A forkhead-domain gene is mutated in a severe speech and language disorder

  title={A forkhead-domain gene is mutated in a severe speech and language disorder},
  author={Cecilia S. L. Lai and Simon E. Fisher and Jane A. Hurst and Faraneh Vargha-Khadem and Anthony P. Monaco},
Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or neurological impairment and despite adequate intelligence and opportunity. [] Key Result Here we show that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS.

Functional genetic analysis of mutations implicated in a human speech and language disorder.

It is hypothesize that expression of alternative isoforms of FOXP2 may provide mechanisms for post-translational regulation of transcription factor function, and explore the properties of different isoforms, resulting from alternative splicing in human brain.

The Genetic Basis of a Severe Speech and Language Disorder

Mutation screening of FOXP2 in the KE family revealed a point mutation in all affected individuals, which leads to alteration of a key residue in the DNA-binding domain, and is predicted to disrupt the func­tion of the protein.

Deciphering the genetic basis of speech and language disorders.

Investigation of a unique three-generation family showing monogenic inheritance of speech and language deficits led to the isolation of the first such gene on chromosome 7, which encodes a transcription factor known as FOXP2.

Genetics of speech and language disorders.

  • C. KangD. Drayna
  • Biology, Psychology
    Annual review of genomics and human genetics
  • 2011
The discovery of mutations in the FOXP2 gene led to a new avenue of investigation into the substrates and mechanisms that underlie human speech development, and linkage studies have identified several loci, and candidate gene association studies are making progress in identifying causal variants at these loci.

A functional genetic link between distinct developmental language disorders.

The FOXP2-CNTNAP2 pathway provides a mechanistic link between clinically distinct syndromes involving disrupted language, and is found to be associated with language delays in children with autism.

The speech gene FOXP2 is not imprinted

The Forkhead-box protein P2 ( FOXP2 ) was the first gene to be linked to an inherited form of speech and language disorder, described as developmental verbal dyspraxia (DVD), and findings have been described as evidence supporting a theoretical role for imprinting in the evolution of language.

Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits.

Investigation of the entire coding region of FOXP2, including alternatively spliced exons, in 49 probands affected with verbal dyspraxia and the discovery of the first nonsense mutation in FoxP2 opens the door for detailed investigations of neurodevelopment in people carrying different etiological variants of the gene.

FOXP2 is not a major susceptibility gene for autism or specific language impairment.

It is concluded that coding-region variants in FOXP2 do not underlie the AUTS1 linkage and that the gene is unlikely to play a role in autism or more common forms of language impairment.

Monogenic and chromosomal causes of isolated speech and language impairment

The clinical features, aetiology and management options of known chromosomal and single gene disorders that are associated with speech and language pathology in the setting of normal or only mildly impaired cognitive function are summarized.

FOXP2 variants in 14 individuals with developmental speech and language disorders broaden the mutational and clinical spectrum

By identifying intragenic deletions or mutations in 14 individuals from eight unrelated families with variable developmental delay/cognitive impairment and speech and language deficits, this work considerably broaden the mutational and clinical spectrum associated with aberrations in FOXP2.



Neural basis of an inherited speech and language disorder.

The genetic mutation or deletion in this region has resulted in the abnormal development of several brain areas that appear to be critical for both orofacial movements and sequential articulation, leading to marked disruption of speech and expressive language.

Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder.

Investigations of the same KE family indicate that the inherited disorder has a broad phenotype which transcends impaired generation of syntactical rules and includes a striking articulatory impairment as well as defects in intellectual, linguistic, and orofacial praxic functions generally.

The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder.

A detailed BAC-/PAC-based sequence map of this interval is assembled, containing 152 sequence tagged sites (STSs), 20 known genes, and >7.75 Mb of completed genomic sequence in the KE family, and refinement of the SPCH1 interval to a region between new markers 013A and 330B is refined.

Mutations of the forkhead/winged-helix gene, FKHL7, in patients with Axenfeld-Rieger anomaly.

These findings demonstrate that, although mutations of FKHL7 result in anterior-segment defects and glaucoma in some patients, it is probable that at least one more locus involved in the regulation of eye development is also located at 6p25.

Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts.

The gene was found to be expressed in the anterior lens epithelium and to be mutated in patients with ocular disorders, and an insertion of G in the coding region of the FOXE3 gene that occurred 15 nucleotides upstream of the stop codon was identified in a family with anterior segment ocular dysgenesis and cataracts.

The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25

FKHL7, encoding a forkhead transcription factor, is in close proximity to the breakpoint in the balanced translocation patient and is deleted in a second PCG patient with partial 6p monosomy, demonstrating that mutations in FKHL 7 cause a spectrum of glaucoma phenotypes.

A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye.

Nine new mutations in the FOXC1 gene are detected in patients with anterior-chamber eye defects, five of which predict loss of the forkhead domain, as a result of premature termination of translation, and these data suggest that both FoxC1 haploinsufficiency and increased gene dosage can cause anterior- chamber defects of the eye.

cDNAs with long CAG trinucleotide repeats from human brain

Eight cDNAs encode 15 or more consecutive glutamine residues, suggesting that the gene products may function as transcription factors, with a potential role in the regulation of neurodevelopment or neuroplasticity, and are candidates for diseases featuring anticipation, neurodegeneration, or abnormalities of neuro development.

Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome.

FoxC2 represents the second known gene to result in hereditary lymphedema, and LD is only the second hereditary disorder known to be caused by a mutation in a forkhead-family gene, and FOXC2 haploinsufficiency results in LD.

Chromosomal duplication involving the forkhead transcription factor gene FOXC1 causes iris hypoplasia and glaucoma.