Nat Neurosci. 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.
Johnson JO#1,
Pioro EP#2,
Boehringer A#3,
Chia R#4,
Feit H5,
Renton AE1,
Pliner HA1,
Abramzon Y1,
Marangi G1,6,
Winborn BJ7,
Gibbs JR8,9,
Nalls MA10,
Morgan S9,
Shoai M9,
Hardy J9,
Pittman A9,
Orrell RW11,
Malaspina A12,
Sidle KC9,
Fratta P13,
Harms MB14,
Baloh RH15,
Pestronk A14,
Weihl CC14,
Rogaeva E16,
Zinman L17,
Drory VE18,
Borghero G19,
Mora G20,
Calvo A21,
Rothstein JD22;
ITALSGEN,
Drepper C23,24,
Sendtner M23,
Singleton AB10,
Taylor JP7,
Cookson MR4,
Restagno G#25,
Sabatelli M#26,
Bowser R#3,
Chiò A#21,
Traynor BJ#1,22.
Moglia C, Cammarosano S, Canosa A, Gallo S, Brunetti M, Ossola I, Marinou K, Papetti L, Pisano F, Pinter GL, Conte A, Luigetti M, Zollino M, Lattante S, Marangi G, La Bella V, Spataro R, Colletti T, Giannini F, Battistini S, Ricci C, Caponnetto C, Mancardi G, Mandich P, Salvi F, Bartolomei I, Mandrioli J, Sola P, Lunetta C, Penco S, Monsurrò MR, Tedeschi G, Conforti FL, Gambardella A, Quattrone A, Volanti P, Floris G, Cannas A, Piras V, Marrosu F, Marrosu MG, Murru MR, Pugliatti M, Parish LD, Sotgiu A, Solinas G, Ulgheri L, Ticca A, Simone I, Logroscino G, Pirisi A.
- 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
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.
Figure 1Pedigrees 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.
Nat Neurosci. 2014 May;17(5):664-666.
Figure 2Lumbar 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.
Nat Neurosci. 2014 May;17(5):664-666.
Figure 3Immunoprecipitation 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).
Nat Neurosci. 2014 May;17(5):664-666.
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