The distinct and overlapping phenotypic spectra of FOXP1 and FOXP2 in cognitive disorders

Abstract

Rare disruptions of FOXP2 have been strongly implicated in deficits in language development. Research over the past decade has suggested a role in the formation of underlying neural circuits required for speech. Until recently no evidence existed to suggest that the closely related FOXP1 gene played a role in neurodevelopmental processes. However, in the last few years, novel rare disruptions in FOXP1 have been reported in multiple cases of cognitive dysfunction, including intellectual disability and autism spectrum disorder, together with language impairment. As FOXP1 and FOXP2 form heterodimers for transcriptional regulation, one may assume that they co-operate in common neurodevelopmental pathways through the co-regulation of common targets. Here we compare the phenotypic consequences of FOXP1 and FOXP2 impairment, drawing on well-known studies from the past as well as recent exciting findings and consider what these tell us regarding the functions of these two genes in neural development. Electronic supplementary material The online version of this article (doi:10.1007/s00439-012-1193-z) contains supplementary material, which is available to authorized users.

Variable phenotype in 17q12 microdeletions: Clinical and molecular characterization of a new case

“…Previous studies demonstrated that FOXP2 is responsible for speech-language disorders and cognitive impairment. To date, disruptions in FOXP2 are the only known monogenic cause of speech and language impairment (Bacon et al, 2012;Benítez-Burraco, 2012. Furthermore, it has been shown that FOXP2 directly regulates CNTNAP2, whose mutations, like FOXP2, were found to be correlated to language impairment (Vernes et al, 2008), and the autism candidate gene MET, involved in neuronal differentiation (Mukamel et al, 2011).…”

What can mice tell us about Foxp2 function?

“…Around half the family members (15 people) carry a heterozygous FOXP2 mutation, yielding an amino-acid substitution which interferes with the encoded protein's capacity to regulate target genes [2,9]. A growing number of other individuals and small families are being identified with mutations, chromosome rearrangements and deletions involving FOXP2 (to date at least 34 people with 25 types of disruption, summarised in Refs [3,10 ]). In all instances only one gene copy is affected, but in some cases the nature of the disruption means that effects of additional genes cannot be discounted.…”

A Molecular Genetic Perspective on Speech and Language

“…In some cells in the central nervous system, these two genes are coexpressed (Teramitsu, Kudo, London, Geschwind, & White, 2004), and the resulting proteins have the capacity to directly interact with each other, acting together to regulate targets in a coordinated manner (Li, Weidenfeld, & Morrisey, 2004). Rare causative mutations of FOXP1 have been implicated in a small number of cases of autism and/or intellectual disability, accompanied by notably severe speech and language problems (Bacon & Rappold, 2012). Moreover, it has been shown that FOXP1 actively represses the CNTNAP2 gene, and an autism screening study that sequenced all human protein-coding genes identified an affected child who carried disruptive mutations in both FOXP1 and CNTNAP2, "hits" in two different parts of the same functional pathway (O'Roak et al, 2011).…”