<i>FOXG1</i> 基因及 FOXG1 相关疾病的研究进展 _West China Medical Journal

Authors：

王芳芳 ,  罗蓉

四川大学华西第二医院儿科/出生缺陷与相关妇儿疾病教育部重点实验室（成都 610041）;

Corresponding author：

罗蓉, Email: 1109329811@qq.com

Keywords：

FOXG1 基因; 14q12; 基因型; 表现型; 发育性疾病

DOI：

10.7507/1002-0179.201604109

Video：

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叉头框 G1（forkhead box G1，FOXG1）基因，原名脑因子 1 基因，位于 14q12，为剂量敏感基因，参与神经元细胞的增殖、分化、迁移定位和凋亡等多个生物程序，在端脑从胚胎期至成年的发育过程中发挥重要作用。近年的研究表明，FOXG1 基因点突变、缺失或重复突变与发育迟缓、智力低下、癫痫及语言障碍等多种神经发育性疾病表型相关，这些疾病统称为 FOXG1 相关疾病。该文就FOXG1 基因的结构特征、表达特征和基因功能的研究进展以及 FOXG1 相关疾病的表型特点进行了综述。

Citation： 王芳芳, 罗蓉. FOXG1 基因及 FOXG1 相关疾病的研究进展 . West China Medical Journal, 2017, 32(5): 772-776. doi: 10.7507/1002-0179.201604109 Copy

1.	Golson ML, Kaestner KH. Fox transcription factors: from development to disease. Development, 2016, 143(24): 4558-4570.
2.	Manuel MN, Martynoga B, Molinek MD,et al. The transcription factor Foxg1 regulates telencephalic progenitor proliferation cell autonomously, in part by controlling Pax6 expression levels. Neural Dev, 2011, 6(1): 9.
3.	Brancaccio M, Pivetta C, Granzotto M,et al. Emx2 and Foxg1 inhibit gliogenesis and promote neuronogenesis. Stem Cells, 2010, 28(7): 1206-1218.
4.	Bredenkamp N, Seoighe C, Illing N. Comparative evolutionary analysis of the FoxG1 transcription factor from diverse vertebrates identifies conserved recognition sites for microRNA regulation. Dev Genes Evol, 2007, 217(3): 227-233.
5.	Pratt T, Tian NM, Simpson TI,et al. The winged helix transcription factor Foxg1 facilitates retinal ganglion cell axon crossing of the ventral midline in the mouse. Development, 2004, 131(15): 3773-3784.
6.	Aguiar DP, Sghari S, Creuzet S. The facial neural crest controls fore- and midbrain patterning by regulating Foxg1 expression through Smad1 activity. Development, 2014, 141(12): 2494-2505.
7.	Dou CL, Li S, Lai E. Dual role of brain factor-1 in regulating growth and patterning of the cerebral hemispheres. Cereb Cortex, 1999, 9(6): 543-550.
8.	Muzio L, Mallamaci A. Foxg1 confines Cajal-Retzius neuronogenesis and hippocampal morphogenesis to the dorsomedial pallium. J Neurosci, 2005, 25(17): 4435-4441.
9.	Frullanti E, Amabile S, Lolli MG,et al. Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice. Eur J Hum Genet, 2016, 24(2): 252-257.
10.	Hébert JM, Mcconnell SK. Targeting of cre to the Foxg1 (BF-1) locus mediates loxP recombination in the telencephalon and other developing head structures. Dev Biol, 2000, 222(2): 296-306.
11.	Shen L, Nam HS, Song P,et al. FoxG1 haploinsufficiency results in impaired neurogenesis in the postnatal hippocampus and contextual memory deficits. Hippocampus, 2006, 16(10): 875-890.
12.	Yang Y, Shen W, Ni Y,et al. Impaired interneuron development after Foxg1 disruption. Cereb Cortex, 2015: bhv297.
13.	Ahlgren S, Vogt P, Bronner-Fraser M. Excess FoxG1 causes overgrowth of the neural tube. J Neurobiol, 2003, 57(3): 337-349.
14.	Dastidar SG, Landrieu PM, D’Mello SR. FoxG1 promotes the survival of postmitotic neurons. J Neurosci, 2011, 31(2): 402-413.
15.	Mcmahon KQ, Papandreou A, Ma M,et al. Familial recurrences of FOXG1-related disorder: evidence for mosaicism. Am J Med Genet A, 2015, 167A(12): 3096-3102.
16.	Le Guen T, Bahi-Buisson N, Nectoux J,et al. AFOXG1 mutation in a boy with congenital variant of Rett syndrome. Neurogenetics, 2011, 12(1): 1-8.
17.	Kortüm F, Das S, Flindt M,et al. The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis. J Med Genet, 2011, 48(6): 396-406.
18.	Takahashi S, Matsumoto N, Okayama A,et al.FOXG1 mutations in Japanese patients with the congenital variant of Rett syndrome. Clin Genet, 2012, 82(6): 569-573.
19.	Seltzer LE, Ma M, Ahmed S,et al. Epilepsy and outcome in FOXG1-related disorders. Epilepsia, 2014, 55(8): 1292-1300.
20.	Ariani F, Hayek G, Rondinella D,et al. FOXG1 is responsible for the congenital variant of Rett syndrome. Am J Hum Genet, 2008, 83(1): 89-93.
21.	Florian C, Bahi-Buisson N, Bienvenu T. FOXG1-Related disorders: from clinical description to molecular genetics. Mol Syndromol, 2012, 2(3/5): 153-163.
22.	Philippe C, Amsallem D, Francannet C,et al. Phenotypic variability in Rett syndrome associated withFOXG1 mutations in females. J Med Genet, 2010, 47(1): 59-65.
23.	Grammatico P, de Sanctis S, di Rosa C,et al. First case of deletion 14q11. 2q13: clinical phenotype. Ann Genet, 1994, 37(1): 30-32.
24.	Bisgaard AM, Kirchhoff M, Tümer Z,et al. Additional chromosomal abnormalities in patients with a previously detected abnormal karyotype, mental retardation, and dysmorphic features. Am J Med Genet A, 2006, 140(20): 2180-2187.
25.	Jacob FD, Ramaswamy V, Andersen J,et al. Atypical Rett syndrome with selective FOXG1 deletion detected by comparative genomic hybridization: case report and review of literature. Eur J Hum Genet, 2009, 17(12): 1577-1581.
26.	Mencarelli MA, Kleefstra T, Katzaki E,et al. 14q12 microdeletion syndrome and congenital variant of Rett syndrome. Eur J Med Genet, 2009, 52(2/3): 148-152.
27.	Papa FT, Mencarelli MA, Caselli R,et al. A 3 Mb deletion in 14q12 causes severe mental retardation, mild facial dysmorphisms and Rett-like features. Am J Med Genet A, 2008, 146A(15): 1994-1998.
28.	Kumakura A, Takahashi S, Okajima K,et al. A haploinsufficiency of FOXG1 identified in a boy with congenital variant of Rett syndrome. Brain Dev, 2014, 36(8): 725-729.
29.	Allou L, Lambert L, Amsallem D,et al. 14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements. Eur J Hum Genet, 2012, 20(12): 1216-1223.
30.	Perche O, Haddad G, Menuet A,et al. Dysregulation of FOXG1 pathway in a 14q12 microdeletion case. Am J Med Genet A, 2013, 161A(12): 3072-3077.
31.	Takagi M, Sasaki G, Mitsui T,et al. A 2.0 Mb microdeletion in proximal chromosome 14q12, involving regulatory elements of FOXG1, with the coding region of FOXG1 being unaffected, results in severe developmental delay, microcephaly, and hypoplasia of the corpus callosum. Eur J Med Genet, 2013, 56(9): 526-528.
32.	Ellaway CJ, Ho G, Bettella E,et al. 14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype. Eur J Hum Genet, 2013, 21(5): 522-527.
33.	Alosi D, Klitten LL, Bak M,et al. Dysregulation of FOXG1 by ring chromosome 14. Mol Cytogenet, 2015, 8(1): 24.
34.	Shoichet SA, Kunde SA, Viertel P,et al. Haploinsufficiency of novel FOXG1B variants in a patient with severe mental retardation, brain malformations and microcephaly. Hum Genet, 2005, 117(6): 536-544.
35.	Cellini E, Vignoli A, Pisano T,et al. The hyperkinetic movement disorder of FOXG1-related epileptic-dyskinetic encephalopathy. Dev Med Child Neurol, 2016, 58(1): 93-97.
36.	Bertossi C, Cassina M, Cappellari A,et al. Forkhead box G1 gene haploinsufficiency: an emerging cause of dyskinetic encephalopathy of infancy. Neuropediatrics, 2015, 46(1): 56-64.
37.	Yeung A, Bruno D, Scheffer IE,et al. 4.45 Mb microduplication in chromosome band 14q12 includingFOXG1 in a girl with refractory epilepsy and intellectual impairment. Eur J Med Genet, 2009, 52(6): 440-442.
38.	Brunetti-Pierri N, Paciorkowski AR, Ciccone R,et al. Duplications ofFOXG1 in 14q12 are associated with developmental epilepsy, mental retardation, and severe speech impairment. Eur J Hum Genet, 2011, 19(1): 102-107.
39.	Pontrelli G, Cappelletti S, Claps D,et al. Epilepsy in patients with duplications of chromosome 14 harboringFOXG1. Pediatr Neurol, 2014, 50(5): 530-535.
40.	Bertossi C, Cassina M, De Palma L,et al. 14q12 duplication includingFOXG1: is there a common age-dependent epileptic phenotype? Brain Dev, 2014, 36(5): 402-407.
41.	Striano P, Paravidino R, Sicca F,et al. West syndrome associated with 14q12 duplications harboringFOXG1. Neurology, 2011, 76(18): 1600-1602.
42.	Tohyama J, Yamamoto T, Hosoki K,et al. West syndrome associated with Mosaic duplication ofFOXG1 in a patient with maternal uniparental disomy of chromosome 14. Am J Med Genet A, 2011, 155A(10): 2584-2588.
43.	Amor DJ, Burgess T, Tan TY,et al. Questionable pathogenicity ofFOXG1 duplication. Eur J Hum Genet, 2012, 20(6): 595-596; author reply 596-7.
44.	Shaikh TH, Gai X, Perin JC,et al. High-resolution mapping and analysis of copy number variations in the human genome: a data resource for clinical and research applications. Genome Res, 2009, 19(9): 1682-1690.
45.	Falace A, Vanni N, Mallamaci A,et al. Do regulatory regions matter inFOXG1 duplications?. Eur J Hum Genet, 2013, 21(4): 365-366.

1. Golson ML, Kaestner KH. Fox transcription factors: from development to disease. Development, 2016, 143(24): 4558-4570.
2. Manuel MN, Martynoga B, Molinek MD,et al. The transcription factor Foxg1 regulates telencephalic progenitor proliferation cell autonomously, in part by controlling Pax6 expression levels. Neural Dev, 2011, 6(1): 9.
3. Brancaccio M, Pivetta C, Granzotto M,et al. Emx2 and Foxg1 inhibit gliogenesis and promote neuronogenesis. Stem Cells, 2010, 28(7): 1206-1218.
4. Bredenkamp N, Seoighe C, Illing N. Comparative evolutionary analysis of the FoxG1 transcription factor from diverse vertebrates identifies conserved recognition sites for microRNA regulation. Dev Genes Evol, 2007, 217(3): 227-233.
5. Pratt T, Tian NM, Simpson TI,et al. The winged helix transcription factor Foxg1 facilitates retinal ganglion cell axon crossing of the ventral midline in the mouse. Development, 2004, 131(15): 3773-3784.
6. Aguiar DP, Sghari S, Creuzet S. The facial neural crest controls fore- and midbrain patterning by regulating Foxg1 expression through Smad1 activity. Development, 2014, 141(12): 2494-2505.
7. Dou CL, Li S, Lai E. Dual role of brain factor-1 in regulating growth and patterning of the cerebral hemispheres. Cereb Cortex, 1999, 9(6): 543-550.
8. Muzio L, Mallamaci A. Foxg1 confines Cajal-Retzius neuronogenesis and hippocampal morphogenesis to the dorsomedial pallium. J Neurosci, 2005, 25(17): 4435-4441.
9. Frullanti E, Amabile S, Lolli MG,et al. Altered expression of neuropeptides in FoxG1-null heterozygous mutant mice. Eur J Hum Genet, 2016, 24(2): 252-257.
10. Hébert JM, Mcconnell SK. Targeting of cre to the Foxg1 (BF-1) locus mediates loxP recombination in the telencephalon and other developing head structures. Dev Biol, 2000, 222(2): 296-306.
11. Shen L, Nam HS, Song P,et al. FoxG1 haploinsufficiency results in impaired neurogenesis in the postnatal hippocampus and contextual memory deficits. Hippocampus, 2006, 16(10): 875-890.
12. Yang Y, Shen W, Ni Y,et al. Impaired interneuron development after Foxg1 disruption. Cereb Cortex, 2015: bhv297.
13. Ahlgren S, Vogt P, Bronner-Fraser M. Excess FoxG1 causes overgrowth of the neural tube. J Neurobiol, 2003, 57(3): 337-349.
14. Dastidar SG, Landrieu PM, D’Mello SR. FoxG1 promotes the survival of postmitotic neurons. J Neurosci, 2011, 31(2): 402-413.
15. Mcmahon KQ, Papandreou A, Ma M,et al. Familial recurrences of FOXG1-related disorder: evidence for mosaicism. Am J Med Genet A, 2015, 167A(12): 3096-3102.
16. Le Guen T, Bahi-Buisson N, Nectoux J,et al. AFOXG1 mutation in a boy with congenital variant of Rett syndrome. Neurogenetics, 2011, 12(1): 1-8.
17. Kortüm F, Das S, Flindt M,et al. The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis. J Med Genet, 2011, 48(6): 396-406.
18. Takahashi S, Matsumoto N, Okayama A,et al.FOXG1 mutations in Japanese patients with the congenital variant of Rett syndrome. Clin Genet, 2012, 82(6): 569-573.
19. Seltzer LE, Ma M, Ahmed S,et al. Epilepsy and outcome in FOXG1-related disorders. Epilepsia, 2014, 55(8): 1292-1300.
20. Ariani F, Hayek G, Rondinella D,et al. FOXG1 is responsible for the congenital variant of Rett syndrome. Am J Hum Genet, 2008, 83(1): 89-93.
21. Florian C, Bahi-Buisson N, Bienvenu T. FOXG1-Related disorders: from clinical description to molecular genetics. Mol Syndromol, 2012, 2(3/5): 153-163.
22. Philippe C, Amsallem D, Francannet C,et al. Phenotypic variability in Rett syndrome associated withFOXG1 mutations in females. J Med Genet, 2010, 47(1): 59-65.
23. Grammatico P, de Sanctis S, di Rosa C,et al. First case of deletion 14q11. 2q13: clinical phenotype. Ann Genet, 1994, 37(1): 30-32.
24. Bisgaard AM, Kirchhoff M, Tümer Z,et al. Additional chromosomal abnormalities in patients with a previously detected abnormal karyotype, mental retardation, and dysmorphic features. Am J Med Genet A, 2006, 140(20): 2180-2187.
25. Jacob FD, Ramaswamy V, Andersen J,et al. Atypical Rett syndrome with selective FOXG1 deletion detected by comparative genomic hybridization: case report and review of literature. Eur J Hum Genet, 2009, 17(12): 1577-1581.
26. Mencarelli MA, Kleefstra T, Katzaki E,et al. 14q12 microdeletion syndrome and congenital variant of Rett syndrome. Eur J Med Genet, 2009, 52(2/3): 148-152.
27. Papa FT, Mencarelli MA, Caselli R,et al. A 3 Mb deletion in 14q12 causes severe mental retardation, mild facial dysmorphisms and Rett-like features. Am J Med Genet A, 2008, 146A(15): 1994-1998.
28. Kumakura A, Takahashi S, Okajima K,et al. A haploinsufficiency of FOXG1 identified in a boy with congenital variant of Rett syndrome. Brain Dev, 2014, 36(8): 725-729.
29. Allou L, Lambert L, Amsallem D,et al. 14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements. Eur J Hum Genet, 2012, 20(12): 1216-1223.
30. Perche O, Haddad G, Menuet A,et al. Dysregulation of FOXG1 pathway in a 14q12 microdeletion case. Am J Med Genet A, 2013, 161A(12): 3072-3077.
31. Takagi M, Sasaki G, Mitsui T,et al. A 2.0 Mb microdeletion in proximal chromosome 14q12, involving regulatory elements of FOXG1, with the coding region of FOXG1 being unaffected, results in severe developmental delay, microcephaly, and hypoplasia of the corpus callosum. Eur J Med Genet, 2013, 56(9): 526-528.
32. Ellaway CJ, Ho G, Bettella E,et al. 14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype. Eur J Hum Genet, 2013, 21(5): 522-527.
33. Alosi D, Klitten LL, Bak M,et al. Dysregulation of FOXG1 by ring chromosome 14. Mol Cytogenet, 2015, 8(1): 24.
34. Shoichet SA, Kunde SA, Viertel P,et al. Haploinsufficiency of novel FOXG1B variants in a patient with severe mental retardation, brain malformations and microcephaly. Hum Genet, 2005, 117(6): 536-544.
35. Cellini E, Vignoli A, Pisano T,et al. The hyperkinetic movement disorder of FOXG1-related epileptic-dyskinetic encephalopathy. Dev Med Child Neurol, 2016, 58(1): 93-97.
36. Bertossi C, Cassina M, Cappellari A,et al. Forkhead box G1 gene haploinsufficiency: an emerging cause of dyskinetic encephalopathy of infancy. Neuropediatrics, 2015, 46(1): 56-64.
37. Yeung A, Bruno D, Scheffer IE,et al. 4.45 Mb microduplication in chromosome band 14q12 includingFOXG1 in a girl with refractory epilepsy and intellectual impairment. Eur J Med Genet, 2009, 52(6): 440-442.
38. Brunetti-Pierri N, Paciorkowski AR, Ciccone R,et al. Duplications ofFOXG1 in 14q12 are associated with developmental epilepsy, mental retardation, and severe speech impairment. Eur J Hum Genet, 2011, 19(1): 102-107.
39. Pontrelli G, Cappelletti S, Claps D,et al. Epilepsy in patients with duplications of chromosome 14 harboringFOXG1. Pediatr Neurol, 2014, 50(5): 530-535.
40. Bertossi C, Cassina M, De Palma L,et al. 14q12 duplication includingFOXG1: is there a common age-dependent epileptic phenotype? Brain Dev, 2014, 36(5): 402-407.
41. Striano P, Paravidino R, Sicca F,et al. West syndrome associated with 14q12 duplications harboringFOXG1. Neurology, 2011, 76(18): 1600-1602.
42. Tohyama J, Yamamoto T, Hosoki K,et al. West syndrome associated with Mosaic duplication ofFOXG1 in a patient with maternal uniparental disomy of chromosome 14. Am J Med Genet A, 2011, 155A(10): 2584-2588.
43. Amor DJ, Burgess T, Tan TY,et al. Questionable pathogenicity ofFOXG1 duplication. Eur J Hum Genet, 2012, 20(6): 595-596; author reply 596-7.
44. Shaikh TH, Gai X, Perin JC,et al. High-resolution mapping and analysis of copy number variations in the human genome: a data resource for clinical and research applications. Genome Res, 2009, 19(9): 1682-1690.
45. Falace A, Vanni N, Mallamaci A,et al. Do regulatory regions matter inFOXG1 duplications?. Eur J Hum Genet, 2013, 21(4): 365-366.

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