A postzygotic de novo NCDN mutation identified in a sporadic FTLD patient results in neurochondrin haploinsufficiency and altered FUS granule dynamics

• DOI: 10.1186/s40478-022-01314-x
• Publication Date: 2022-02-12T13:02:41Z
• Authors: Gaël Nicolas; Myriam Sévigny; François Lecoquierre; Florent Marguet; Andréanne Deschênes; Maria Carment del...; Sébastien Feuillette; Anaïs Audebrand; Magalie Lecourtois; Stéphane Rousseau; Anne-Claire Richard; Kévin Cassinari; Vincent Deramecourt; Charles Duyckaerts; Anne Boland; Jean-François Del...; Vincent Meyer; Jordi Clarimon Ec...; Ellen Gelpi; Haruhiko Akiyama; Masato Hasegawa; Ito Kawakami; Tsz H. Wong; Jeroen G. J. Van ...; John C. Van Swieten; Dominique Campion; Paul A. Dutchak; David Wallon; Flavie Lavoie-Car...; Annie Laquerrière; Anne Rovelet-Lecrux; Chantelle F. Sephton
• Keywords: Haploinsufficiency; Frontotemporal lobar degeneration; C9ORF72

Abstract Frontotemporal dementia (FTD) is a heterogeneous clinical disorder characterized by progressive abnormalities in behavior, executive functions, personality, language and/or motricity. A neuropathological subtype of FTD, frontotemporal lobar degeneration (FTLD)-FET, protein aggregates consisting the RNA-binding fused sarcoma (FUS). The cause FTLD-FET not well understood and there lack genetic evidence to aid investigation mechanisms disease. goal this study was identify variants contributing investigate their effects on FUS pathology. We performed whole-exome sequencing 50-year-old FTLD patient with ubiquitin FUS-positive neuronal inclusions unaffected parents, identified de novo postzygotic nonsense variant NCDN gene encoding Neurochondrin (NCDN), NM_014284.3:c.1206G > A, p.(Trp402*). associated ~ 31% reduction full-length levels patient’s brain, suggesting that mutation leads haploinsufficiency. examined haploinsufficiency found depleting primary cortical neurons causes total number cytoplasmic granules. Moreover, we these granules were significantly larger more highly enriched FUS. then loss function cells decrease mRNA levels. Our identifies as likely contributor pathophysiology. provide for negative feedback loop toxicity between FUS, where alters dynamics, which turn has an impact expression.