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

5 years ago

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

Hirotomo Saitsu, Nobuhiko Okamoto, Naomichi Matsumoto, Astrid S. Plomp, Claudia A.L. Ruivenkamp, Elliot Sollis, Emilia K. Bijlsma, Pelagia Deriziotis, Mariëlle Alders, Noriko Miyake, Mariëtte J.V. Hoffer, Simon E. Fisher

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 cosegregates 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. In this article, we demonstrate that equivalent variants in the closely-related FOXP2 and FOXP1 genes produce dysfunctional proteins with very similar properties, including the formation of aggregates in the nucleus and cytoplasm. Despite these similarities, the FOXP2 (p.R553H) and FOXP1 (p.R514H) variants result in distinct neurodevelopmental disorders.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/humu.23303