Genetic Modifiers Of Repeat Expansions In C9ORF72 | 21926
Journal of Alzheimers Disease & Parkinsonism
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Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are currently the most frequent genetic cause
of frontotemporal dementia (FTD) and motor neuron disease (MND). These devastating neurodegenerative diseases
demonstrate considerable clinical heterogeneity, including variability in age at onset and disease duration. To identify genetic
modifiers that may account for this heterogeneity, we selected potential modifiers based on literature, and assessed these
candidates in more than 300 expansion carriers using Mass Array iPLEX and Taqman genotyping assays, in addition to
fragment analysis with fluorescent-labeled primers and multiplex ligation-dependent probe amplification (MLPA) assays.
Our studies revealed many interesting variants; for instance, we discovered that variants in transmembrane protein 106
B (TMEM106B) protect against developing FTD in C9ORF72 expansion carriers. On the other hand, intermediate repeat
lengths in ataxin-2 (ATXN2) may render C9ORF72 expansion carriers more susceptible to the development of MND. We also
identified genetic modifiers associated with age at onset and/or survival after onset, such as prion protein (PRNP), ubiquitinassociated
protein 1 (UBAP1), progranulin (GRN), and elongator acetyltransferase complex subunit 3 (ELP3). Although these
variants have previously been linked to FTD and/or MND, we are the first to describe their effects on the background of a
pathogenic expansion in C9ORF72. Importantly, these variants represent promising targets for new therapeutic interventions
and prognostic tests aiming at the FTD and MND spectrum.
Markavan Blitterswijk joined the Mayo Clinic in 2012 to investigate the role of C9ORF72 in FTD and MND. She graduated at Utrecht University, Utrecht, The
Netherlands, where she received her MD degree in 2008. Subsequently, she worked at Harvard Medical School, Boston, USA, and University of Massachusetts
Medical School, Worcester, USA. She obtained her PhD degree at Utrecht University in 2012. She has already published more than 30 articles in the field of
neuroscience, and she was appointed Assistant Professor of Neuroscience, Mayo Clinic College of Medicine, in 2014.
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