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Journal article
C9ORF72 repeat expansions in cases with previously identified pathogenic mutations
Neurology, v 81(15), pp 1332-1341
08 Oct 2013
PMCID: PMC3806926
PMID: 24027057
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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- Title
- C9ORF72 repeat expansions in cases with previously identified pathogenic mutations
- Creators
- Marka van Blitterswijk - Mayo Clinic in FloridaMatthew C. Baker - Mayo Clinic in FloridaMariely DeJesus-Hernandez - Mayo Clinic in FloridaRoberta Ghidoni - Centro San Giovanni di Dio FatebenefratelliLuisa Benussi - Centro San Giovanni di Dio FatebenefratelliElizabeth Finger - Western UniversityGing-Yuek R. Hsiung - University of British ColumbiaBrendan J. Kelley - Mayo ClinicMelissa E. Murray - Mayo Clinic in FloridaNicola J. Rutherford - Mayo Clinic in FloridaPatricia E. Brown - Mayo Clinic in FloridaThomas Ravenscroft - Mayo Clinic in FloridaBianca Mullen - Mayo Clinic in FloridaPeter E. A. Ash - Mayo Clinic in FloridaKevin F. Bieniek - Mayo Clinic in FloridaKimmo J. Hatanpaa - The University of Texas Southwestern Medical CenterAnna Karydas - University of California, San FranciscoElisabeth McCarty Wood - Raymond and Ruth Perelman School of Medicine at the University of PennsylvaniaGiovanni Coppola - University of California, Los AngelesEileen H. Bigio - Northwestern UniversityCarol Lippa - Drexel UniversityMichael J. Strong - Western UniversityThomas G. Beach - Banner Sun Health Research InstituteDavid S. Knopman - Mayo ClinicEdward D. Huey - National Institute of Neurological Disorders and StrokeMarsel Mesulam - Northwestern UniversityThomas Bird - University of Washington School of MedicineCharles L. White - The University of Texas Southwestern Medical CenterAndrew Kertesz - University of California, San FranciscoDan H. Geschwind - University of California, Los AngelesVivianna M. Van Deerlin - Raymond and Ruth Perelman School of Medicine at the University of PennsylvaniaRonald C. Petersen - Mayo ClinicGiuliano Binetti - Centro San Giovanni di Dio FatebenefratelliBruce L. Miller - University of California, San FranciscoLeonard Petrucelli - Mayo Clinic in FloridaZbigniew K. Wszolek - Mayo Clinic in FloridaKevin B. Boylan - Mayo Clinic in FloridaNeill R. Graff-Radford - Mayo Clinic in FloridaIan R. Mackenzie - University of British ColumbiaBradley F. Boeve - Mayo ClinicDennis W. Dickson - Mayo Clinic in FloridaRosa Rademakers - Mayo Clinic in Florida
- Publication Details
- Neurology, v 81(15), pp 1332-1341
- Publisher
- Lippincott Williams & Wilkins
- Number of pages
- 10
- Grant note
- Ricerca Corrente Italian Ministry of Health; Ministry of Health, Italy R01ES020395 / NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS) R01 NS080882; R01 NS065782; R01 AG026251; P01 AG017586; P50 NS072187; P50 AG 016574; P30 AG13854; P30 AG12300; U01 AG006786 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA ALS Therapy Alliance UL1TR000150 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) Consortium for Frontotemporal Dementia Research R01NS076837 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) P50AG016574 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurology
- Web of Science ID
- WOS:000330768600013
- Scopus ID
- 2-s2.0-84888235194
- Other Identifier
- 991019312448404721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Clinical Neurology