NPTX1 mutations trigger endoplasmic reticulum stress and cause autosomal dominant cerebellar ataxia

Abstract

With more than forty causative genes identified so far, autosomal dominant cerebellar ataxias exhibit a remarkable genetic heterogeneity. Yet, half the patients are lacking a molecular diagnosis. In a large family with nine sampled affected members, we performed exome sequencing combined with whole-genome linkage analysis. We identified a missense variant in NPTX1, NM_002522.3: c.1165G>A: p.G389R, segregating with the phenotype. Further investigations with whole exome sequencing and an amplicon-based panel identified four additional unrelated families segregating the same variant, for whom a common founder effect could be excluded. A second missense variant, NM_002522.3: c.980A>G: p.E327G, was identified in a fifth familial case. The NPTX1-associated phenotype consists of 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. NPTX1 encodes the neuronal pentraxin 1, a secreted protein with various cellular and synaptic functions. Both variants affect conserved amino-acid residues and are extremely rare or absent from public databases. In COS7 cells, overexpression of both neuronal pentraxin 1 variants altered endoplasmic reticulum morphology and induced ATF6-mediated endoplasmic reticulum stress, associated with cytotoxicity. In addition, the p. E327G variant abolished neuronal pentraxin 1 secretion, as well as its capacity to form a high molecular weight complex with the wild-type protein. Co-immunoprecipitation experiments coupled with mass spectrometry analysis demonstrated abnormal interactions of this variant with the cytoskeleton. In agreement with these observations, in silico modelling of the neuronal pentraxin 1 complex evidenced a destabilizing effect for the p. E327G substitution, located at the interface between monomers. On the contrary, the p. G389 residue, located at the protein surface, had no predictable effect on the complex stability. Our results establish NPTX1 as a new causative gene in autosomal dominant cerebellar ataxias. We suggest 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.

NPTX1-related oculomotor apraxia: an intra-hemispheric disconnection disorder

“…Symptoms progressed over 15 years as she developed severe OMA with the inability to initiate horizontal saccades and smooth pursuit eye movements. Similar symptoms were reported by her brother, father and her uncle [ 13 ]. The index patient, her brother and father were tested positive for the missense mutation in the NPTX 1 gene.…”

“…The aim of this study was to test competing pathophysiological hypotheses by functional and structural MRI, stating that OMA is related to either abnormal (i) inter- hemispheric [ 11 , 12 ] or (ii) intra- hemispheric connectivity between the FEF and related oculomotor structures (oculomotor network) or (iii) both mechanisms. We tested these hypotheses in a patient with an adult-onset progressive OMA and a positive family history, in whom we recently identified a novel mutation in the Neuronal Pentraxin 1 ( NPTX1 ) gene [ 13 ], with strong gene expression patterns in the frontal cortex.…”

A Novel NPTX1 de novo Variant in a Late‐Onset Ataxia Patient

“…Recently, two missense mutations in NPTX1 were identified as a cause of autosomal dominant cerebellar ataxia by triggering endoplasmic reticulum stress. 1 The NPTX1encoded protein neuronal pentraxin 1 (NP1) is exclusively expressed in the nervous system with high expression levels in neurons of the cerebellum, cerebral cortex, and hippocampus (Human Protein Atlas 2 ).…”

“…Our patient's clinical phenotype characterized by late-onset, slowly progressive cerebellar ataxia and multiple noncerebellar symptoms resembles the ones previously described (Table 1). 1 Localization and de novo status of the variant in our patient underline the importance of considering NPTX1 ---------------------------------------------------------------------------------------------------------------------- mutations beyond the mutations in the pentraxin domain not only in familial autosomal dominant cerebellar ataxia but also in sporadic cases of late-onset ataxia.…”

“…For more than 25 years since its inception, a single-source programmable implantable pulse generator (IPG) was the mainstay technology of modern deep brain stimulation (DBS) systems used for medication-refractory movement disorders. 1 However, multiple independent current control (MICC) was a recent innovation in IPG design, which was approved by the United States Food and Drug Administration. MICC attempts to control current fluctuations and enhance precision delivery by using an independent current source directed to each contact on the electrode lead.…”