You are here: Home Publications Equivalent missense variant in the FOXP2 and FOXP1 transcription factors causes distinct neurodevelopmental disorders

Equivalent missense variant in the FOXP2 and FOXP1 transcription factors causes distinct neurodevelopmental disorders

Sollis, E., Deriziotis, P., Saitsu, H., Miyake, N., Matsumoto, N., J.V.Hoffer, M. J. V., Ruivenkamp, C. A., Alders, M., Okamoto, N., Bijlsma, E. K., Plomp, A. S., & Fisher, S. E. (2017). Equivalent missense variant in the FOXP2 and FOXP1 transcription factors causes distinct neurodevelopmental disorders. Human Mutation, 38(11), 1542-1554. doi:10.1002/humu.23303.
The closely related paralogues FOXP2 and FOXP1 encode transcription factors with shared functions in the development of many tissues, including the brain. However, while mutations in FOXP2 lead to a speech/language disorder characterized by childhood apraxia of speech (CAS), the clinical profile of FOXP1 variants includes a broader neurodevelopmental phenotype with global developmental delay, intellectual disability and speech/language impairment. Using clinical whole-exome sequencing, we report an identical de novo missense FOXP1 variant identified in three unrelated patients. The variant, p.R514H, is located in the forkhead-box DNA-binding domain and is equivalent to the well-studied p.R553H FOXP2 variant that co-segregates with CAS in a large UK family. We present here for the first time a direct comparison of the molecular and clinical consequences of the same mutation affecting the equivalent residue in FOXP1 and FOXP2. Detailed functional characterization of the two variants in cell model systems revealed very similar molecular consequences, including aberrant subcellular localization, disruption of transcription factor activity and deleterious effects on protein interactions. Nonetheless, clinical manifestations were broader and more severe in the three cases carrying the p.R514H FOXP1 variant than in individuals with the p.R553H variant related to CAS, highlighting divergent roles of FOXP2 and FOXP1 in neurodevelopment.

Supplementary materials

About MPI

This is the MPI

The Max Planck Institute for Psycholinguistics is an institute of the German Max Planck Society. Our mission is to undertake basic research into the psychological,social and biological foundations of language. The goal is to understand how our minds and brains process language, how language interacts with other aspects of mind, and how we can learn languages of quite different types.

The institute is situated on the campus of the Radboud University. We participate in the Donders Institute for Brain, Cognition and Behaviour, and have particularly close ties to that institute's Centre for Cognitive Neuroimaging. We also participate in the Centre for Language Studies. A joint graduate school, the IMPRS in Language Sciences, links the Donders Institute, the CLS and the MPI.

 

Street address
Wundtlaan 1
6525 XD Nijmegen
The Netherlands


Mailing address
P.O. Box 310
6500 AH Nijmegen
The Netherlands

Phone:   +31-24-3521911
Fax:        +31-24-3521213
E-mail:   


Public Outreach Officer
Charlotte Horn