Year: 2013
Type: article
Study design: Observational Study
Abstract: OBJECTIVE: To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases. METHODS: A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology. RESULTS: We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations. CONCLUSIONS: Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.
Source: Neurology
Authors: Marka van Blitterswijk, Matthew C. Baker, Mariely DeJesus-Hernandez, Roberta Ghidoni, Luisa Benussi, Elizabeth Finger, Ging-Yuek R. Hsiung, Brendan J. Kelley, Melissa E. Murray, Nicola J. Rutherford, Patricia E. Brown, Thomas Ravenscroft, Bianca Mullen, Peter E.A. Ash, Kevin F. Bieniek, Kimmo J. Hatanpaa, Anna Karydas, Elisabeth McCarty Wood, Giovanni Coppola, Eileen H. Bigio, Carol Lippa, Michael J. Strong, Thomas G. Beach, David S. Knopman, Edward D. Huey, Marsel Mesulam, Thomas Bird, Charles L. White, Andrew Kertesz, Dan H. Geschwind, Vivianna M. Van Deerlin, Ronald C. Petersen, Giuliano Binetti, Bruce L. Miller, Leonard Petrucelli, Zbigniew K. Wszolek, Kevin B. Boylan, Neill R. Graff-Radford, Ian R. Mackenzie, Bradley F. Boeve, Dennis W. Dickson, Rosa Rademakers
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: U.S. Department of Defense, Autism Speaks, Michael J. Fox Foundation for Parkinson's Research, Mayo Clinic, Simons Foundation, March of Dimes Foundation, Alzheimer's Association, ALS Association, Larry L. Hillblom Foundation, Dystonia Medical Research Foundation, Bristol-Myers Squibb, Association for Frontotemporal Degeneration, Eli Lilly and Company, Pfizer, Biogen, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, ALS Therapy Alliance, Mayo Foundation for Medical Education and Research, Arizona Department of Health Services, Danone, Alere, University of Cincinnati, CurePSP, Lawson Health Research Institute, Demensförbundet, Strong, Avanir Pharmaceuticals, Cytokinetics, Alzheimer's Society, Lewy Body Dementia Association, John Douglas French Alzheimer's Foundation, TauRx Pharmaceuticals, Alzheimer Society, Michael Smith Health Research BC, University of Cambridge, University of Oxford, Elan, Ministero della Salute, H. Lundbeck A/S, Arizona Biomedical Research Commission, National Institutes of Health, Genentech, Allergan, Avid Radiopharmaceuticals, Tau Consortium, Canadian Institutes of Health Research, National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, National Center for Advancing Translational Sciences, Janssen Pharmaceuticals
Awards: G1052080286, G1083877947, G1315589061, Genetic, Genomic, and Imaging Biomarkers in Degenerative Dementia, G1576660248, G1606131442, TDP-43, RNA Metabolism, and ALS/FTD Pathology, G1719844825, Examination of the earliest symptoms and biomarkers of FTLD MAPT carriers, G1845811550, G2056188304, Misregulation of the TDP-43 RNA target, Sortilin, in neurodegeneration, G2159780861, G2161113364, Investigation of the dopamine system in frontotemporal dementia, G2387188009, Neurobiology of Alzheimer's Disease and Aging, G2800912446, G2817105044, G282710236, G2898431357, G3251040009, G3261834735, G3540482749, G3703561073, G3739245758, G378970345, Alzheimers Disease Patient Registry, G3917207315, G3921025641, Einstein Aging Study, G4119534169, G4193400840, G4298864339, G4369927624, Frontotemporal Dementias: Genotypes and Phenotypes, Stress Granules and the Biology of TDP-43, G4791902628, G506964936, Progranulin: Mutation and Regulation in Neurodegenerative disease, G5527280043, G570682065, Multidisciplinary Clinical and Translational Science (MCTS) Program (UL1), G5849337688, G5850682332, G5884129571, G6030318873, G6125194395, G6138759730, G6492025387, G6674657880, G682375611, G6875889451, GGGGCC hexanucleotide repeat expansions in neurodegenerative disease, Arizona Alzheimer's Disease Core Center, G7247542487, G7327235705, G7457190523, Progranulin, TDP-43 and Cell Death, G76164443, National Brain and Tissue Resource for Parkinson's Disease and Related Disorders, Genetics and Molecular Biology of Parkinsonism, G7836467104, Alzheimer's Disease Core Center, G7887587830, G7924111682, G81576382, Novel Genetic Risk Factors for Alzheimer's Disease (AD) & Frontotemporal Dementia, G8508790466, G8566758, G8569069536, G877894594, G9000028495, G9000033656, G9000036492, G9000052518, G9000113569, G9000159448, G9000161801, G9000190830, G9000209522, G9000244707, G9000259012, G9000281426, Frontotemporal Dementia: Genes, Images, and Emotions, New Approaches to Dementia Heterogeneity, Mayo Alzheimer's Disease Research Center, G961669115, G989695202
OpenAlex ID: W1975314800