Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis

doi:10.1038/nn.3688

. 2014 May;17(5):664-666.

doi: 10.1038/nn.3688. Epub 2014 Mar 30.

Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis

Janel O Johnson^#¹, Erik P Pioro^#², Ashley Boehringer^#³, Ruth Chia^#⁴, Howard Feit⁵, Alan E Renton¹, Hannah A Pliner¹, Yevgeniya Abramzon¹, Giuseppe Marangi^{1

6}, Brett J Winborn⁷, J Raphael Gibbs^{8

9}, Michael A Nalls¹⁰, Sarah Morgan⁹, Maryam Shoai⁹, John Hardy⁹, Alan Pittman⁹, Richard W Orrell¹¹, Andrea Malaspina¹², Katie C Sidle⁹, Pietro Fratta¹³, Matthew B Harms¹⁴, Robert H Baloh¹⁵, Alan Pestronk¹⁴, Conrad C Weihl¹⁴, Ekaterina Rogaeva¹⁶, Lorne Zinman¹⁷, Vivian E Drory¹⁸, Giuseppe Borghero¹⁹, Gabriele Mora²⁰, Andrea Calvo²¹, Jeffrey D Rothstein²²; ITALSGEN; Carsten Drepper^{23

24}, Michael Sendtner²³, Andrew B Singleton¹⁰, J Paul Taylor⁷, Mark R Cookson⁴, Gabriella Restagno^#²⁵, Mario Sabatelli^#²⁶, Robert Bowser^#³, Adriano Chiò^#²¹, Bryan J Traynor^#^{1

22}

Collaborators, Affiliations

Collaborators

ITALSGEN:
Cristina Moglia, Stefania Cammarosano, Antonia Canosa, Sara Gallo, Maura Brunetti, Irene Ossola, Kalliopi Marinou, Laura Papetti, Fabrizio Pisano, Giuseppe Lauria Pinter, Amelia Conte, Marco Luigetti, Marcella Zollino, Serena Lattante, Giuseppe Marangi, Vincenzo La Bella, Rossella Spataro, Tiziana Colletti, Fabio Giannini, Stefania Battistini, Claudia Ricci, Clauida Caponnetto, Gianluigi Mancardi, Paola Mandich, Fabrizio Salvi, Ilaria Bartolomei, Jessica Mandrioli, Patrizia Sola, Christian Lunetta, Silvana Penco, Maria Rosaria Monsurrò, Gioacchino Tedeschi, Francesca Luisa Conforti, Antonio Gambardella, Aldo Quattrone, Paolo Volanti, Gianluca Floris, Antonino Cannas, Valeria Piras, Francesco Marrosu, Maria Giovanna Marrosu, Maria Rita Murru, Maura Pugliatti, Leslie D Parish, Alessandra Sotgiu, Giuliana Solinas, Lucia Ulgheri, Anna Ticca, Isabella Simone, Giancarlo Logroscino, Angelo Pirisi

Affiliations

¹ Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892, USA.
² Department of Neurology, Neurological Institute, Neuromuscular Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
³ Division of Neurology, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ 85013, USA.
⁴ Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
⁵ Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA.
⁶ Institute of Medical Genetics, Catholic University of Sacred Heart, 10100 Rome, Italy.
⁷ Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
⁸ Computational Biology Core, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
⁹ Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
¹⁰ Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
¹¹ Department of Clinical Neuroscience, Institute of Neurology, University College London, London NW3 2PG, UK.
¹² Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, North-East London and Essex Regional MND Care Centre, E1 2AT, UK.
¹³ Department of Neurodegenerative Disease, University College London, Queen Square, London WC1N 3BG, UK.
¹⁴ Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
¹⁵ Department of Neurology, Cedars-Sinai Medical Center, 8730 Alden Drive, Los Angeles, CA 90048, USA.
¹⁶ Tanz Centre for Research of Neurodegenerative Diseases, Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, M5S 3H2, Canada.
¹⁷ Division of Neurology, Department of Internal Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada.
¹⁸ Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
¹⁹ Department of Neurology, Azienda Universitaria-Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy.
²⁰ ALS Center, Salvatore Maugeri Foundation, Milan, Italy.
²¹ 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, 10126 Turin, Italy.
²² Brain Science Institute and Department of Neurology, Johns Hopkins Hospital, 855 N. Wolfe Street, Baltimore, MD 21205, USA.
²³ Institute for Clinical Neurobiology, University of Würzburg, D-97078 Würzburg, Germany.
²⁴ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, D-97080 Würzburg, Germany.
²⁵ Molecular Genetics Unit, Department of Clinical Pathology, A.S.O. O.I.R.M.-S. Anna, 10126 Turin, Italy.
²⁶ Neurological Institute, Catholic University and I.C.O.M.M. Association for ALS Research, 10100 Rome, Italy.

^# Contributed equally.

PMID: 24686783
PMCID: PMC4000579
DOI: 10.1038/nn.3688

Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis

Janel O Johnson et al. Nat Neurosci. 2014 May.

. 2014 May;17(5):664-666.

doi: 10.1038/nn.3688. Epub 2014 Mar 30.

Authors

Collaborators

ITALSGEN:
Cristina Moglia, Stefania Cammarosano, Antonia Canosa, Sara Gallo, Maura Brunetti, Irene Ossola, Kalliopi Marinou, Laura Papetti, Fabrizio Pisano, Giuseppe Lauria Pinter, Amelia Conte, Marco Luigetti, Marcella Zollino, Serena Lattante, Giuseppe Marangi, Vincenzo La Bella, Rossella Spataro, Tiziana Colletti, Fabio Giannini, Stefania Battistini, Claudia Ricci, Clauida Caponnetto, Gianluigi Mancardi, Paola Mandich, Fabrizio Salvi, Ilaria Bartolomei, Jessica Mandrioli, Patrizia Sola, Christian Lunetta, Silvana Penco, Maria Rosaria Monsurrò, Gioacchino Tedeschi, Francesca Luisa Conforti, Antonio Gambardella, Aldo Quattrone, Paolo Volanti, Gianluca Floris, Antonino Cannas, Valeria Piras, Francesco Marrosu, Maria Giovanna Marrosu, Maria Rita Murru, Maura Pugliatti, Leslie D Parish, Alessandra Sotgiu, Giuliana Solinas, Lucia Ulgheri, Anna Ticca, Isabella Simone, Giancarlo Logroscino, Angelo Pirisi

Affiliations

¹ Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892, USA.
² Department of Neurology, Neurological Institute, Neuromuscular Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
³ Division of Neurology, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ 85013, USA.
⁴ Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
⁵ Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA.
⁶ Institute of Medical Genetics, Catholic University of Sacred Heart, 10100 Rome, Italy.
⁷ Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
⁸ Computational Biology Core, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
⁹ Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
¹⁰ Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
¹¹ Department of Clinical Neuroscience, Institute of Neurology, University College London, London NW3 2PG, UK.
¹² Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, North-East London and Essex Regional MND Care Centre, E1 2AT, UK.
¹³ Department of Neurodegenerative Disease, University College London, Queen Square, London WC1N 3BG, UK.
¹⁴ Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
¹⁵ Department of Neurology, Cedars-Sinai Medical Center, 8730 Alden Drive, Los Angeles, CA 90048, USA.
¹⁶ Tanz Centre for Research of Neurodegenerative Diseases, Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, M5S 3H2, Canada.
¹⁷ Division of Neurology, Department of Internal Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada.
¹⁸ Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
¹⁹ Department of Neurology, Azienda Universitaria-Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy.
²⁰ ALS Center, Salvatore Maugeri Foundation, Milan, Italy.
²¹ 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, 10126 Turin, Italy.
²² Brain Science Institute and Department of Neurology, Johns Hopkins Hospital, 855 N. Wolfe Street, Baltimore, MD 21205, USA.
²³ Institute for Clinical Neurobiology, University of Würzburg, D-97078 Würzburg, Germany.
²⁴ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, D-97080 Würzburg, Germany.
²⁵ Molecular Genetics Unit, Department of Clinical Pathology, A.S.O. O.I.R.M.-S. Anna, 10126 Turin, Italy.
²⁶ Neurological Institute, Catholic University and I.C.O.M.M. Association for ALS Research, 10100 Rome, Italy.

^# Contributed equally.

PMID: 24686783
PMCID: PMC4000579
DOI: 10.1038/nn.3688

Abstract

MATR3 is an RNA- and DNA-binding protein that interacts with TDP-43, a disease protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in ALS-affected spinal cords with and without MATR3 mutations. Our data provide more evidence supporting the role of aberrant RNA processing in motor neuron degeneration.

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Figures

**Figure 1. Pedigrees of patients with *MATR3* mutations**
Mutant alleles are indicated by mt, whereas wild-type alleles are indicated by wt. Genotypes of presumed obligate carriers are in brackets. Red asterisks indicate individuals who underwent clinical examination.

**Figure 2. Lumbar spinal cord tissue immunostained for MATR3 and counterstained with hemotoxylin**
(a) Control spinal cord exhibits MATR3 nuclear immunoreactivity in some motor neurons, with weak glial cell immunostaining. (b) ALS cases exhibit strong nuclear immunoreactivity with cytoplasmic immunoreactivity present in some motor neurons either diffusely or in cytoplasmic puncta. Strong glial immunostaining is also noted in ALS patients. (c) Patient with the p.Phe115Cys MATR3 mutation exhibits strong nuclear staining, as well as cytoplasmic staining in many cells. Images are taken at 20× magnification and insets are at 40× magnification. Scale bars represent 50um.

**Figure 3. Immunoprecipitation of MATR3 with TDP-43**
(a) FLAG-MATR3 was expressed in HEK293FT cells, immunoprecipitated using anti-FLAG antibody, and probed with TDP-43 and DHX9 antibodies. (b) Graphs show mean +/− SEM based on 10 replicate immunoprecipitation experiments. Differences in interaction between MATR3 and TDP-43 were tested with Wilcoxon signed rank test (**p<0.01).

See this image and copyright information in PMC

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References

1. Renton AE, Chiò A, Traynor BJ. Nat. Neurosci. 2013 Epub ahead of print. - PMC - PubMed
1. Feit H, et al. Am. J. Hum. Genet. 1998;63:1732–1742. - PMC - PubMed
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[1] Renton AE, Chiò A, Traynor BJ. Nat. Neurosci. 2013 Epub ahead of print. - PMC - PubMed

[2] Renton AE, Chiò A, Traynor BJ. Nat. Neurosci. 2013 Epub ahead of print. - PMC - PubMed

[3] Feit H, et al. Am. J. Hum. Genet. 1998;63:1732–1742. - PMC - PubMed

[4] Feit H, et al. Am. J. Hum. Genet. 1998;63:1732–1742. - PMC - PubMed

[5] Senderek J, et al. Am. J. Hum. Genet. 2009;84:511–518. - PMC - PubMed

[6] Senderek J, et al. Am. J. Hum. Genet. 2009;84:511–518. - PMC - PubMed

[7] Eisen A, Kuwabara S. J. Neurol. Neurosurg. Psychiatry. 2012;83:399–403. - PubMed

[8] Eisen A, Kuwabara S. J. Neurol. Neurosurg. Psychiatry. 2012;83:399–403. - PubMed

[9] Ling SC, et al. Proc. Natl. Acad. Sci. USA. 2010;107:13318–13323. - PMC - PubMed

[10] Ling SC, et al. Proc. Natl. Acad. Sci. USA. 2010;107:13318–13323. - PMC - PubMed

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Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis

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Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis

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