Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.
Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Chi-Hong
CH
Wu
Claudia
C
Fallini
Nicola
N
Ticozzi
Pamela J
PJ
Keagle
Peter C
PC
Sapp
Katarzyna
K
Piotrowska
Patrick
P
Lowe
Max
M
Koppers
Diane
D
McKenna-Yasek
Desiree M
DM
Baron
Jason E
JE
Kost
Paloma
P
Gonzalez-Perez
Andrew D
AD
Fox
Jenni
J
Adams
Franco
F
Taroni
Cinzia
C
Tiloca
Ashley Lyn
AL
Leclerc
Shawn C
SC
Chafe
Dev
D
Mangroo
Melissa J
MJ
Moore
Jill A
JA
Zitzewitz
Zuo-Shang
ZS
Xu
Leonard H
LH
van den Berg
Jonathan D
JD
Glass
Gabriele
G
Siciliano
Elizabeth T
ET
Cirulli
David B
DB
Goldstein
Francois
F
Salachas
Vincent
V
Meininger
Wilfried
W
Rossoll
Antonia
A
Ratti
Cinzia
C
Gellera
Daryl A
DA
Bosco
Gary J
GJ
Bassell
Vincenzo
V
Silani
Vivian E
VE
Drory
Robert H
RH
Brown
John E
JE
Landers
D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D020439:Growth Cones / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007585:Jews / Q000235:genetics; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D051304:Profilins / Q000235:genetics* / Q000378:metabolism*; D011487:Protein Conformation; D054875:Ubiquitination; D044465:White People / Q000235:genetics
D000199:Actins; D050505:Mutant Proteins; C495738:PFN1 protein, human; D051304:Profilins