NPTX1 mutations trigger endoplasmic reticulum stress, and cause autosomal dominant cerebellar ataxia
A new study published in Brain identified two missense variant in NPTX1 (a genes coding a neuronal pentraxin 1, a secreted protein with various cellular and synaptic functions), within respectively a large family with nine sampled members affected, and another familial case. Patients express a late-onset, slowly progressive, cerebellar ataxia, with downbeat nystagmus, cognitive impairment reminiscent of cerebellar cognitive affective syndrome, myoclonic tremor and mild cerebellar vermian atrophy on brain imaging. Both variants are extremely rare or absent from public databases. Various analyses (histological investigation, co-immunoprecipitation experiments coupled with mass spectrometry analysis, in silico modelling) revealed NPTX1 as a new causative gene in autosomal dominant cerebellar ataxias. It is suggested that variants in NPTX1 can lead to cerebellar ataxia due to endoplasmic reticulum stress, mediated by ATF6, and associated to a destabilization of NP1 polymers in a dominant-negative manner for one of the variants.
- To read more about “Autosomal dominant cerebellar ataxia”
- Brain . 2022 May 24;145(4):1519-1534