A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts
2013 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, no 6, 1708.e1-1708.e6 p.Article in journal (Refereed) Published
Profilin 1 is a central regulator of actin dynamics. Mutations in the gene profilin 1 (PFN1) have veryrecently been shown to be the cause of a subgroup of amyotrophic lateral sclerosis (ALS). Here, weperformed a large screen of US, Nordic, and German familial and sporadic ALS and frontotemporaldementia (FTLD) patients for PFN1 mutations to get further insight into the spectrum and pathogenicrelevance of this gene for the complete ALS/FTLD continuum. Four hundred twelve familial and 260sporadic ALS cases and 16 ALS/FTLD cases from Germany, the Nordic countries, and the United Stateswere screened for PFN1 mutations. Phenotypes of patients carrying PFN1 mutations were studied. Ina German ALS family we identified the novel heterozygous PFN1 mutation p.Thr109Met, which wasabsent in controls. This novel mutation abrogates a phosphorylation site in profilin 1. The recentlydescribed 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 overtcognitive involvement. PFN1 mutations were absent in patients with motor neuron disease anddementia, and in patients with only FTLD. We provide further evidence that PFN1 mutations can causeALS 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 proofof-principle that mutant proteins involved in the regulation of cytoskeletal dynamics can cause motorneuron degeneration. Moreover, this new mutation suggests that fine-tuning of actin polymerization byphosphorylation of profilin 1 might be necessary for motor neuron survival.
Place, publisher, year, edition, pages
2013. Vol. 34, no 6, 1708.e1-1708.e6 p.
Amyotrophic lateral sclerosis, ALS, FTLD, profilin1, Cytoskeleton, Actin
Research subject Neurology
IdentifiersURN: urn:nbn:se:umu:diva-67457DOI: 10.1016/j.neurobiolaging.2012.10.009OAI: oai:DiVA.org:umu-67457DiVA: diva2:612008
ProjectsOn the aetiology of ALS: A comprehensive genetic study