Monoallelic expression of the human
            <i>FOXP2</i>
            speech gene

Adegbola, Abidemi; Cox, Gerald F.; Bradshaw, Elizabeth M.; Hafler, David A.; Gimelbrant, Alexander A.; Chess, Andrew

doi:10.1073/pnas.1411270111

Cited by 30 publications

(30 citation statements)

References 56 publications

(71 reference statements)

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“…In support of this view, all documented patients were heterozygous for the etiological mutation (Vernes and Fisher, 2009) in either the gene itself (point mutations, deletions, chromosomal rearrangements; e.g., Turner et al, 2013 and references therein) or downstream regulatory elements (e.g., Adegbola et al, 2015). Random mono-allelic expression (RMAE) with some cells having half the FOXP2 dosage and others expressing none at all (Adegbola et al, 2015) and mosaic deletion with some cells possessing two functional alleles and others none (Palka et al, 2012) also play a role.…”

Section: Introductionmentioning

confidence: 85%

The FOXP2-Driven Network in Developmental Disorders and Neurodegeneration

Oswald

Klöble

Ruland

et al. 2017

Front. Cell. Neurosci.

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The transcription repressor FOXP2 is a crucial player in nervous system evolution and development of humans and songbirds. In order to provide an additional insight into its functional role we compared target gene expression levels between human neuroblastoma cells (SH-SY5Y) stably overexpressing FOXP2 cDNA of either humans or the common chimpanzee, Rhesus monkey, and marmoset, respectively. RNA-seq led to identification of 27 genes with differential regulation under the control of human FOXP2, which were previously reported to have FOXP2-driven and/or songbird song-related expression regulation. RT-qPCR and Western blotting indicated differential regulation of additional 13 new target genes in response to overexpression of human FOXP2. These genes may be directly regulated by FOXP2 considering numerous matches of established FOXP2-binding motifs as well as publicly available FOXP2-ChIP-seq reads within their putative promoters. Ontology analysis of the new and reproduced targets, along with their interactors in a network, revealed an enrichment of terms relating to cellular signaling and communication, metabolism and catabolism, cellular migration and differentiation, and expression regulation. Notably, terms including the words “neuron” or “axonogenesis” were also enriched. Complementary literature screening uncovered many connections to human developmental (autism spectrum disease, schizophrenia, Down syndrome, agenesis of corpus callosum, trismus-pseudocamptodactyly, ankyloglossia, facial dysmorphology) and neurodegenerative diseases and disorders (Alzheimer’s, Parkinson’s, and Huntington’s diseases, Lewy body dementia, amyotrophic lateral sclerosis). Links to deafness and dyslexia were detected, too. Such relations existed for single proteins (e.g., DCDC2, NURR1, PHOX2B, MYH8, and MYH13) and groups of proteins which conjointly function in mRNA processing, ribosomal recruitment, cell–cell adhesion (e.g., CDH4), cytoskeleton organization, neuro-inflammation, and processing of amyloid precursor protein. Conspicuously, many links pointed to an involvement of the FOXP2-driven network in JAK/STAT signaling and the regulation of the ezrin–radixin–moesin complex. Altogether, the applied phylogenetic perspective substantiated FOXP2’s importance for nervous system development, maintenance, and functioning. However, the study also disclosed new regulatory pathways that might prove to be useful for understanding the molecular background of the aforementioned developmental disorders and neurodegenerative diseases.

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Section: Introductionmentioning

confidence: 85%

The FOXP2-Driven Network in Developmental Disorders and Neurodegeneration

Oswald

Klöble

Ruland

et al. 2017

Front. Cell. Neurosci.

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“…In a study of SPCH1 families, O'Brien et al found that significant associations between the language phenotype and the markers around by not within FOXP2 ; one marker (D7S3052) is <5 Mb proximal and the other ( CFTR GATT repeat) is 3 Mb distal to FOXP2 [O'Brien et al, ]. It was shown recently that a 2 Mb deletion 3 Mb upstream of the FOXP2 gene impacts its expression in cis [Adegbola et al, ]. Similarly, a cis element >200 Kb downstream of FOXP2 was shown to have epigenetic characteristics of an enhancer; its displacement from the FOXP2 coding sequence resulted from a chromosomal inversion was postulated to be responsible for language impairment in a recent case [Becker et al, ; Moralli et al, ].…”

Section: Discussionmentioning

confidence: 99%

A de novo interstitial deletion of 7q31.2q31.31 identified in a girl with developmental delay and hearing loss

Zhao¹,

Noon²,

Krantz³

et al. 2016

American J of Med Genetics Pt C

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We report on a 4-year-old female who presented with unilateral sensorineural hearing loss and a concern for developmental delay. A genome-wide SNP array analysis was performed and revealed a de novo 3.2 Mb interstitial deletion of chromosome 7q31.2q31.31. This region contains thirteen protein-encoding genes. It is unknown whether haploinsufficiency of any of these genes is responsible for the clinical features of our patient. We reviewed, the clinical phenotype of a previously published 7q31.3 deletion patient and 18 additional patients with overlapping 7q31 deletions listed in the DECIPHER database. The most consistent feature in these patients and our proband is delayed speech and language development. Hearing loss is presented both in our proband and the published 7q31.3 patient. Our study suggests that a small region on chromosome 7q31.3 encompassing four genes, CFTR, CTTNBP2, NAA38, and ANKRD7, may represent a new locus for congenital hearing loss and/or speech development. © 2016 Wiley Periodicals, Inc.

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“…Notably, the low MAF for this variant in Han Chinese (<1%, compared to 24% in European cohorts) means this association is driven by a tiny number of individuals. A very large schizophrenia GWAS found no associations within FOXP2, but two signals mapped to a putative FOXP2 regulatory region that is deleted in CAS (1,140). Thus, whereas most FOXP2 association studies have targeted SNPs within the primary transcript or proximal promoter, future work should also consider variants in distal regulatory regions.…”

Section: Making the Most Of High-throughput Technologiesmentioning

confidence: 99%

Understanding Language from a Genomic Perspective

2015

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Language is a defining characteristic of the human species, but its foundations remain mysterious. Heritable disorders offer a gateway into biological underpinnings, as illustrated by the discovery that FOXP2 disruptions cause a rare form of speech and language impairment. The genetic architecture underlying language-related disorders is complex, and although some progress has been made, it has proved challenging to pinpoint additional relevant genes with confidence. Next-generation sequencing and genome-wide association studies are revolutionizing understanding of the genetic bases of other neurodevelopmental disorders, like autism and schizophrenia, and providing fundamental insights into the molecular networks crucial for typical brain development. We discuss how a similar genomic perspective, brought to the investigation of language-related phenotypes, promises to yield equally informative discoveries. Moreover, we outline how follow-up studies of genetic findings using cellular systems and animal models can help to elucidate the biological mechanisms involved in the development of brain circuits supporting language.

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Monoallelic expression of the human FOXP2 speech gene

Cited by 30 publications

References 56 publications

The FOXP2-Driven Network in Developmental Disorders and Neurodegeneration

The FOXP2-Driven Network in Developmental Disorders and Neurodegeneration

A de novo interstitial deletion of 7q31.2q31.31 identified in a girl with developmental delay and hearing loss

Understanding Language from a Genomic Perspective

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