title: A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic, and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts.
abstract: Profilin 1 is a central regulator of actin dynamics. Mutations in the gene profilin 1 (PFN1) have very recently been shown to be the cause of a subgroup of amyotrophic lateral sclerosis (ALS). Here, we performed a large screen of US, Nordic, and German familial and sporadic ALS and frontotemporal dementia (FTLD) patients for PFN1 mutations to get further insight into the spectrum and pathogenic relevance of this gene for the complete ALS/FTLD continuum. Four hundred twelve familial and 260 sporadic ALS cases and 16 ALS/FTLD cases from Germany, the Nordic countries, and the United States were screened for PFN1 mutations. Phenotypes of patients carrying PFN1 mutations were studied. In a German ALS family we identified the novel heterozygous PFN1 mutation p.Thr109Met, which was absent in controls. This novel mutation abrogates a phosphorylation site in profilin 1. The recently described p.Gln117Gly sequence variant was found in another familial ALS patient from the United States. The ALS patients with mutations in PFN1 displayed spinal onset motor neuron disease without overt cognitive involvement. PFN1 mutations were absent in patients with motor neuron disease and dementia, and in patients with only FTLD. We provide further evidence that PFN1 mutations can cause ALS as a Mendelian dominant trait. Patients carrying PFN1 mutations reported so far represent the "classic" ALS end of the ALS-FTLD spectrum. The novel p.Thr109Met mutation provides additional proof-of-principle that mutant proteins involved in the regulation of cytoskeletal dynamics can cause motor neuron degeneration. Moreover, this new mutation suggests that fine-tuning of actin polymerization by phosphorylation of profilin 1 might be necessary for motor neuron survival.
authors.affiliation: Institute of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Ingre
authors.forename: John E
authors.initials: JE
authors.lastname: Landers
authors.forename: Naji
authors.initials: N
authors.lastname: Rizik
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Volk
authors.forename: Chizuru
authors.initials: C
authors.lastname: Akimoto
authors.forename: Anna
authors.initials: A
authors.lastname: Birve
authors.forename: Annemarie
authors.initials: A
authors.lastname: Hübers
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Keagle
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Piotrowska
authors.forename: Rayomand
authors.initials: R
authors.lastname: Press
authors.forename: Peter Munch
authors.initials: PM
authors.lastname: Andersen
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D057180:Frontotemporal Dementia / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008297:Male; D008403:Mass Screening / Q000379:methods; D008875:Middle Aged; D010375:Pedigree; D010766:Phosphorylation / Q000235:genetics; D017354:Point Mutation / Q000235:genetics*; D051304:Profilins / Q000235:genetics* / Q000378:metabolism; D013548:Sweden / Q000453:epidemiology; D014481:United States / Q000453:epidemiology; D055815:Young Adult
chemical_list: C495738:PFN1 protein, human; D051304:Profilins