Screening a UK amyotrophic lateral sclerosis cohort provides evidence of multiple origins of the C9orf72 expansion

Pietro Fratta; James M Polke; Jia Newcombe; Sarah Mizielinska; Tammaryn Lashley; Mark Poulter; Jon Beck; Elisavet Preza; Anny Devoy; Katie Sidle; Robin Howard; Andrea Malaspina; Richard W Orrell; Jan Clarke; Ching-Hua Lu; Kin Mok; Toby Collins; Maryam Shoaii; Tina Nanji; Selina Wray; Gary Adamson; Alan Pittman; Alan E Renton; Bryan J Traynor; Mary G Sweeney; Tamas Revesz; Henry Houlden; Simon Mead; Adrian M Isaacs; Elizabeth M C Fisher

doi:10.1016/j.neurobiolaging.2014.07.037

Screening a UK amyotrophic lateral sclerosis cohort provides evidence of multiple origins of the C9orf72 expansion

Neurobiol Aging. 2015 Jan;36(1):546.e1-7. doi: 10.1016/j.neurobiolaging.2014.07.037. Epub 2014 Aug 1.

Authors

Pietro Fratta¹, James M Polke², Jia Newcombe³, Sarah Mizielinska⁴, Tammaryn Lashley⁵, Mark Poulter⁶, Jon Beck⁶, Elisavet Preza⁷, Anny Devoy⁴, Katie Sidle⁸, Robin Howard⁹, Andrea Malaspina¹⁰, Richard W Orrell¹¹, Jan Clarke⁹, Ching-Hua Lu¹², Kin Mok¹³, Toby Collins⁴, Maryam Shoaii⁷, Tina Nanji¹⁴, Selina Wray⁷, Gary Adamson⁶, Alan Pittman⁷, Alan E Renton¹⁵, Bryan J Traynor¹⁵, Mary G Sweeney¹⁴, Tamas Revesz⁵, Henry Houlden¹⁶, Simon Mead⁴, Adrian M Isaacs⁴, Elizabeth M C Fisher¹⁷

Affiliations

¹ Department of Neurodegenerative Disease, University College London, Queen Square, London, UK; MRC Centre for Neuromuscular Diseases, University College London, Queen Square, London, UK. Electronic address: [email protected].
² Neurogenetics Unit, Queen Square, London, UK. Electronic address: [email protected].
³ NeuroResource, Institute of Neurology, University College London, Queen Square, London, UK.
⁴ Department of Neurodegenerative Disease, University College London, Queen Square, London, UK.
⁵ Queen Square Brain Bank for Neurological Disorders, University College London, Queen Square, London, UK.
⁶ Department of Neurodegenerative Disease, University College London, Queen Square, London, UK; MRC Prion Unit, University College London, Queen Square, London, UK.
⁷ Department of Molecular Neuroscience, University College London, Queen Square, London, UK.
⁸ Department of Molecular Neuroscience, University College London, Queen Square, London, UK; National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
⁹ National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
¹⁰ National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; Centre for Neuroscience & Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
¹¹ MRC Centre for Neuromuscular Diseases, University College London, Queen Square, London, UK; Department of Molecular Neuroscience, University College London, Queen Square, London, UK; National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
¹² Centre for Neuroscience & Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK; Sobell Department of Motor Neuroscience and Movement Disorders, University College London, Queen Square, London, UK.
¹³ Sobell Department of Motor Neuroscience and Movement Disorders, University College London, Queen Square, London, UK.
¹⁴ Neurogenetics Unit, Queen Square, London, UK.
¹⁵ Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institutes of Health, National Institute on Aging, Bethesda, MD, USA.
¹⁶ Neurogenetics Unit, Queen Square, London, UK; Department of Molecular Neuroscience, University College London, Queen Square, London, UK.
¹⁷ Department of Neurodegenerative Disease, University College London, Queen Square, London, UK; MRC Centre for Neuromuscular Diseases, University College London, Queen Square, London, UK. Electronic address: [email protected].

PMID: 25179228
PMCID: PMC4270445
DOI: 10.1016/j.neurobiolaging.2014.07.037

Abstract

An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Although 0-30 hexanucleotide repeats are present in the general population, expansions >500 repeats are associated with C9ALS/FTD. Large C9ALS/FTD expansions share a common haplotype and whether these expansions derive from a single founder or occur more frequently on a predisposing haplotype is yet to be determined and is relevant to disease pathomechanisms. Furthermore, although cases carrying 50-200 repeats have been described, their role and the pathogenic threshold of the expansions remain to be identified and carry importance for diagnostics and genetic counseling. We present clinical and genetic data from a UK ALS cohort and report the detailed molecular study of an atypical somatically unstable expansion of 90 repeats. Our results across different tissues provide evidence for the pathogenicity of this repeat number by showing they can somatically expand in the central nervous system to the well characterized pathogenic range. Our results support the occurrence of multiple expansion events for C9ALS/FTD.

Keywords: Amyotrophic lateral sclerosis; Frontotemporal dementia; Somatic instability.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis / genetics*
C9orf72 Protein
Cohort Studies*
DNA Repeat Expansion / genetics*
Frontotemporal Dementia / genetics
Humans
Proteins / genetics*
United Kingdom

Substances

C9orf72 Protein
C9orf72 protein, human
Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding