title: Jump from pre-mutation to pathologic expansion in C9orf72.
abstract: An expanded G4C2 repeat in C9orf72 represents the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the lower limit for pathological expansions is unknown (the suggested cutoff is 30 repeats). It has been proposed that the expansion might have occurred only once in human history and subsequently spread throughout the population. However, our present findings support a hypothesis of multiple origins for the expansion. We report a British-Canadian family in whom a ∼70-repeat allele from the father (unaffected by ALS or FTLD at age 89 years) expanded during parent-offspring transmission and started the first generation affected by ALS (four children carry an ∼1,750-repeat allele). Epigenetic and RNA-expression analyses further discriminated the offspring's large expansions (which were methylated and associated with reduced C9orf72 expression) from the ∼70-repeat allele (which was unmethylated and associated with upregulation of C9orf72). Moreover, RNA foci were only detected in fibroblasts from offspring with large expansions, but not in the father, who has the ∼70-repeat allele. All family members with expansions were found to have an ancient known risk haplotype, although it was inherited on a unique 5-Mb genetic backbone. We conclude that small expansions (e.g., 70 repeats) might be considered "pre-mutations" to reflect their propensity to expand in the next generation. Follow-up studies might help explain the high frequency of ALS- or FTLD-affected individuals with an expansion but without a familial history (e.g., 21% among Finnish ALS subjects).
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.
authors.forename: Zhengrui
authors.initials: Z
authors.lastname: Xi
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Marka
authors.initials: M
authors.lastname: van Blitterswijk
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: McGoldrick
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.
authors.forename: Jesse R
authors.initials: JR
authors.lastname: McLean
authors.affiliation: Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Speech Language Pathology, University of Toronto, 500 University Avenue, Toronto, ON M5G 1V7, Canada.
authors.forename: Yana
authors.initials: Y
authors.lastname: Yunusova
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.
authors.forename: Erin
authors.initials: E
authors.lastname: Knock
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.
authors.forename: Danielle
authors.initials: D
authors.lastname: Moreno
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Sato
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 27 King's College Circle, Toronto, ON M5S 1A1, Canada.
authors.forename: Paul M
authors.initials: PM
authors.lastname: McKeever
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 27 King's College Circle, Toronto, ON M5S 1A1, Canada.
authors.forename: Raphael
authors.initials: R
authors.lastname: Schneider
authors.affiliation: Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
authors.forename: Julia
authors.initials: J
authors.lastname: Keith
authors.affiliation: Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Division of Neurology, Department of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Nicolae
authors.initials: N
authors.lastname: Petrescu
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Fraser
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada; Division of Neurology, Department of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Maria Carmela
authors.initials: MC
authors.lastname: Tartaglia
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Baker
authors.affiliation: Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.affiliation: Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Boylan
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, 2329 West Mall, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackenzie
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 27 King's College Circle, Toronto, ON M5S 1A1, Canada.
authors.forename: Janice
authors.initials: J
authors.lastname: Robertson
authors.affiliation: Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Division of Neurology, Department of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. Electronic address: lorne.zinman@sunnybrook.ca.
authors.forename: Lorne
authors.initials: L
authors.lastname: Zinman
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Street, Toronto, ON M5T 2S8, Canada; Division of Neurology, Department of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. Electronic address: ekaterina.rogaeva@utoronto.ca.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Rogaeva
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology*; D015139:Blotting, Southern; D000073885:C9orf72 Protein; D002170:Canada; D019175:DNA Methylation / Q000235:genetics; D042622:DNA Repeat Expansion / Q000235:genetics*; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins