TY - JOUR
T1 - Targeted genetic screen in amyotrophic lateral sclerosis reveals novel genetic variants with synergistic effect on clinical phenotype
AU - Cooper-Knock, Johnathan
AU - Robins, Henry
AU - Niedermoser, Isabell
AU - Wyles, Matthew
AU - Heath, Paul R.
AU - Higginbottom, Adrian
AU - Walsh, Theresa
AU - Kazoka, Mbombe
AU - Al Kheifat, Ahmad
AU - Al-Chalabi, Ammar
AU - Basak, Nazli
AU - Blair, Ian
AU - Dekker, Annelot
AU - Hardiman, Orla
AU - Hide, Winston
AU - Iacoangeli, Alfredo
AU - Kenna, Kevin
AU - Landers, John
AU - McLaughlin, Russel
AU - Mill, Jonathan
AU - Middelkoop, Bas
AU - Moisse, Mattieu
AU - Pardina, Jesus Mora
AU - Morrison, Karen
AU - Newhouse, Stephen
AU - Pulit, Sara
AU - Shatunov, Aleksey
AU - Shaw, Chris
AU - Sproviero, William
AU - Tazelaar, Gijs
AU - van Damme, Philip
AU - van den Berg, Leonard
AU - van der Spek, Rick
AU - Eijk, Kristelvan
AU - van Es, Michael
AU - van Rheenen, Wouter
AU - van Vugt, Joke
AU - Veldink, Jan
AU - Kooyman, Maarten
AU - Glass, Jonathan
AU - Robberecht, Wim
AU - Gotkine, Marc
AU - Drory, Vivian
AU - Kiernan, Matthew
AU - Neto, Miguel Mitne
AU - Ztaz, Mayana
AU - Couratier, Philippe
AU - Corcia, Philippe
AU - Silani, Vincenzo
AU - Chio, Adriano
AU - de Carvalho, Mamede
AU - Pinto, Susana
AU - Redondo, Alberto Garcia
AU - Andersen, Peter
AU - Weber, Markus
AU - Ticozzi, Nicola
AU - Project MinE ALS Sequencing Consortium
AU - Ince, Paul G.
AU - Hautbergue, Guillaume M.
AU - McDermott, Christopher J.
AU - Kirby, Janine
AU - Shaw, Pamela J.
N1 - Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.
PY - 2017/11/9
Y1 - 2017/11/9
N2 - Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025). Our data are consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development.
AB - Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025). Our data are consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development.
KW - Amyotrophic lateral sclerosis
KW - C9ORF72
KW - DNA sequencing
KW - Oligogenic inheritance
KW - RNA binding proteins
UR - http://www.scopus.com/inward/record.url?scp=85041891653&partnerID=8YFLogxK
U2 - 10.3389/fnmol.2017.00370
DO - 10.3389/fnmol.2017.00370
M3 - Article
C2 - 29170628
AN - SCOPUS:85041891653
SN - 1662-5099
VL - 10
SP - 1
EP - 11
JO - Frontiers in Molecular Neuroscience
JF - Frontiers in Molecular Neuroscience
M1 - 370
ER -