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

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

doi:10.1093/brain/awad314

Title

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

Publication Date

2023-12-01

Author(s)

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

Subject

PPID gene

brain MRI

chaperone

cyclophilin-40

stuttering

Type of document

Journal Article

OrcId

0000-0003-1147-7405

#PLACEHOLDER_PARENT_METADATA_VALUE#

0000-0001-9298-3072

0000-0002-7884-6861

#PLACEHOLDER_PARENT_METADATA_VALUE#

0000-0003-3096-0910

#PLACEHOLDER_PARENT_METADATA_VALUE#

0000-0002-7535-8651

0000-0001-5132-0774

0000-0003-2739-0515

DOI

10.1093/brain/awad314

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.

Link

link

Citation

Brain : a journal of Neurology 2023-12-01; 146(12)

Jornal Title

Brain : a journal of Neurology

ISSN

1460-2156

Austin Health

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