Stuttering associated with a pathogenic variant in the chaperone protein cyclophilin 40

Morgan, AT; Scerri, TS; Vogel, AP; Reid, CA; Quach, M; Jackson, VE; McKenzie, C; Burrows, EL; Bennett, MF; Turner, SJ; Reilly, S; Horton, SE; Block, S; Kefalianos, E; Frigerio-Domingues, C; Sainz, E; Rigbye, KA; Featherby, TJ; Richards, KL; Kueh, A; Herold, MJ; Corbett, MA; Gecz, J; Helbig, I; Thompson-Lake, DGY; Li&#233;geois, FJ; Morell, RJ; Hung, A; Drayna, D; Scheffer, IE; Wright, DK; Bahlo, M; Hildebrand, MS

Author(s): Morgan, AT; Scerri, TS; Vogel, AP; Reid, CA; Quach, M; Jackson, VE; McKenzie, C; Burrows, EL; Bennett, MF; Turner, SJ; Reilly, S; Horton, SE; Block, S; Kefalianos, E; Frigerio-Domingues, C; Sainz, E; Rigbye, KA; Featherby, TJ; Richards, KL; Kueh, A; Herold, MJ; Corbett, MA; Gecz, J; Helbig, I; Thompson-Lake, DGY; Liégeois, FJ; Morell, RJ; Hung, A; Drayna, D; Scheffer, IE; Wright, DK; Bahlo, M; Hildebrand, MS;
Details: Publication Year 2023-11-18,Volume 146,Issue #12,Page 5086-5097
Journal Title: Brain
Abstract: Stuttering is a common speech disorder that interrupts speech fluency and tends to cluster in families. Typically, stuttering is characterized by speech sounds, words or syllables which may be repeated or prolonged and speech that may be further interrupted by hesitations or 'blocks'. Rare variants in a small number of genes encoding lysosomal pathway proteins have been linked to stuttering. We studied a large four-generation family in which persistent stuttering was inherited in an autosomal dominant manner with disruption of the cortico-basal-ganglia-thalamo-cortical network found on imaging. Exome sequencing of three affected family members revealed the PPID c.808C>T (p.Pro270Ser) variant that segregated with stuttering in the family. We generated a Ppid p.Pro270Ser knock-in mouse model and performed ex vivo imaging to assess for brain changes. Diffusion-weighted MRI in the mouse revealed significant microstructural changes in the left corticospinal tract, as previously implicated in stuttering. Quantitative susceptibility mapping also detected changes in cortico-striatal-thalamo-cortical loop tissue composition, consistent with findings in affected family members. This is the first report to implicate a chaperone protein in the pathogenesis of stuttering. The humanized Ppid murine model recapitulates network findings observed in affected family members.
Publisher: Oxford Academic
Keywords: PPID gene; brain MRI; chaperone; cyclophilin-40; stuttering
Research Division(s): Blood Cells And Blood Cancer; Population Health And Immunity; Blood Cells and Blood Cancer
PubMed ID: 37977818
Publisher's Version: https://doi.org/10.1093/brain/awad314
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-11-20 03:32:54

Last Modified: 2023-12-13 10:19:48