Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/34281
Title: Stuttering associated with a pathogenic variant in the chaperone protein cyclophilin 40.
Austin Authors: Morgan, Angela T;Scerri, Thomas S;Vogel, Adam P;Reid, Christopher A;Quach, Mara;Jackson, Victoria E;McKenzie, Chaseley;Burrows, Emma L;Bennett, Mark F ;Turner, Samantha J;Reilly, Sheena;Horton, Sarah E;Block, Susan;Kefalianos, Elaina;Frigerio-Domingues, Carlos;Sainz, Eduardo;Rigbye, Kristin A;Featherby, Travis J;Richards, Kay L;Kueh, Andrew;Herold, Marco J;Corbett, Mark A;Gecz, Jozef;Helbig, Ingo;Thompson-Lake, Daisy G Y;Liégeois, Frédérique J;Morell, Robert J;Hung, Andrew;Drayna, Dennis;Scheffer, Ingrid E ;Wright, David K;Bahlo, Melanie;Hildebrand, Michael S 
Affiliation: Murdoch Children's Research Institute, Parkville 3052, Australia.;Department of Audiology and Speech Pathology, University of Melbourne, Parkville 3052, Australia.
Department of Audiology and Speech Pathology, University of Melbourne, Parkville 3052, Australia.;Centre for Neuroscience of Speech, The University of Melbourne, Parkville 3053, Australia.;Clinical Trials, Redenlab Inc., Melbourne 3000, Australia.
Florey Institute of Neuroscience and Mental Health, University of Melbourne, 3052, Parkville 3052, Australia.;Department of Medicine, Epilepsy Research Centre, University of Melbourne, Heidelberg 3084, Australia.
Department of Neuroscience, Central Clinical School, Monash University, Melbourne 3004, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.;Department of Medical Biology, University of Melbourne, Parkville 3052, Australia.
Florey Institute of Neuroscience and Mental Health, University of Melbourne, 3052, Parkville 3052, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.;Department of Medical Biology, University of Melbourne, Parkville 3052, Australia.;Department of Medicine, Epilepsy Research Centre, University of Melbourne, Heidelberg 3084, Australia.
Murdoch Children's Research Institute, Parkville 3052, Australia.
Murdoch Children's Research Institute, Parkville 3052, Australia.;Menzies Health Institute Queensland, Griffith University, 4215 Southport, Australia.
Murdoch Children's Research Institute, Parkville 3052, Australia.;Department of Audiology and Speech Pathology, University of Melbourne, Parkville 3052, Australia.
Discipline of Speech Pathology, School of Allied Health, La Trobe University, Bundoora 3086, Australia.
Murdoch Children's Research Institute, Parkville 3052, Australia.;Department of Audiology and Speech Pathology, University of Melbourne, Parkville 3052, Australia.
Laboratory of Communication Disorders, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892-2320, USA.
Laboratory of Communication Disorders, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892-2320, USA.
Department of Medicine, Epilepsy Research Centre, University of Melbourne, Heidelberg 3084, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.;Department of Medical Biology, University of Melbourne, Parkville 3052, Australia.
Adelaide Medical School, The University of Adelaide, Adelaide 5000, Australia.;Neurogenetics Research Program, South Australian Health and Medical Research Institute, Adelaide 5000, Australia.
Department of Neurology, Children's Hospital, Philadelphia, PA 19104, USA.
Developmental Neurosciences Department, UCL Great Ormond Street Institute of Child Health, London, UK.
Developmental Neurosciences Department, UCL Great Ormond Street Institute of Child Health, London, UK.
Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.;Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
School of Science, STEM College, RMIT University, Melbourne 3001, Australia.
Laboratory of Communication Disorders, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892-2320, USA.
Murdoch Children's Research Institute, Parkville 3052, Australia.;Florey Institute of Neuroscience and Mental Health, University of Melbourne, 3052, Parkville 3052, Australia.;Department of Medicine, Epilepsy Research Centre, University of Melbourne, Heidelberg 3084, Australia.;Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville 3052, Australia.
Department of Neuroscience, Central Clinical School, Monash University, Melbourne 3004, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.;Department of Medical Biology, University of Melbourne, Parkville 3052, Australia.;School of Mathematics and Statistics, University of Melbourne, 3010 Parkville, Australia.
Epilepsy Research Centre
Issue Date: 1-Dec-2023
Date: 2023
Publication information: Brain : a journal of Neurology 2023-12-01; 146(12)
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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/34281
DOI: 10.1093/brain/awad314
ORCID: 0000-0003-1147-7405
0000-0001-9298-3072
0000-0002-7884-6861
0000-0003-3096-0910
0000-0002-7535-8651
0000-0001-5132-0774
0000-0003-2739-0515
Journal: Brain : a journal of Neurology
PubMed URL: 37977818
ISSN: 1460-2156
Type: Journal Article
Subjects: PPID gene
brain MRI
chaperone
cyclophilin-40
stuttering
Appears in Collections:Journal articles

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