Research Notes

Carlos Frigerio Domingues, Tae-Un Han, and Dennis Drayna, National Institutes of Health, Bethesda, Maryland This email address is being protected from spambots. You need JavaScript enabled to view it.  

The ability to produce fluent speech is developedand maintained to a large degree by the products of our genes; defects in genes have been repeatedly associated with stuttering.  Starting with studies in large families in which there are many cases of persistent developmental stuttering, mutations in the GNPTABGNPTGNAGPA,and AP4E1genes have been associated with this communication disorder (Kang et al, N Engl J Med, 2010, Raza et al, Am J Hum Genet, 2015.  Together, mutations in these these four genes seem to account for approximately 20% of cases of persistent stuttering in the general population (Raza et al, Eur J Hum Genet, 2015, Frigerio-Domingues and Drayna, Mol Genet Genome Med2017) . All of these genes encode components of the machinery that moves molecules to their proper location within cells, a process known as intracellular trafficking.  Deficits in various aspects of intracellular trafficking are now recognized as causative in other neurological disorders, ranging from rare disorders such as Huntington’s Disease to common disorders such as Alzheimer’s Disease. 

The identification of stuttering-associated mutations in humans has allowed the engineering of these mutations into mice to develop an animal model of stuttering. Although mice lack the speech articulatory apparatus analogous to that of humans, they share a number of brain functional regions associated with speech in humans. It has thus been hypothesized that the mouse could provide a useful model for the volitional control of vocalization, which evidence suggests is a problem in human stuttering. Mice carrying mutations equivalent to those causing human stuttering have been successfully generated, and while many aspects of their vocalizations are normal, it was discovered that the mutant mice have abnormally increased pauses during their vocalization (Barnes et al. Current Biology 2016).  These pauses were shown to be similar to the features of stuttering speech in humans who carried these mutations (Barnes et al, Current Biology, 2016.

Studies of these “stuttering” mice did not reveal any changes in their tissues, and they behave normally in a wide variety of mouse behavior tests. This suggests that any changes in the brain caused by the human stuttering mutations would be subtle or highly localized.  The latest studies are now pinpointing the cells specifically affected by the mutation, and their location in the brains of these mice.

Opinions expressed in this article are those of the author(s) and not of the International Fluency Association.References:

Kang C, Riazuddin S, Mundorff J, Krasnewich D, Friedman P, Mullikin J, and Drayna D. Lysosomal Enzyme Targetting Pathway Mutaions and Persistent Stuttering. New England Journal of Medicine362:677-685 (2010)

Fisher S. Genetic Susceptibility to Stuttering. Editorial, New England Journal of Medicine 362:75—752 (2010)

Raza MH, Mattera M, Morell R, Sainz E, Rahn R, Gutierrez J, Paris E, Root J, Solomon B, Brewer C, Basra M, Khan S, Riazuddin S, Braun A, Bonifacino J, and Drayna D. Association of rare variants in AP4E1, a component of intracellular trafficking, with persistent stuttering. American Journal of Human Genetics97:715-725 (2015).

Barnes T, Wozniak D, Gutierrez J, Han T-U, Drayna D, and Holy T. A mutation associated with stuttering alters mouse pup ultrasonic vocalizations. Current Biology26:1-10 (2016)

Frigerio-Domingues C, Drayna D. Genetic contributions to stuttering: the current evidence.  Mol Genet Genomic Med. 2017 Feb 19;5(2):95-102. doi: 10.1002/mgg3.276.  eCollection 2017 Mar.