Genetic contributions to stuttering: the current evidence

Frigerio-Domingues, Carlos; Drayna, Dennis

doi:10.1002/mgg3.276

Cited by 91 publications

(70 citation statements)

References 55 publications

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“…In addition, studies of our animal models show that astrocyte pathology persists into adulthood in these animals. Thus, human genetic findings (2), animal model studies, and independent human brain imaging studies (3,4) now all support a role for a cellular deficit in the CC in the genesis of persistent developmental stuttering.…”

Section: Discussionmentioning

confidence: 90%

“…stuttering | astrocytes | white matter | mouse vocalization | Cre-drivers S tuttering is a common neurodevelopmental disorder characterized by disruptions in the fluent flow of speech (1), typically in the absence of other neurological deficits. Stuttering displays high heritability (2), and recent studies have identified mutations in the GNPTAB, GNPTG, NAGPA, and AP4E1 genes that are associated with this disorder (3)(4)(5). The products of these genes interact with each other in vivo and in vitro (3,4), and participate in the control of intracellular trafficking, deficits in which are recognized in a wide range of neurological disorders (6).…”

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confidence: 99%

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HumanGNPTABstuttering mutations engineered into mice cause vocalization deficits and astrocyte pathology in the corpus callosum

Han

Root

Reyes

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 99%

HumanGNPTABstuttering mutations engineered into mice cause vocalization deficits and astrocyte pathology in the corpus callosum

Han

Root

Reyes

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…(Packman & Attanasio, 2004). Several research groups' recent accomplishments in the areas of neuroimaging (e.g., Beal et al, 2013;Cai et al, 2014;Chang et al, 2011;Choo et al, 2012;Sitek et al, 2016;Wymbs et al, 2013) and gene discovery (e.g., Benito-Aragón et al, 2020;Frigerio-Domingues & Drayna, 2017;Frigerio-Domingues et al, 2019;Kang et al, 2010;Raza et al, 2012) indicate substantial progress regarding the former of these two causality questions. Progress in addressing the latter question continues to lag as very few specific hypotheses have been formulated to suggest biologically plausible mechanisms that may explain the individual occurrences of sound/syllable repetitions and sound prolongations.…”

Section: Introductionmentioning

confidence: 99%

Dissociated development of speech and limb sensorimotor learning in stuttering: speech auditory-motor learning is impaired in both children and adults who stutter

Kim

Daliri

Flanagan

et al. 2020

Preprint

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Stuttering is a neurodevelopmental disorder of speech fluency. Various experimental paradigms have demonstrated that affected individuals show limitations in sensorimotor control and learning. However, controversy exists regarding two core aspects of this perspective. First, it has been claimed that sensorimotor learning limitations are detectable only in adults who stutter (after years of coping with the disorder) but not during childhood close to the onset of stuttering. Second, it remains unclear whether stuttering individuals' sensorimotor learning limitations affect only speech movements or also unrelated effector systems involved in nonspeech movements. We report data from separate experiments investigating speech auditory-motor learning (N = 60) and limb visuomotor learning (N = 84) in both children and adults who stutter versus matched nonstuttering individuals. Both children and adults who stutter showed statistically significant limitations in speech auditory-motor adaptation with formant-shifted feedback. This limitation was more profound in children than in adults and in younger children versus older children. Between-group differences in the adaptation of reach movements performed with rotated visual feedback were subtle but statistically significant for adults. In children, even the nonstuttering groups showed limited visuomotor adaptation just like their stuttering peers. We conclude that sensorimotor learning is impaired in individuals who stutter, and that the ability for speech auditory-motor learning -- which was already adult-like in 3-6 year-old typically developing children -- is severely compromised in young children near the onset of stuttering. Thus, motor learning limitations may play an important role in the fundamental mechanisms contributing to the onset of this speech disorder.

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“…In this review we will only cite those genes that are present in non-syndromic stuttering. Around 9% of patients with a familiar background associates with the GNPTAB, GNPTG, and NAGPA genes [68] . The importance of these genes is based on replication in subsequent studies, confirming a key role in stuttering [69] .…”

Section: Stutteringmentioning

confidence: 99%

“…These genes may also be affected in mucolipidosis. Unlike mucolipidosis, the characteristics of the mutations found in stuttering lie in their typically heterozygous character, with nonsense mutations, a modest reduction of enzyme function and different mutation sites [68] .…”

Section: Stutteringmentioning

confidence: 99%

Genomics of Speech and Language Disorders

Guerra¹,

Cacabelos²

2018

Preprint

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There are multiple factors involved in speech and language. Investigating animal models, mainly through songbirds, have allowed a better understanding of the language process. Verbal dyspraxia, dysarthria, speech sound disorder, and stuttering are some examples of speech disorders, and specific language disorder, aphasia and, dyslexia of language disorders. More complex syndromes such as Autism-spectrum disorders, Down’s or Fragile X have more variable features. Genetic factors, such as hereditary or de novo mutations may be responsible for their development. In addition, most of them are involved in neurodevelopment with a huge range of molecular mechanisms and pathways that interact with each other, and there may be co-morbidity with other communication disorders or develop phenotypes unrelated to communication. Genes with heterogeneous functions in speech and language such as FOXP1, FOXP2, KIAA0319, ROBO1, APOE or CNTNAP2 are some examples. Epigenetic factors, especially miRNAs, influence their expressiveness. The genomics of these disorders allows us to understand language acquisition, carry out early detection strategies, genetic counseling and optimize future treatments, not only in communication disorders but also those neurological alterations that incorporate these mutations.

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Genetic contributions to stuttering: the current evidence

Abstract: Evidence for genetic factors in persistent developmental stuttering has accumulated over the past four decades, and the genes that underlie this disorder are starting to be identified. The genes identified to date, all point to deficits in intracellular trafficking in this disorder.

Cited by 91 publications

References 55 publications

HumanGNPTABstuttering mutations engineered into mice cause vocalization deficits and astrocyte pathology in the corpus callosum

HumanGNPTABstuttering mutations engineered into mice cause vocalization deficits and astrocyte pathology in the corpus callosum

Dissociated development of speech and limb sensorimotor learning in stuttering: speech auditory-motor learning is impaired in both children and adults who stutter

Genomics of Speech and Language Disorders

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