Functional genetic analysis of mutations implicated in a human speech and language disorder
Open accessAbstract
Mutations in the FOXP2 gene cause a severe communication disorder involving speech deficits (developmental verbal dyspraxia), accompanied by wide-ranging impairments in expressive and receptive language. The protein encoded by FOXP2 belongs to a divergent subgroup of forkhead-box transcription factors, with a distinctive DNA-binding domain and motifs that mediate hetero- and homodimerization. Here we report the first direct functional genetic investigation of missense and nonsense mutations in FOXP2 using human cell-lines, including a well-established neuronal model system. We focused on three unusual FOXP2 coding variants, uniquely identified in cases of verbal dyspraxia, assessing expression, subcellular localization, DNA-binding and transactivation properties. Analysis of the R553H forkhead-box substitution, found in all affected members of a large three-generation family, indicated that it severely affects FOXP2 function, chiefly by disrupting nuclear localization and DNA-binding properties. The R328X truncation mutation, segregating with speech/language disorder in a second family, yields an unstable, predominantly cytoplasmic product that lacks transactivation capacity. A third coding variant (Q17L) observed in a single affected child did not have any detectable functional effect in the present study. In addition, we used the same systems to explore the properties of different isoforms of FOXP2, resulting from alternative splicing in human brain. Notably, one such isoform, FOXP2.10+, contains dimerization domains, but no DNA-binding domain, and displayed increased cytoplasmic localization, coupled with aggresome formation. We hypothesize that expression of alternative isoforms of FOXP2 may provide mechanisms for post-translational regulation of transcription factor function.
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The DLX5/6 locus is regulated by FoxP2.
“The DLX5/6 locus is regulated by FoxP2”
From <i>DLX5/6</i> GABAergic Expression Affects Social Vocalization: Implications for Human Evolution (2021) · cites this paper as Vernes, et al. 2006
The section “Transactivation capacities of variant forms of human FOXP2” says that FOXP2’s in vivo downstream targets remain largely unknown and examines repression of an SV40 promoter. Searches for DLX5, DLX6, and the DLX5/6 locus found no passage in our copy addressing whether FOXP2 regulates that locus; page numbers were unavailable. (LLM, conf=0.73)
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“This suggests that the introduction of this mutation yields a stable, but nonfunctional protein product, a conclusion that is supported by in vitro functional studies [30].”
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“SH-SY5Y cells have been exploited commonly for many years as a standard model for investigating human neuronal function(36) and were used effectively in a previous investigation to explore properties of etiological FOXP2 mutations implicated in speech-language disorder.(18) For the present study, we employed stable tr…”
MethodResultInfluentialDe Novo Mutations in FOXP1 in Cases with Intellectual Disability, Autism, and Language Impairment
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“In in vitro cell culture experiments, two possible factors have been proposed for the mutated FOXP2, FOXP2 (R553H)-induced and FOXP2 (R328X)-induced impairment of speech-language ability (8–10): one is the lack of DNA binding activity (8), and the other is mislocalization of mutated FOXP2 (8, 9).”
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“These data are consistent with previous reports expressing it in cell lines (Vernes et al., 2006; Mizutani et al., 2007), which showed that the KE mutant protein was present in the cytoplasm and that it even caused aberrant localization of wild-type FoxP2 protein in the cytoplasm.”
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“Intriguingly, this negative effect of FOXP2 is counteracted by two distinct FOXP2 mutations, R553H and R328X, that are associated with developmental verbal dyspraxia, a speech and language disorder (Vernes et al., 2006).”
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“…interactions, differential splicing of FOXP transcripts may provide further molecular regulation of neuronal development and function, as demonstrated by studies of a FOXP2 isoform lacking the DBD (Bruce & Margolis, 2002; Burkett et al., 2018; Teramitsu & White, 2006; Vernes et al., 2006).”
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“To date, FOXP2 is the only gene clearly linked to this aspect of neurological function, providing a unique opportunity to study the molecular mechanisms involved (Marcus and Fisher, 2003; Vernes et al., 2006).”
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“As vocalizing behavior is highly susceptible to genetics (Lai et al., 2001; Vernes et al., 2006; Enard et al., 2009; Deriziotis et al., 2014), one may expect strain differences to affect vocal behavior and USV structure (Sugimoto et al., 2011).”
BackgroundProspective investigation of FOXP1 syndrome
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“Arg553His has been shown to cause protein mislocalization, with the formation of nuclear and cytoplasmic aggregates, and abolish the binding to DNA and transactivation [61].”
BackgroundGenetics of Speech and Language Disorders
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“Foxp2-R552H mutants carry an arginineto-histidine substitution in the DNA-binding domain of the encoded protein, matching a human FOXP2-R553H mutation which impairs speech and language in a large family (Lai et al. 2001) and disrupts protein function (Vernes et al. 2006).”
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“Such systems enabled us to assess disturbances in subcellular localization, DNA binding, and transactivation properties associated with the R553H and R328X mutations (Vernes et al., 2006).”
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Foxp2 Mutations Impair Auditory-Motor Association Learning
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“the nucleus [34,35].”
Petrin, A., Giacheti, C. M., Maximino, L. P., Abramides, D., Zanchetta, S., Rossi, N. F., Richieri-Costa, A., & Murray, J. C. (2010) · American Journal of Medical Genetics. Part A · doi:10.1002/ajmg.a.33749 · Cited by 65 · see citing works
“…et al., 2007; Alarcon et al., 2008; Rossi et al., 2008; Vernes et al., 2008; Poot et al., 2009], is highly expressed in the cerebral cortex in areas involved with language function [Vernes et al., 2006; Abrahams et al., 2007] and is in the same pathway of FOXP2, another important language gene.”
Beysen, D., Moumné, L., Veitia, R. A., et al. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn100 · Cited by 79 · see citing works
“R103C Helix 3 S BPES in 1-year old female Nuclear and cytoplasmic aggregation FOXC1-R127H Nuclear and cytoplasmic localization (12,15, 16 ,24)”
BackgroundThe Role of the FOXP Family of Transcription Factors in ASD
Bowers, J. M., & Konopka, G. (2012) · Disease Markers · doi:10.1155/2012/456787 · Cited by 65 · see citing works
Hickey, S. L., Berto, S., & Konopka, G. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.04.044 · Cited by 63 · see citing works
Molecular networks of the FOXP2 transcription factor in the brain
den Hoed, J., Devaraju, K., & Fisher, S. E. (2021) · EMBO Reports · doi:10.15252/embr.202152803 · Cited by 62 · see citing works
“The FOXP2-R553H protein, which harbors an etiological substitution disrupting the DNA-binding domain (Vernes et al , 2006), retains its ability to bind to CTBP1 and CTBP2, suggesting that DNA binding of FOXP2 is not essential for the CTBP-FOXP2 interaction (Estruch et al , 2016a).”
Ultrasonic vocalizations of adult male Foxp2‐mutant mice: behavioral contexts of arousal and emotion
Gaub, S., Fisher, S. E., & Ehret, G. (2015) · Genes Brain & Behavior · doi:10.1111/gbb.12274 · Cited by 61 · see citing works
“…243 lines carried either a R552H missense mutation leading to defective protein with disturbed transcription factor function (Vernes & Fisher 2009; Vernes et al. 2006), or a S321X mutation with a null allele and reduced levels of functional Foxp2 protein (Groszer et al. 2008; MacDermot et al.…”
BackgroundEstruch, S. B., Graham, S. A., Quevedo, M., Vino, A., Dekkers, D. H. W., Deriziotis, P., Sollis, E., Demmers, J., Poot, R. A., & Fisher, S. E. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy035 · Cited by 63 · see citing works
“R553H, which is unable to bind to its typical DNA target sequence (15,51).”
BackgroundWhat can mice tell us about Foxp2 function?
French, C. A., & Fisher, S. E. (2014) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.07.003 · Cited by 58 · see citing works
Tang, B., Bečanović, K., Desplats, P., Spencer, B. J., Hill, A. M., Connolly, C., Masliah, E., Leavitt, B. R., & Thomas, E. A. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds132 · Cited by 58 · see citing works
FOXP Genes, Neural Development, Speech and Language Disorders
Takahashi, H., Takahashi, K., & Liu, F. (2009) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-1599-3_9 · Cited by 58 · see citing works
The DISC1 promoter: characterization and regulation by FOXP2
Walker, R. M., Hill, A. E., Newman, A. C., Hamilton, G., Torrance, H. S., Anderson, S. M., Ogawa, F., Deriziotis, P., Nicod, J., Vernes, S. C., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds111 · Cited by 54 · see citing works
“A previous study has shown HEK293, but not SH-SY5Y, cells to express FOXP2 endogenously (31).”
BackgroundInfluentialDevanna, P., Chen, X., Ho, J., Gajewski, D., Smith, S. D., Gialluisi, A., Francks, C., Fisher, S. E., Newbury, D. F., & Vernes, S. C. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.30 · Cited by 49 · see citing works
Horng, S. H., Kreiman, G., Ellsworth, C., Page, D. T., Blank, M. C., Millen, K. J., & Sur, M. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.2127-09.2009 · Cited by 48 · see citing works
“Foxp2 and activity-dependent regulation in the mammalian brain Foxp2 is a transcriptional repressor implicated in orofacial dyspraxia and corticostriatal abnormalities in humans with a heterozygous loss-of-function mutation (Vernes et al., 2006).”
FOXP2 variation modulates functional hemispheric asymmetries for speech perception.
Ocklenburg, S., Arning, L., Gerding, W. M., Epplen, J., Güntürkün, O., & Beste, C. (2013) · Brain and Language · doi:10.1016/j.bandl.2013.07.001 · Cited by 58 · see citing works
“One of these candidates for language lateralization is the forkhead box P2 gene, FOXP2, a developmental transcriptional regulator which controls the growth and differentiation of a class of neurons destined to innervate tissues primarily involved in speech production (Vernes et al., 2006).”
BackgroundThe FOXP2-Driven Network in Developmental Disorders and Neurodegeneration
Oswald, F., Klöble, P., Ruland, A., Rosenkranz, D., Hinz, B., Butter, F., Ramljak, S., Zechner, U., & Herlyn, H. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00212 · Cited by 48 · see citing works
“The investigation of how mutations that associate with verbal dyspraxia affect FOXP2 expression, subcellular localization, DNA-binding and transactivation properties in human neuronrelated cells (SH-SY5Y) inspired a series of further in vitro analyses (Vernes et al., 2006).”
BackgroundShi, Z., Luo, G., Fu, L., Fang, Z., Wang, X., & Li, X.-C. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.0838-13.2013 · Cited by 44 · see citing works
“The reduced functional dosage of the FOXP2 protein presumably is the etiological basis underlying speech and language impairments (Lai et al., 2001; Vernes et al., 2006).”
BackgroundEicher, J. D., & Gruen, J. R. (2013) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2013.07.001 · Cited by 48 · see citing works
Estruch, S. B., Graham, S. A., Deriziotis, P., & Fisher, S. E. (2016) · Scientific Reports · doi:10.1038/srep20911 · Cited by 47 · see citing works
Language Features in a Mother and Daughter of a Chromosome 7;13 Translocation InvolvingFOXP2
Tomblin, J. B., O’Brien, M., Shriberg, L. D., Williams, C. A., Murray, J., Patil, S. R., Bjork, J., Anderson, S., & Ballard, K. J. (2009) · Journal of Speech Language and Hearing Research · doi:10.1044/1092-4388(2009/07-0162 · Cited by 44 · see citing works
Li, T., Zeng, Z., Zhao, Q., Wang, T., Huang, K., Li, J., Li, Y., Liu, J., Wei, Z., Wang, Y., et al. (2012) · The World Journal of Biological Psychiatry · doi:10.3109/15622975.2011.615860 · Cited by 44 · see citing works
“…between FoxP2 and human language and cognition abilities (Fisher et al. 1998; Lai et al. 2001; Enard et al. 2002, 2009; Mac Dermot et al. 2005; Vernes et al. 2006; Vernes et al. 2008; Groszer et al. 2008) What is more, language disorder and cognitive defi ciency are important symptoms of many…”
BackgroundFOXP2 drives neuronal differentiation by interacting with retinoic acid signaling pathways
Devanna, P., Middelbeek, J., & Vernes, S. C. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00305 · Cited by 46 · see citing works
Assessing the effects of common variation in the FOXP2 gene on human brain structure
Hoogman, M., Guadalupe, T. M., Zwiers, M. P., Klarenbeek, P., Francks, C., & Fisher, S. E. (2014) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2014.00473 · Cited by 45 · see citing works
“ORIGINAL RESEARCH ARTICLE published: 01 July 2014 doi: 10.3389/fnhum.2014.00473 Assessing the effects of common variation in the FOXP2 gene on human brain structure”
MethodInfluentialMendoza, E., & Scharff, C. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00112 · Cited by 44 · see citing works
“Zebra finch FoxP1/2/4 repressed the SV40 promoter activity, as reported for mouse and human (Wang et al., 2003; Vernes et al., 2006).”
InfluentialSollis, E., Deriziotis, P., Saitsu, H., Miyake, N., Matsumoto, N., Hoffer, M. J. V., Ruivenkamp, C. A. L., Alders, M. M., Okamoto, N., Bijlsma, E. K., et al. (2017) · Human Mutation · doi:10.1002/humu.23303 · Cited by 44 · see citing works
Assessing the impact of FOXP1 mutations on developmental verbal dyspraxia
Vernes, S. C., MacDermot, K. D., Monaco, A. P., & Fisher, S. E. (2009) · European Journal of Human Genetics · doi:10.1038/ejhg.2009.43 · Cited by 44 · see citing works
Nelson, C. S., Fuller, C. K., Fordyce, P. M., Greninger, A. L., Li, H., & DeRisi, J. L. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt259 · Cited by 42 · see citing works
“Previous EMSA studies did not detect binding of the R553H mutant to SV40 DNA sequence (21).”
BackgroundMethodReading and Language Disorders: The Importance of Both Quantity and Quality
Newbury, D. F., Monaco, A. P., & Paracchini, S. (2014) · Genes · doi:10.3390/genes5020285 · Cited by 40 · see citing works
“For example, individuals with FOXP2 disruptions invariably present with dyspraxic speech (the inability to make fine-tuned oromotor movements necessary for coherent speech), while others can present with both receptive and expressive language difficulties, only an expressive deficit, only with intellectual deficits or…”
BackgroundThe Biological Nature of Human Language
Sciullo, A. M. D., Piattelli‐Palmarini, M., Wexler, K. N., Berwick, R. C., Boeckx, C. A., Jenkins, L., Uriagereka, J., Stromswold, K., Cheng, L. L., Harley, H., et al. (2010) · Biolinguistics · doi:10.5964/bioling.8759 · Cited by 39 · see citing works
Ramus, F., & Fisher, S. E. (2009) · The MIT Press eBooks · doi:10.7551/mitpress/8029.003.0074 · Cited by 39 · see citing works
Nudel, R., & Newbury, D. F. (2013) · Wiley Interdisciplinary Reviews Cognitive Science · doi:10.1002/wcs.1247 · Cited by 38 · see citing works
Neurogenomics of speech and language disorders: the road ahead
Deriziotis, P., & Fisher, S. E. (2013) · Genome biology · doi:10.1186/gb-2013-14-4-204 · Cited by 36 · see citing works
“The functional assays demonstrated that these mutations severely disrupt nuclear localization, DNA-binding ability and transactivation potential of the protein [77].”
BackgroundResultFunctional characterization of TBR1 variants in neurodevelopmental disorder
den Hoed, J., Sollis, E., Venselaar, H., Estruch, S. B., Deriziotis, P., & Fisher, S. E. (2018) · Scientific Reports · doi:10.1038/s41598-018-32053-6 · Cited by 36 · see citing works
White, S. A. (2009) · Brain and Language · doi:10.1016/j.bandl.2009.10.002 · Cited by 36 · see citing works
There are Two Different Language Systems in the Brain
Ardila, A. (2011) · Journal of Behavioral and Brain Science · doi:10.4236/jbbs.2011.12005 · Cited by 36 · see citing works
“to some specific genetic mutations [6,28,29].”
BackgroundFoxp2 Regulates Identities and Projection Patterns of Thalamic Nuclei During Development
Ebisu, H., Iwai, L., Fujita‐Jimbo, E., Momoi, T., & Kawasaki, H. (2016) · Cerebral Cortex · doi:10.1093/cercor/bhw187 · Cited by 32 · see citing works
“This mutation corresponds to a human FOXP2 (R553H) mutation in human FOXP2, and disrupts the DNA binding and transactivation properties of FOXP2 protein (Vernes et al. 2006; Nelson et al. 2013).”
BackgroundMomoi, T., Fujita, E., Senoo, H., & Momoi, M. Y. (2010) · Cell Biology International · doi:10.1042/cbi20090250 · Cited by 32 · see citing works
“The mutated FOXP2 (R553H) exhibits reduced DNA binding and defects in nuclear localization in vitro (Vernes et al., 2006; Mizutani et al., 2007), suggesting that loss of transcriptional activity causes a lack of expression of genes required for speech– language ability, including those associated…”
BackgroundJeyabalan, N., Laissue, P., Batista, F., et al. (2008) · Human Mutation · doi:10.1002/humu.20809 · Cited by 32 · see citing works
“It is known that missense mutations in the FKH domains of FOXC1, FOXC2 and FOXP2 lead to defective localization of the protein and to changes in transactivation (Berry et al., 2005; Saleem et al., 2004; Saleem et al., 2003; Vernes et al., 2006).”
BackgroundBlok, L. S., Vino, A., den Hoed, J., Underhill, H. R., Monteil, D. C., Li, H., Santos, F. J. R., Chung, W. K., Amaral, M. D., Schnur, R. E., et al. (2020) · Genetics in Medicine · doi:10.1038/s41436-020-01016-6 · Cited by 31 · see citing works
Mapping of Human FOXP2 Enhancers Reveals Complex Regulation
Becker, M., Devanna, P., Fisher, S. E., & Vernes, S. C. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00047 · Cited by 28 · see citing works
“HEK293 cells are already known to endogenously express FOXP2 and have been previously used by us and others to study its function (Vernes et al., 2006; Fu et al., 2014; Sin et al., 2015; Estruch et al., 2016).”
BackgroundLüffe, T., D’Orazio, A., Bauer, M., Gioga, Z., Schoeffler, V., Lesch, K., Romanos, M., Drepper, C., & Lillesaar, C. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01651-w · Cited by 30 · see citing works
The Key Regulator for Language and Speech Development, FOXP2, is a Novel Substrate for SUMOylation
Meredith, L. J., Wang, C., Nascimento, L. A., Liu, R., Wang, L., & Yang, W. (2015) · Journal of Cellular Biochemistry · doi:10.1002/jcb.25288 · Cited by 30 · see citing works
“IMPAIRED SUMOylation DOES NOT AFFECT FOXP2 CELLULAR LOCALIZATION AND STABILITY A previous report has demonstrated that while the WT FOXP2 is predominantly localized in the nucleus, significant amounts (approximately 50%) of human etiological R553H FOXP2 are found in the cytoplasm [Vernes et al., 2006].”
BackgroundInfluential<i>DLX5/6</i> GABAergic Expression Affects Social Vocalization: Implications for Human Evolution
Levi, G., de Lombares, C., Giuliani, C., Iannuzzi, V., Aouci, R., Garagnani, P., Franceschi, C., Grimaud-Hervé, D., & Narboux-Nême, N. (2021) · Molecular Biology and Evolution · doi:10.1093/molbev/msab181 · Cited by 29 · see citing works
Recent Advances in the Genetics of Vocal Learning
Condro, M. C., & White, S. A. (2014) · Comparative Cognition & Behavior Reviews · doi:10.3819/ccbr.2014.90003 · Cited by 27 · see citing works
“The KE mutation results in an amino acid substitution, R553H (Figure 1), in the conserved DNA-binding forkhead box (FOX) region of the protein, which, in in vitro studies, causes abnormal levels of extra-nuclear FOXP2 and impedes its ability to bind to DNA (Mizutani et al., 2007; Vernes et al., 2006).”
InfluentialFoxP2 directly regulates the reelin receptor VLDLR developmentally and by singing
Adam, I., Mendoza, E., Kobalz, U., Wohlgemuth, S., & Scharff, C. (2016) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2016.04.002 · Cited by 28 · see citing works
Multiple transcription start sites for FOXP2 with varying cellular specificities
Schroeder, D. I., & Myers, R. (2008) · Gene · doi:10.1016/j.gene.2008.01.015 · Cited by 28 · see citing works
Three-Dimensional Domain Swapping Changes the Folding Mechanism of the Forkhead Domain of FoxP1
Medina, E., Córdova, C., Villalobos, P., Reyes, J., Komives, E. A., Ramírez‐Sarmiento, C. A., & Babul, J. (2016) · Biophysical Journal · doi:10.1016/j.bpj.2016.04.043 · Cited by 28 · see citing works
Modified sound-evoked brainstem potentials in Foxp2 mutant mice
Kurt, S., Groszer, M., Fisher, S. E., et al. (2009) · Brain Research · doi:10.1016/j.brainres.2009.06.092 · Cited by 28 · see citing works
Insights into the Genetic Foundations of Human Communication
Graham, S. A., Deriziotis, P., & Fisher, S. E. (2015) · Neuropsychology Review · doi:10.1007/s11065-014-9277-2 · Cited by 26 · see citing works
Fu, L., Shi, Z., Luo, G., Tu, W., Wang, X., Fang, Z., & Li, X.-C. (2014) · Molecular Brain · doi:10.1186/s13041-014-0071-0 · Cited by 27 · see citing works
“, R553H) results in a transcription factor with compromised DNA binding and transcriptional regulatory activity [1,20].”
BackgroundFunctional characterization of rare FOXP2 variants in neurodevelopmental disorder
Estruch, S. B., Graham, S. A., Chinnappa, S. M., Deriziotis, P., & Fisher, S. E. (2016) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-016-9177-2 · Cited by 27 · see citing works
“To assess the ability of the FOXP2 variants to regulate transcription, we performed luciferase reporter assays using the SV40 promoter, a viral promoter which is repressed by FOXP2 [6, 23].”
BackgroundMethodFoxp2 loss of function increases striatal direct pathway inhibition via increased GABA release
van Rhijn, J.-R., Fisher, S. E., Vernes, S. C., & Kasri, N. N. (2018) · Brain Structure and Function · doi:10.1007/s00429-018-1746-6 · Cited by 26 · see citing works
Interaction between lexical and grammatical language systems in the brain
Ardila, A. (2012) · Physics of Life Reviews · doi:10.1016/j.plrev.2012.05.001 · Cited by 28 · see citing works
Unravelling neurogenetic networks implicated in developmental language disorders
Vernes, S. C., & Fisher, S. E. (2009) · Biochemical Society Transactions · doi:10.1042/bst0371263 · Cited by 25 · see citing works
Deriziotis, P., Graham, S. A., Estruch, S. B., & Fisher, S. E. (2014) · Journal of Visualized Experiments · doi:10.3791/51438 · Cited by 24 · see citing works
Yang, M., Wang, Y., Wang, X., et al. (2009) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2009.11.007 · Cited by 24 · see citing works
Todeschini, A., Dipietromaria, A., L’Hôte, D., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr244 · Cited by 23 · see citing works
Burkett, Z. D., Day, N. F., Kimball, T. H., Aamodt, C., Heston, J. B., Hilliard, A. T., Xiao, X. G., & White, S. A. (2018) · eLife · doi:10.7554/elife.30649 · Cited by 23 · see citing works
“FL through heterodimerization and the formation of 119 cytoplasmic aggresomes [11].”
BackgroundInfluentialCompensation between FOXP transcription factors maintains proper striatal function
Ahmed, N. I., Khandelwal, N., Anderson, A. G., Oh, E., Vollmer, R. M., Kulkarni, A., Gibson, J. R., & Konopka, G. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114257 · Cited by 22 · see citing works
Effect of pH on the Structure and DNA Binding of the FOXP2 Forkhead Domain
Blane, A., & Fanucchi, S. (2015) · Biochemistry · doi:10.1021/acs.biochem.5b00155 · Cited by 22 · see citing works
What Does it Mean to be Human? Life, Death, Personhood and the Transhumanist Movement
Doyle, D. J. (2018) · Anticipation Science · doi:10.1007/978-3-319-94950-5 · Cited by 22 · see citing works
“The gene, known as FOXP2, is not unique to humans; however, humans have a unique form of FOXP2 that is essential to language production (Vernes et al. 2006).”
BackgroundAlpha-synuclein deficiency affects brain Foxp1 expression and ultrasonic vocalization
Kurz, A., Wöhr, M., Walter, M. J., Bonin, M., Auburger, G. W. J., Gispert, S., & Schwarting, R. K. W. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2009.12.054 · Cited by 21 · see citing works
Perumal, K., Dirr, H. W., & Fanucchi, S. (2015) · The Protein Journal · doi:10.1007/s10930-015-9603-4 · Cited by 21 · see citing works
“Axenfeld-Rieger syndrome (FOXC1) [11, 12], tumorigenesis and intellectual disability (FOXP1) [11–13], a speech deficit disorder (FOXP2) [14] and IPEX (immune”
Helldén, A., Odar‐Cederlöf, I., Larsson, K., Fehrman‐Ekholm, I., & Linden, T. K. A. (2007) · BMJ · doi:10.1136/bmj.39408.393137.be · Cited by 19 · see citing works
DNA binding and mitotic phosphorylation protect polyglutamine proteins from assembly formation
Saad, S., Swigut, T., Tabatabaee, S., Lalgudi, P. V., Jarosz, D. F., & Wysocka, J. (2025) · Cell · doi:10.1016/j.cell.2025.03.031 · Cited by 18 · see citing works
“37,39 Since this mutation also causes FOXP2 to form nuclear puncta, we hypothesized that DNA binding might prevent assembly.”
Speech- and language-linked FOXP2 mutation targets protein motors in striatal neurons
Kuo, H., Chen, S.-Y., Huang, R.-C., Takahashi, H., Lee, Y., Pang, H.-Y., Wu, C.-H., Graybiel, A. M., & Liu, F. (2023) · Brain · doi:10.1093/brain/awad090 · Cited by 18 · see citing works
- Authors
- Vernes, S. C., Nicod, J., Elahi, F. M., Coventry, J. A., Kenny, N., Coupe, A.-M., Bird, L. E., Davies, K. E., & Fisher, S. E.
- Affiliations
- Centre for Human Genetics (GB)
- University of Oxford (GB)
- Corresponding author
- Fisher, Simon E.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-09-19
- Volume
- 15
- Issue
- 21
- Pages
- 3154-3167
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2131915909
- Semantic Scholar
- 24bc72b59948202c3ddd8953676c692635b0ec5f
- Cited by
- 167
- References
- 44
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 1 · 2021: 6 · 2020: 6 · 2019: 6 · 2018: 11 · 2017: 11 · 2016: 10 · 2015: 10 · 2014: 9 · 2013: 11 · 2012: 15
- FWCI
- 5.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Directorate for Biological Sciences
- Medical Research Council
- Clarendon Fund
- National Institute on Aging (T32AG023481)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Social Sciences › Psychology › Developmental and Educational Psychology › Language Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- FOXP2, developmental verbal dyspraxia, speech and language disorders, forkhead transcription factor, alternative splicing, nuclear localization, DNA-binding activity, transcriptional activation, protein dimerization, aggresome formation, post-translational regulation, neuronal cell lines
- MeSH terms
- Amino Acid Sequence, Apraxias, Brain, Cell Line, Cell Nucleus, DNA-Binding Proteins, Humans, Language Development Disorders, Molecular Sequence Data, Recombinant Proteins, Transfection, Transcriptional Activation, Mutagenesis, Site-Directed, Point Mutation, Alternative Splicing, Protein Structure, Tertiary, Codon, Nonsense, Protein Isoforms, Mutation, Missense, Forkhead Transcription Factors
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