Human GNPTAB stuttering mutations engineered into mice cause vocalization deficits and astrocyte pathology in the corpus callosum

Proc Natl Acad Sci U S A. 2019 Aug 27;116(35):17515-17524. doi: 10.1073/pnas.1901480116. Epub 2019 Aug 12.


Stuttering is a common neurodevelopmental disorder that has been associated with mutations in genes involved in intracellular trafficking. However, the cellular mechanisms leading to stuttering remain unknown. Engineering a mutation in N-acetylglucosamine-1-phosphate transferase subunits α and β (GNPTAB) found in humans who stutter into the mouse Gnptab gene resulted in deficits in the flow of ultrasonic vocalizations similar to speech deficits of humans who stutter. Here we show that other human stuttering mutations introduced into this mouse gene, Gnptab Ser321Gly and Ala455Ser, produce the same vocalization deficit in 8-day-old pup isolation calls and do not affect other nonvocal behaviors. Immunohistochemistry showed a marked decrease in staining of astrocytes, particularly in the corpus callosum of the Gnptab Ser321Gly homozygote mice compared to wild-type littermates, while the staining of cerebellar Purkinje cells, oligodendrocytes, microglial cells, and dopaminergic neurons was not significantly different. Diffusion tensor imaging also detected deficits in the corpus callosum of the Gnptab Ser321Gly mice. Using a range of cell type-specific Cre-drivers and a Gnptab conditional knockout line, we found that only astrocyte-specific Gnptab-deficient mice displayed a similar vocalization deficit. These data suggest that vocalization defects in mice carrying human stuttering mutations in Gnptab derive from abnormalities in astrocytes, particularly in the corpus callosum, and provide support for hypotheses that focus on deficits in interhemispheric communication in stuttering.

Keywords: Cre-drivers; astrocytes; mouse vocalization; stuttering; white matter.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Cell Count
  • Corpus Callosum / metabolism*
  • Disease Models, Animal
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Phenotype
  • Phosphoric Diester Hydrolases / blood
  • Stuttering / genetics*
  • Transferases (Other Substituted Phosphate Groups) / genetics*
  • Vocalization, Animal*


  • Transferases (Other Substituted Phosphate Groups)
  • GNPTAB protein, human
  • Phosphoric Diester Hydrolases