Editing FOXP2 (section)

== Clinical significance ==
The FOXP2 gene has been implicated in several cognitive functions including; general brain development, language, and synaptic plasticity. The FOXP2 gene region acts as a transcription factor for the forkhead box P2 protein. Transcription factors affect other regions, and the forkhead box P2 protein has been suggested to also act as a transcription factor for hundreds of genes. This prolific involvement opens the possibility that the FOXP2 gene is much more extensive than originally thought.<ref name="GHR_FOXP2" /> Other targets of transcription have been researched without correlation to FOXP2. Specifically, FOXP2 has been investigated in correlation with autism and dyslexia, however with no mutation was discovered as the cause.<ref name="Gauthier_2003">{{cite journal | vauthors = Gauthier J, Joober R, Mottron L, Laurent S, Fuchs M, De Kimpe V, Rouleau GA | title = Mutation screening of FOXP2 in individuals diagnosed with autistic disorder | journal = American Journal of Medical Genetics. Part A | volume = 118A | issue = 2 | pages = 172–5 | date = April 2003 | pmid = 12655497 | doi = 10.1002/ajmg.a.10105 | s2cid = 39762074 }}</ref><ref name="MacDermot_2005" /> One well identified target is language.<ref name="GHR_FOXP2_disorders">{{cite web |title=FOXP2-related speech and language disorder |url=https://ghr.nlm.nih.gov/condition/foxp2-related-speech-and-language-disorder | work = Genetics Home Reference | publisher = U.S. National Library of Medicine, National Institutes of Health |access-date=2019-02-26}}</ref> Although some research disagrees with this correlation,<ref>{{cite journal | vauthors = Newbury DF, Bonora E, Lamb JA, Fisher SE, Lai CS, Baird G, Jannoun L, Slonims V, Stott CM, Merricks MJ, Bolton PF, Bailey AJ, Monaco AP | title = FOXP2 is not a major susceptibility gene for autism or specific language impairment | journal = American Journal of Human Genetics | volume = 70 | issue = 5 | pages = 1318–27 | date = May 2002 | pmid = 11894222 | pmc = 447606 | doi = 10.1086/339931 }}</ref> the majority of research shows that a mutated FOXP2 causes the observed production deficiency.<ref name="GHR_FOXP2" /><ref name="GHR_FOXP2_disorders"/><ref name="Lennon_2007">{{cite journal | vauthors = Lennon PA, Cooper ML, Peiffer DA, Gunderson KL, Patel A, Peters S, Cheung SW, Bacino CA | title = Deletion of 7q31.1 supports involvement of FOXP2 in language impairment: clinical report and review | journal = American Journal of Medical Genetics. Part A | volume = 143A | issue = 8 | pages = 791–8 | date = April 2007 | pmid = 17330859 | doi = 10.1002/ajmg.a.31632 | s2cid = 22021740 }}</ref><ref name="Gauthier_2003" /><ref>{{Cite journal | vauthors = Rossell S, Tan E, Bozaoglu K, Neill E, Sumner P, Carruthers S, Van Rheenen T, Thomas E, Gurvich C |date=2017|title=Is language Impairment in Schizophrenia related to Language Genes? |journal=European Neuropsychopharmacology |volume=27 |pages=S459–S460 |doi=10.1016/j.euroneuro.2016.09.532 |s2cid=54316143}}</ref><ref name="Reuter_2017">{{cite journal | vauthors = Reuter MS, Riess A, Moog U, Briggs TA, Chandler KE, Rauch A, Stampfer M, Steindl K, Gläser D, Joset P, Krumbiegel M, Rabe H, Schulte-Mattler U, Bauer P, Beck-Wödl S, Kohlhase J, Reis A, Zweier C | title = FOXP2 variants in 14 individuals with developmental speech and language disorders broaden the mutational and clinical spectrum | journal = Journal of Medical Genetics | volume = 54 | issue = 1 | pages = 64–72 | date = January 2017 | pmid = 27572252 | doi = 10.1136/jmedgenet-2016-104094 | s2cid = 24589445 }}</ref>

There is some evidence that the linguistic impairments associated with a mutation of the ''FOXP2'' gene are not simply the result of a fundamental deficit in motor control. Brain imaging of affected individuals indicates functional abnormalities in language-related cortical and basal ganglia regions, demonstrating that the problems extend beyond the motor system.<ref>{{cite journal | vauthors = Liégeois F, Baldeweg T, Connelly A, Gadian DG, Mishkin M, Vargha-Khadem F | title = Language fMRI abnormalities associated with FOXP2 gene mutation | journal = Nature Neuroscience | volume = 6 | issue = 11 | pages = 1230–7 | date = November 2003 | pmid = 14555953 | doi = 10.1038/nn1138 | url = https://www.nature.com/articles/nn1138 | s2cid = 31003547 | url-access = subscription }}</ref>

Mutations in FOXP2 are among several (26 genes plus 2 intergenic) loci which correlate to [[ADHD]] diagnosis in adults – clinical ADHD is an umbrella label for a heterogeneous group of genetic and neurological phenomena which may result from FOXP2 mutations or other causes.<ref name="Demontis 2018">{{cite journal | vauthors = Demontis D, Walters RK, Martin J, Mattheisen M, Als TD, Agerbo E, Baldursson G, Belliveau R, Bybjerg-Grauholm J, Bækvad-Hansen M, Cerrato F, Chambert K, Churchhouse C, Dumont A, Eriksson N, Gandal M, Goldstein JI, Grasby KL, Grove J, Gudmundsson OO, Hansen CS, Hauberg ME, Hollegaard MV, Howrigan DP, Huang H, Maller JB, Martin AR, Martin NG, Moran J, Pallesen J, Palmer DS, Pedersen CB, Pedersen MG, Poterba T, Poulsen JB, Ripke S, Robinson EB, Satterstrom FK, Stefansson H, Stevens C, Turley P, Walters GB, Won H, Wright MJ, Andreassen OA, Asherson P, Burton CL, Boomsma DI, Cormand B, Dalsgaard S, Franke B, Gelernter J, Geschwind D, Hakonarson H, Haavik J, Kranzler HR, Kuntsi J, Langley K, Lesch KP, Middeldorp C, Reif A, Rohde LA, Roussos P, Schachar R, Sklar P, Sonuga-Barke EJ, Sullivan PF, Thapar A, Tung JY, Waldman ID, Medland SE, Stefansson K, Nordentoft M, Hougaard DM, Werge T, Mors O, Mortensen PB, Daly MJ, Faraone SV, Børglum AD, Neale BM | title = Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder | journal = Nature Genetics | volume = 51 | issue = 1 | pages = 63–75 | date = January 2019 | pmid = 30478444 | pmc = 6481311 | doi = 10.1038/s41588-018-0269-7 }}</ref>

A 2020 [[genome-wide association study]] (GWAS) implicates [[single-nucleotide polymorphisms]] (SNPs) of FOXP2 in susceptibility to [[cannabis use disorder]].<ref name="Johnson_2020">{{cite journal | vauthors = Johnson EC, Demontis D, Thorgeirsson TE, Walters RK, Polimanti R, Hatoum AS, Sanchez-Roige S, Paul SE, Wendt FR, Clarke TK, Lai D, Reginsson GW, Zhou H, He J, Baranger DA, Gudbjartsson DF, Wedow R, Adkins DE, Adkins AE, Alexander J, Bacanu SA, Bigdeli TB, Boden J, Brown SA, Bucholz KK, Bybjerg-Grauholm J, Corley RP, Degenhardt L, Dick DM, Domingue BW, Fox L, Goate AM, Gordon SD, Hack LM, Hancock DB, Hartz SM, Hickie IB, Hougaard DM, Krauter K, Lind PA, McClintick JN, McQueen MB, Meyers JL, Montgomery GW, Mors O, Mortensen PB, Nordentoft M, Pearson JF, Peterson RE, Reynolds MD, Rice JP, Runarsdottir V, Saccone NL, Sherva R, Silberg JL, Tarter RE, Tyrfingsson T, Wall TL, Webb BT, Werge T, Wetherill L, Wright MJ, Zellers S, Adams MJ, Bierut LJ, Boardman JD, Copeland WE, Farrer LA, Foroud TM, Gillespie NA, Grucza RA, Harris KM, Heath AC, Hesselbrock V, Hewitt JK, Hopfer CJ, Horwood J, Iacono WG, Johnson EO, Kendler KS, Kennedy MA, Kranzler HR, Madden PA, Maes HH, Maher BS, Martin NG, McGue M, McIntosh AM, Medland SE, Nelson EC, Porjesz B, Riley BP, Stallings MC, Vanyukov MM, Vrieze S, Davis LK, Bogdan R, Gelernter J, Edenberg HJ, Stefansson K, Børglum AD, Agrawal A | title = A large-scale genome-wide association study meta-analysis of cannabis use disorder | journal = The Lancet. Psychiatry | volume = 7 | issue = 12 | pages = 1032–1045 | date = December 2020 | pmid = 33096046 | pmc = 7674631 | doi = 10.1016/S2215-0366(20)30339-4 | doi-access = free }}</ref>

=== Language disorder ===
It is theorized that the translocation of the 7q31.2 region of the FOXP2 gene causes a severe language impairment called [[developmental verbal dyspraxia]] (DVD)<ref name="GHR_FOXP2_disorders"/> or childhood apraxia of speech (CAS)<ref>{{cite journal | vauthors = Morgan A, Fisher SE, Scheffer I, Hildebrand M | title = FOXP2-Related Speech and Language Disorders | journal = GenReviews | date = 23 June 2016 | pmid = 27336128 | publisher = University of Washington | veditors = Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A }}</ref> So far this type of mutation has only been discovered in three families across the world including the original KE family.<ref name="Reuter_2017"/> A missense mutation causing an arginine-to-histidine substitution (R553H) in the DNA-binding domain is thought to be the abnormality in KE.<ref name="Preuss_2012" /> This would cause a normally basic residue to be fairly acidic and highly reactive at the body's pH. A heterozygous nonsense mutation, R328X variant, produces a truncated protein involved in speech and language difficulties in one KE individual and two of their close family members. R553H and R328X mutations also affected nuclear localization, DNA-binding, and the transactivation (increased gene expression) properties of FOXP2.<ref name="MacDermot_2005" />

These individuals present with deletions, translocations, and missense mutations. When tasked with repetition and verb generation, these individuals with DVD/CAS had decreased activation in the putamen and Broca's area in fMRI studies. These areas are commonly known as areas of language function.<ref>{{cite journal | vauthors = Vargha-Khadem F, Gadian DG, Copp A, Mishkin M | title = FOXP2 and the neuroanatomy of speech and language | journal = Nature Reviews. Neuroscience | volume = 6 | issue = 2 | pages = 131–8 | date = February 2005 | pmid = 15685218 | doi = 10.1038/nrn1605 | s2cid = 2504002 }}</ref> This is one of the primary reasons that FOXP2 is known as a language gene. They have delayed onset of speech, difficulty with articulation including slurred speech, stuttering, and poor pronunciation, as well as dyspraxia.<ref name="Reuter_2017"/> It is believed that a major part of this speech deficit comes from an inability to coordinate the movements necessary to produce normal speech including mouth and tongue shaping.<ref name="GHR_FOXP2_disorders" /> Additionally, there are more general impairments with the processing of the grammatical and linguistic aspects of speech.<ref name="MacDermot_2005" /> These findings suggest that the effects of FOXP2 are not limited to motor control, as they include comprehension among other cognitive language functions. General mild motor and cognitive deficits are noted across the board.<ref name="Lennon_2007"/> Clinically these patients can also have difficulty coughing, sneezing, or clearing their throats.<ref name="GHR_FOXP2_disorders" />

While FOXP2 has been proposed to play a critical role in the development of speech and language, this view has been challenged by the fact that the gene is also expressed in other mammals as well as birds and fish that do not speak.<ref>{{cite book | vauthors = Friederici AD | author-link = Angela D. Friederici | title = 'Language in the Brain | date = 2016 | publisher = The MIT Press | location = Cambridge, MA | isbn = 978-0-262-03692-4 | page = 222 }}</ref> It has also been proposed that the FOXP2 transcription-factor is not so much a hypothetical 'language gene' but rather part of a regulatory machinery related to externalization of speech.<ref>{{cite book | vauthors = Berwick RC, Chomsky N | date = 2016 | title = Why Only Us? | isbn = 978-0-262-53349-2 | publisher = The MIT Press | location = Cambridge, MA | page = 76 }}</ref>