.} and Pablo Lapunzina and Grace Yoon and Ruiz-Perez, {Victor L.}",

note = "Funding Information: We are grateful to patients and their families for their participation in this study. We thank Dr. Edward W Khandjian for the kind gift of anti-FXR1P antibodies (#ML13, #27-15, and #27-17)5,9,12,55, Dr. Robert Bloch for the anti-SLN antibody56 and the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa, for monoclonal antibodies. We also would like to thank M. Dolores Garc{\'i}a-Concepci{\'o}n, M. Gracia Gonz{\'a}lez-Bueno, Francisco R Urbano, Cova-donga Aguado, Jos{\'e} A Rodr{\'i}guez, M{\'o}nica Mart{\'i}n-Belinch{\'o}n, Diego Navarro, the Genomics and MRISS core facilities at IIB, Carmen S{\'a}nchez-Palomo, Rupleen Kaur, Juan C Trivi{\~n}o, and Guillermo Marco for technical assistance. 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 http://exac.broadinstitute.org/ about. This Article resulted in part from a successful GeneMatcher match63. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-08548-9",

language = "English",

volume = "10",

journal = "Nature Communications",

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T1 - Recessive mutations in muscle-specific isoforms of FXR1 cause congenital multi-minicore myopathy

AU - Estañ, María Cristina

AU - Fernández-Núñez, Elisa

AU - Zaki, Maha S.

AU - Esteban, María Isabel

AU - Donkervoort, Sandra

AU - Hawkins, Cynthia

AU - Caparros-Martin, José A.

AU - Saade, Dimah

AU - Hu, Ying

AU - Bolduc, Véronique

AU - Chao, Katherine Ru Yui

AU - Nevado, Julián

AU - Lamuedra, Ana

AU - Largo, Raquel

AU - Herrero-Beaumont, Gabriel

AU - Regadera, Javier

AU - Hernandez-Chico, Concepción

AU - Tizzano, Eduardo F.

AU - Martinez-Glez, Victor

AU - Carvajal, Jaime J.

AU - Zong, Ruiting

AU - Nelson, David L.

AU - Otaify, Ghada A.

AU - Temtamy, Samia

AU - Aglan, Mona

AU - Issa, Mahmoud

AU - Bönnemann, Carsten G.

AU - Lapunzina, Pablo

AU - Yoon, Grace

AU - Ruiz-Perez, Victor L.

N1 - Funding Information: We are grateful to patients and their families for their participation in this study. We thank Dr. Edward W Khandjian for the kind gift of anti-FXR1P antibodies (#ML13, #27-15, and #27-17)5,9,12,55, Dr. Robert Bloch for the anti-SLN antibody56 and the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa, for monoclonal antibodies. We also would like to thank M. Dolores García-Concepción, M. Gracia González-Bueno, Francisco R Urbano, Cova-donga Aguado, José A Rodríguez, Mónica Martín-Belinchón, Diego Navarro, the Genomics and MRISS core facilities at IIB, Carmen Sánchez-Palomo, Rupleen Kaur, Juan C Triviño, and Guillermo Marco for technical assistance. 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 http://exac.broadinstitute.org/ about. This Article resulted in part from a successful GeneMatcher match63. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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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JO - Nature Communications

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ER -

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

Abstract

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