Alternative titles; symbols
HGNC Approved Gene Symbol: FOXG1
SNOMEDCT: 702450004;
Cytogenetic location: 14q12 Genomic coordinates (GRCh38) : 14:28,766,787-28,770,277 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q12 | Rett syndrome, congenital variant | 613454 | Autosomal dominant | 3 |
The FOXG1 gene encodes a developmental transcription factor with repressor activities (Murphy et al., 1994; Li et al., 1995).
The QIN gene was identified by Li and Vogt (1993) as the cell-derived insert in avian sarcoma virus-31 and is the putative oncogene of that virus. The QIN product belongs to a large family of transcription factors that includes the product of the homeotic gene forkhead (fkh) of Drosophila and hepatocyte nuclear factor-3 (HNF3; see HNF3A, 602294) and brain factor-1 (BF1) of mammals. Members of the family, referred to as the fkh/HNF3 family, share a unique DNA-binding domain, the FKH box.
By analyzing cDNA clones that cross-hybridized with the FKH domain of the rat Hnf3a, Murphy et al. (1994) isolated 10 cDNAs from human fetal brain and human testis cDNA libraries. One of these cDNAs, which they called HFK1 (for human forkhead-1), encodes a putative 476-amino acid protein that shares 87.5% identity with rat Bf1 at the amino acid level. HFK1 was found to be highly conserved among mammalian species and possibly among birds. Northern blot analysis detected a 3.2-kb transcript in human and mouse fetal brain and adult mouse brain. In situ hybridization with sections of mouse embryo and human fetal brain demonstrated that HFK1 expression was restricted to the neuronal cells in the telencephalon, with strong expression in the developing dentate gyrus and hippocampus. Murphy et al. (1994) obtained 2 other cDNAs, which they called HFK2 (FOXG1A) and HFK3 (FOXG1C), that they considered to be closely related but distinct from HFK1. Wiese et al. (1995) reported that FOXG1A, or BF2, was a duplicated copy of FOXG1B. However, by genomic sequence analysis, Bredenkamp et al. (2007) determined that there is only a single FOXG1 gene, which corresponds to the FOXG1B sequence.
Shoichet et al. (2005) identified 4 additional exons 3-prime to exon 1 of FOXG1. RT-PCR analysis isolated 4 splice variants that lack the last 113 nucleotides of FOXG1 exon 1 and have C-terminal ends defined by the additional exonic sequences. Northern blot analysis of human fetal brain detected transcripts of 8.5, 7.0, and 6.0 kb that were not present in adult brain.
Bredenkamp et al. (2007) found that FOXG1 was highly conserved among 6 mammalian and 3 reptilian species examined, with highest conservation in the DNA-binding and C-terminal domains. The N-terminal domain of mammalian FOXG1 contains an extended proline- and glutamine-rich region specific to mammals. Bredenkamp et al. (2007) also identified conserved miR9 (MIRN9; see 611186) and miR33 (see MIRN33A; 612156) recognition sites in the FOXG1 3-prime UTR.
Wiese et al. (1995) found that the human BF1 gene contains a 500-bp intron situated between exons encoding the DNA-binding domain II and the forkhead domain. Shoichet et al. (2005) determined that the FOXG1 gene contains 5 exons. By genomic sequence analysis, Bredenkamp et al. (2007) determined that the FOXG1 gene contains no introns.
By analysis of rodent/human somatic cell hybrids and by fluorescence in situ hybridization, Kastury et al. (1994) mapped the human QIN gene to chromosome 14q13. Using chromosomal in situ hybridization, Murphy et al. (1994) localized the HFK1 gene to chromosome 14q12. By isotopic in situ hybridization, Wiese et al. (1995) demonstrated that BF1 and the closely related BF2 gene map to chromosome 14q11-q13. However, by genomic sequence analysis, Bredenkamp et al. (2007) found no evidence of multiple FOXG1 genes in the human genome and showed that the 3 reported FOXG1 sequences map to an identical interval of chromosome 14.
Li et al. (1995) found that both the cellular QIN protein and viral QIN protein acted as transcriptional repressors. The major transcriptional repression domain mapped to amino acids 252 to 395 of viral QIN.
In mouse postnatal cortex, Ariani et al. (2008) found overlapping expression of Foxg1 and Mecp2 (300005) in differentiating cortical compartments and neuronal subnuclear localization.
Using conditional inactivation in mice, Cargnin et al. (2018) found that Foxg1 action in cortical neurons was required for formation of cortical laminar structure, corpus callosum, and hippocampus, as well as in generation of cortical layers. Full gene dosage of Foxg1 in cortical neurons was needed to establish cortico-cortical projections, and loss of Foxg1 action in neurons led to deficits in midline glia that played an important role in establishing callosal projections. Examination of a subset of late-born neurons in cortices of conditional knockout mice revealed that Foxg1 controlled the timely integration of cortical pyramidal neurons to the upper layers and the navigation of callosal axons in cell-autonomous and Foxg1 dosage-sensitive manners. Chromatin immunoprecipitation-sequencing analysis revealed that Foxg1 and Rp58 (613617) formed a complex in cortical pyramidal neurons and controlled transcription of common target genes during cortex development. The Foxg1-Rp58 complex bound directly to and repressed a set of genes that controlled neuronal migration and axonal projection, including Robo1 (602430), Slit3 (603745), and reelin (RELN; 600514), thereby orchestrating the timely integration of cortical neurons into the correct laminar position and subsequent callosal axon navigation.
Shoichet et al. (2005) reported a girl with several mental retardation associated with complete agenesis of the corpus callosum and microcephaly associated with a balanced de novo translocation, t(2;14)(p22;q12) and a neighboring 720-kb inversion on chromosome 14q12. The cytogenetic changes disrupted the C terminus of splice variants of the FOXG1 gene. The patient's disorder was first noted at age 2 weeks, when she showed severe muscle rigidity. At 6 months, she was unable to lift her head and microcephaly was noted. At age 7 years, she was unable to sit or stand without assistance, had no language development, and had seizures and tetraplegia.
In 7 unrelated patients with mental retardation who were referred for genomewide array CGH analysis, Brunetti-Pierri et al. (2011) identified 7 different but overlapping duplications of chromosome 14q12. The duplications ranged in size from 3 to 14 Mb and the minimal common duplicated region included 3 genes: FOXG1, C14ORF32, and PRKD1 (605435). All patients had developmental delay, mental retardation, and absent or delayed speech, and 4 had infantile spasms or other seizures, including 2 with hypsarrhythmia (see 613454). Otherwise, the features were highly variable, and although 4 had dysmorphic features, there was no recognizable pattern. Brunetti-Pierri et al. (2011) concluded that increased dosage of FOXG1 was the best candidate to explain the neurodevelopmental phenotypes in these patients.
Tohyama et al. (2011) reported a Japanese girl who developed infantile seizures and spasms at age 4 months with progression to hypsarrhythmia. Treatment with adrenocorticotropic hormone resulted in seizure control by age 6 months, but she had mild psychomotor delay and poor speech at age 6 years. Chromosome analysis revealed mosaicism for maternal uniparental disomy of chromosome 14q. Microarray-based CGH delineated an 11.2-Mb duplication of 14q11.2-q12, which contained 124 genes, including FOXG1. Tohyama et al. (2011) concluded that increased dosage of the FOXG1 gene was responsible for the phenotype.
In 2 unrelated girls with the congenital variant of Rett syndrome (613454), Ariani et al. (2008) identified 2 different heterozygous truncating mutations in the FOXG1 gene (164874.0001 and 164874.0002, respectively). Both girls had infantile onset of microcephaly, mental retardation, and peculiar jerky movements similar to that observed in classic Rett syndrome (RTT; 312750).
Mencarelli et al. (2010) identified 4 different heterozygous mutations in the FOXG1 gene (see, e.g., 164874.0003-164874.0004) in 4 unrelated girls with the congenital variant of Rett syndrome. All had severe mental retardation with lack of speech and motor development and stereotypic movements.
Philippe et al. (2010) identified 2 different de novo heterozygous mutations in the FOXG1 gene (164874.0005 and 164874.0006, respectively) in 2 unrelated females with the congenital variant of Rett syndrome. One of the girls had a phenotype that could be considered compatible with classic Rett syndrome, and the authors suggested that individuals with classic Rett syndrome should also be tested for mutations in the FOXG1 gene.
Kortum et al. (2011) identified heterozygous deletions or mutations in the FOXG1 gene in 11 of 210 patients with severe mental retardation, microcephaly, and/or brain abnormalities. One known mutation (164874.0007) was identified in 2 patients, and 9 novel mutations, including 2 large deletions, a balanced translocation and a deletion that both may have disrupted/displaced putative cis-regulatory elements of FOXG1, and 5 sequence changes, were identified. All mutations that could be evaluated were of de novo origin.
Mitter et al. (2018) compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1, and identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain.
Mitter et al. (2018) reviewed the genotype-phenotype correlation in 83 patients with mutations in FOXG1. They found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurologic features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.
Hanashima et al. (2004) demonstrated that the generation of the earliest born neurons, the Cajal-Retzius cells, is suppressed by the telencephalic transcription factor Foxg1. In Foxg1-null mice, Hanashima et al. (2004) observed an excess of Cajal-Retzius neuron production in the cortex. By conditionally inactivating Foxg1 in cortical progenitors that normally produce deep-layer cortical neurons, they demonstrated that Foxg1 is constitutively required to suppress Cajal-Retzius cell fate. Hence, Hanashima et al. (2004) concluded that the competence to generate the earliest born neurons during late cortical development is actively suppressed but not lost.
In a 22-year-old girl with the congenital variant of Rett syndrome (613454), Ariani et al. (2008) identified a heterozygous 765G-A transition in the FOXG1 gene, resulting in a trp255-to-ter (W255X) substitution and predicted to disrupt of the forkhead domain and impair DNA binding. The patient had a normal birth but developed microcephaly at age 3 months. She did not respond, was unable to lift her head, and was never able to sit unaided. She was always apraxic and showed peculiar jerky movements of the upper limbs and midline stereotypic activities, typical of classic Rett syndrome (RTT; 312750). She never acquired spoken language and developed seizures at age 14 years. EEG showed a multifocal pattern with spikes and sharp waves and occasional paroxysmal activity. There was also corpus callosum hypoplasia, microcephaly, occasional abnormal breathing patterns, and bruxism. The mutation affected all 4 fetal brain isoforms of FOXG1.
In a 7-year-old girl with the congenital variant of Rett syndrome (613454), Ariani et al. (2008) identified a heterozygous 1-bp deletion (969delC) in the FOXG1 gene, resulting in loss of the JARID1B (605393)-interacting domain and misfolding of the groucho-binding domain. The patient had a normal birth but developed microcephaly at age 3 months. She did not respond and was unable to lift her head. She was always apraxic and showed peculiar jerky movements of the upper limbs and midline stereotypic activities, typical of classic Rett syndrome (RTT; 312750). She never acquired spoken language. EEG showed a multifocal pattern with spikes and sharp waves and occasional paroxysmal activity. There was also corpus callosum hypoplasia, microcephaly, occasional abnormal breathing patterns, and bruxism. The mutation affected all 4 fetal brain isoforms of FOXG1.
In a 3-year-old Spanish girl with the congenital variant of Rett syndrome (613454), Mencarelli et al. (2010) identified a de novo heterozygous 624C-G transversion in the FOXG1 gene, resulting in a tyr208-to-ter (Y208X) substitution. She had hypotonia at birth and subsequently showed progressive microcephaly and delayed psychomotor development. She never achieved sitting, walking, or speech, and showed stereotypic hand movements.
In an 8-year-old French girl with the congenital variant of Rett syndrome (613454), Mencarelli et al. (2010) identified a de novo heterozygous 643T-C transition in the FOXG1 gene, resulting in a phe215-to-leu (F215L) substitution in a conserved residue. She had sleep disturbance and severe crying in the neonatal period, and showed psychomotor retardation at age 6 months. She had hypotonia, poor eye contact, manual stereotypies, microcephaly, and never achieved walking or speech.
In a 22-year-old woman with the congenital variant of Rett syndrome (613454), Philippe et al. (2010) identified a de novo heterozygous 924G-A transition in the FOXG1 gene, resulting in a trp308-to-ter (W308X) substitution. The resultant truncated protein lacks both the Groucho and JARID1C-binding domains. Deceleration of head growth was noted at age 2 months, followed by impaired interaction. She later showed sleep disruption associated with EEG abnormalities, and never acquired speech or purposeful hand movements. Brain MRI showed hypoplasia of the corpus callosum with decreased white matter volume.
In a 10-year-old girl with the congenital variant of Rett syndrome (613454), Philippe et al. (2010) identified a de novo heterozygous 1200C-G transversion in the FOXG1 gene, resulting in a tyr400-to-ter (Y400X) substitution. She was noted to have delayed development at 6 months of age, followed by postnatal deceleration of head growth at 9 months. At age 5 years, she had repetitive stereotypic hand movements, absence of speech, and inappropriate laughter. At age 9 years, she had poor eye contact, ataxia, and drooling. Brain MRI did not reveal any malformations. Philippe et al. (2010) suggested that this patient's phenotype could be compatible with a diagnosis of classic Rett syndrome (RTT; 312750), and noted that the W400X-mutant protein retains an intact Groucho-binding domain, which the authors suggested may have resulted in some residual activity and a somewhat less severe phenotype.
In 2 unrelated patients with the congenital variant of Rett syndrome (613454), Kortum et al. (2011) identified a heterozygous de novo 1-bp duplication (460dupG), resulting in a duplication of guanine after 7 subsequent guanine nucleotides in the FOXG1 gene. The recurrence of this mutation suggested that this guanine stretch is prone to replication errors, thus representing a mutation hotspot.
Ariani, F., Hayek, G., Rondinella, D., Artuso, R., Mencarelli, M. A., Spanhol-Rosseto, A., Pollazzon, M., Buoni, S., Spiga, O., Ricciardi, S., Meloni, I., Longo, I., Mari, F., Broccoli, V., Zappella, M., Renieri, A. FOXG1 is responsible for the congenital variant of Rett syndrome. Am. J. Hum. Genet. 83: 89-93, 2008. [PubMed: 18571142] [Full Text: https://doi.org/10.1016/j.ajhg.2008.05.015]
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. 217: 227-233, 2007. [PubMed: 17260156] [Full Text: https://doi.org/10.1007/s00427-006-0128-x]
Brunetti-Pierri, N., Paciorkowski, A. R., Ciccone, R., Mina, E. D., Bonaglia, M. C., Borgatti, R., Schaaf, C. P., Sutton, V. R., Xia, Z., Jelluma, N., Ruivenkamp, C., Bertrand, M., and 10 others. Duplications of FOXG1 in 14q12 are associated with developmental epilepsy, mental retardation, and severe speech impairment. Europ. J. Hum. Genet. 19: 102-107, 2011. [PubMed: 20736978] [Full Text: https://doi.org/10.1038/ejhg.2010.142]
Cargnin, F., Kwon, J.-S., Katzman, S., Chen, B., Lee, J. W., Lee, S.-K. FOXG1 orchestrates neocortical organization and cortico-cortical connections. Neuron 100: 1083-1096, 2018. [PubMed: 30392794] [Full Text: https://doi.org/10.1016/j.neuron.2018.10.016]
Hanashima, C., Li, S. C., Shen, L., Lai, E., Fishell, G. Foxg1 suppresses early cortical cell fate. Science 303: 56-59, 2004. [PubMed: 14704420] [Full Text: https://doi.org/10.1126/science.1090674]
Kastury, K., Li, J., Druck, T., Su, H., Vogt, P. K., Croce, C. M., Huebner, K. The human homologue of the retroviral oncogene qin maps to chromosome 14q13. Proc. Nat. Acad. Sci. 91: 3616-3618, 1994. [PubMed: 8170957] [Full Text: https://doi.org/10.1073/pnas.91.9.3616]
Kortum, F., Das, S., Flindt, M., Morris-Rosendahl, D. J., Stefanova, I., Goldstein, A., Horn, D., Klopocki, E., Kluger, G., Martin, P., Rauch, A., Roumer, A., Saitta, S., Walsh, L. E., Wieczorek, D., Uyanik, G., Kutsche, K., Dobyns, W. B. The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis. J. Med. Genet. 48: 396-406, 2011. [PubMed: 21441262] [Full Text: https://doi.org/10.1136/jmg.2010.087528]
Li, J., Chang, H. W., Lai, E., Parker, E. J., Vogt, P. K. The oncogene qin codes for a transcriptional repressor. Cancer Res. 55: 5540-5544, 1995. [PubMed: 7585630]
Li, J., Vogt, P. K. The retroviral oncogene qin belongs to the transcription factor family that includes the homeotic gene fork head. Proc. Nat. Acad. Sci. 90: 4490-4494, 1993. [PubMed: 8099441] [Full Text: https://doi.org/10.1073/pnas.90.10.4490]
Mencarelli, M. A., Spanhol-Rosseto, A., Artuso, R., Rondinella, D., De Filippis, R., Bahi-Buisson, N., Nectoux, J., Rubinsztajn, R., Bienvenu, T., Moncla, A., Chabrol, B., Villard, L., Krumina, Z., Armstrong, J., Roche, A., Pineda, M., Gak, E., Mari, F., Ariani, F., Renieri, A. Novel FOXG1 mutations associated with the congenital variant of Rett syndrome. J. Med. Genet. 47: 49-53, 2010. [PubMed: 19578037] [Full Text: https://doi.org/10.1136/jmg.2009.067884]
Mitter, D., Pringsheim, M., Kaulisch, M., Plumacher, K. S., Schroder, S., Warthemann, R., Abou Jamra, R., Baethmann, M., Bast, T., Buttel, H. M., Cohen, J. S., Conover, E., and 29 others. FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants. Genet. Med. 20: 98-108, 2018. [PubMed: 28661489] [Full Text: https://doi.org/10.1038/gim.2017.75]
Murphy, D. B., Wiese, S., Burfeind, P., Schmundt, D., Mattei, M.-G., Schulz-Schaeffer, W., Thies, U. Human brain factor 1, a new member of the fork head gene family. Genomics 21: 551-557, 1994. [PubMed: 7959731] [Full Text: https://doi.org/10.1006/geno.1994.1313]
Philippe, C., Amsallem, D., Francannet, C., Lambert, L., Saunier, A., Verneau, F., Jonveaux, P. Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females. J. Med. Genet. 47: 59-65, 2010. [PubMed: 19564653] [Full Text: https://doi.org/10.1136/jmg.2009.067355]
Shoichet, S. A., Kunde, S.-A., Viertel, P., Schell-Apacik, C., von Voss, H., Tommerup, N., Ropers, H.-H., Kalscheuer, V. M. Haploinsufficiency of novel FOXG1B variants in a patient with severe mental retardation, brain malformations, and microcephaly. Hum. Genet. 117: 536-544, 2005. [PubMed: 16133170] [Full Text: https://doi.org/10.1007/s00439-005-1310-3]
Tohyama, J., Yamamoto, T., Hosoki, K., Nagasaki, K., Akasaka, N., Ohashi, T., Kobayashi, Y., Saitoh, S. West syndrome associated with mosaic duplication of FOXG1 in a patient with maternal uniparental disomy of chromosome 14. Am. J. Med. Genet. 155A: 2584-2588, 2011. [PubMed: 21910242] [Full Text: https://doi.org/10.1002/ajmg.a.34224]
Wiese, S., Murphy, D. B., Schlung, A., Burfeind, P., Schmundt, D., Schnulle, V., Mattei, M.-G., Thies, U. The genes for human brain factor 1 and 2, members of the fork head gene family, are clustered on chromosome 14q. Biochim. Biophys. Acta 1262: 105-112, 1995. [PubMed: 7599184] [Full Text: https://doi.org/10.1016/0167-4781(95)00059-p]