A study of the role of the FOXP2 and CNTNAP2 genes in persistent developmental stuttering

Abstract

A number of speech disorders including stuttering have been shown to have important genetic contributions, as indicated by high heritability estimates from twin and other studies. We studied the potential contribution to stuttering from variants in the FOXP2 gene, which have previously been associated with developmental verbal dyspraxia, and from variants in the CNTNAP2 gene, which have been associated with specific language impairment (SLI). DNA sequence analysis of these two genes in a group of 602 unrelated cases, all with familial persistent developmental stuttering, revealed no excess of potentially deleterious coding sequence variants in the cases compared to a matched group of 487 well characterized neurologically normal controls. This was compared to the distribution of variants in the GNPTAB, GNPTG, and NAGPA genes which have previously been associated with persistent stuttering. Using an expanded subject data set, we again found that NAGPA showed significantly different mutation frequencies in North Americans of European descent (p = 0.0091) and a significant difference existed in the mutation frequency of GNPTAB in Brazilians (p = 0.00050). No significant differences in mutation frequency in the FOXP2 and CNTNAP2 genes were observed between cases and controls. To examine the pattern of expression of these five genes in human brain, real time quantitative reverse transcription PCR was performed on RNA purified from 27 different human brain regions. The expression patterns of FOXP2 and CNTNAP2 were generally different from those of GNPTAB, GNPTG and NAPGA in terms of relatively lower expression in cerebellum. This study provides an improved estimate of the contribution of mutations in the GNPTAB, GNPTG and NAGPA to persistent stuttering, and suggests that variants in the FOXP2 and CNTNAP2 are not involved in the genesis of familial persistent stuttering. This, together with the different brain expression patterns of GNPTAB, GNPTG, and NAGPA compared to that of FOXP2 and CNTNAP2, suggests that the genetic neuropathological origins of stuttering differ from those of verbal dyspraxia and SLI.

Understanding Language from a Genomic Perspective

“…Two other genes in this pathway, GNPTG and NAGPA, were reported to have an increased burden of rare nonsynonymous variants in stuttering cases from Pakistan and North America (73). The same research team followed up these genes in case-control cohorts from Brazil and North America (partially overlapping the earlier study) and again suggested an excess of rare nonsynonymous variants in cases, although no gene showed a consistent pattern in both cohorts (58). The GNPTAB variant in the original family was not fully penetrant and a substantial proportion of stutterers in that family did not carry it (high phenocopy rate).…”

“…These cases illustrate the diversity of genetic lesions that can (91). Targeted resequencing of FOXP2 has been performed in individuals with speech/language disorders that do not include features of CAS (58,103,137). Exome sequencing data are now also available from large cohorts of individuals with various developmental disorders (25).…”

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

“…The present study suggests astrocytes as a previously unsuspected site of the pathophysiology underlying human stuttering. Because Gnptab is universally expressed in brain cells and tissues (49,58,59), a current question is why astrocytes present an increased susceptibility to pathology from partial loss of function mutations in Gnptab compared to other brain cell types. We note that our data do not completely rule out the possibility that other brain cells are involved in pathogenesis of stuttering associated with mutations in Gnptab (22).…”

Insights into the Genetic Foundations of Human Communication

“…Subsequent targeted sequencing in unrelated individuals of Asian and European descent uncovered further missense variants in GNPTAB, and in the related genes GNPTG and NAGPA (Kang et al 2010). The same research team recently reported an excess of rare coding variants in GNPTAB and NAGPA (although not in GNPTG) in an expanded sample of stuttering cases (Han et al 2014), but further independent replication studies are needed to determine the overall contribution of mutations in these genes to the etiology of developmental stuttering.…”

“…FOXP2 has not been directly implicated in other communication disorders beyond CAS, underlining the specificity of the phenotype resulting from FOXP2 disruptions (Newbury et al 2002;Han et al 2014;Toma et al 2013). However, given that it is a transcription factor, genes regulated by FOXP2 could have roles in other forms of language disorder.…”