Alternative titles; symbols
HGNC Approved Gene Symbol: POU4F1
Cytogenetic location: 13q31.1 Genomic coordinates (GRCh38): 13:78,598,362-78,603,552 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q31.1 | Ataxia, intention tremor, and hypotonia syndrome, childhood-onset | 619352 | Autosomal dominant | 3 |
BRN3A (POU4F1) is a class IV POU domain-containing transcription factor highly expressed in the developing sensory nervous system and in cells of the B- and T-lymphocytic lineages (Gerrero et al., 1993).
Xiang et al. (1995) cloned human cDNAs and genomic DNAs encoding BRN3. The BRN3A gene encodes a 423-amino acid polypeptide that contains several identifiable motifs, including a POU domain.
Xiang et al. (1995) analyzed the expression patterns of Brn3a, Brn3b (113725), and Brn3c (602460) in fetal and adult mouse retina and brain. Antibodies to Brn3a identified a large fraction of retinal ganglion cells (RGCs). The 3 factors identified overlapping subsets of retinal ganglion cells and of neurons in the dorsal root and trigeminal ganglia, suggesting that primary somatosensory neurons and retinal ganglion cells share genetic regulatory hierarchies.
Liu et al. (1996) noted that Brn3a and Brn3b are alternatively spliced to produce 2 distinct mRNAs encoding long and short isoforms that differ at their N termini. Using PCR analysis, the authors showed that the relative levels of the 2 variants of Brn3a and Brn3b were regulated to produce different proportions of transcripts in different rat neuronal tissues, as well as in cultured primary and immortalized rat neuronal cells. Similarly, the ratio of these variants was modulated by specific stimuli in a rat neuronal cell line and rat primary neurons.
Xiang et al. (1995) determined that BRN3A contains 2 exons and has a splicing pattern identical to that of BRN3B and BRN3C.
Collum et al. (1992) mapped the human BRN3A gene, which they termed RDC1, to 13q14-q22. Still and Cowell (1996) obtained regional assignment of the POU4F1 gene by PCR of a panel of somatic cell hybrids carrying translocation/deletion breakpoints in the region 13q14-q22. The proximal location of POU4F1 was defined by a breakpoint at 13q21.1 and the distal location by a breakpoint in 13q22. These breakpoints are bounded by the microsatellite markers D13S152 and D13S271, an 11-cM region of 13q. Still and Cowell (1996) screened by PCR for the presence of POU4F1 in a series of YACs previously isolated with microsatellite markers assigned to this region. They noted that this gene, because of involvement in the growth and differentiation of neurons and because of its chromosomal location, is a strong candidate for the site of the defect in CLN5 (256731).
Stumpf (2021) mapped the POU4F1 gene to chromosome 13q31.1 based on an alignment of the POU4F1 sequence (GenBank BC148330) with the genomic sequence (GRCh38).
Smith et al. (1997) reported that the induced differentiation of the ND7 neuronal cell line into nondividing cells bearing neurites is accompanied by a dramatic increase in the level of BRN3A and a corresponding decrease in the level of BRN3B. Overexpression of BRN3B reduces process outgrowth and prevents the normal differentiation response. This inhibitory effect is abolished by mutating a single amino acid in the POU homeodomain of BRN3B to its equivalent in BRN3A. The converse mutation in BRN3A allows it to inhibit process outgrowth in response to induction of differentiation.
Using a yeast 2-hybrid system, Calissano and Latchman (2003) found that mouse Rin (RIT2; 609592) interacted with the N terminus of Brn3a. In human neuroblastoma cells expressing mouse Rin, BRN3A was expressed almost entirely in the nucleus, while Rin localized to both the nucleus and the cytoplasm. Transfection of wildtype mouse Rin with the Brn3a-long isoform in a rat dorsal root ganglion cell line resulted in upregulated transcription from the Egr1 (128990) promoter. In contrast, transfection of a constitutively active Rin mutant with Brn3a-long or transfection of wildtype Rin with Brn3a-short did not upregulate transcription from the Egr1 promoter.
Using transcriptome analysis, Sajgo et al. (2017) showed that Brn3b and Brn3a controlled only small subsets of transcripts in mouse RGC populations. The authors identified extensive combinatorial sets of RGC transcription factors, cell surface molecules, and determinants of neuronal morphology that were differentially expressed in specific RGC populations and selectively regulated by Brn3a and/or Brn3b. Some of these genes intrinsically induced arbor-like processes in epithelial cells, suggesting cell-autonomous neuronal arbor formation mechanisms.
In 4 unrelated patients with childhood-onset ataxia, intention tremor, and hypotonia syndrome (ATITHS; 619352), Webb et al. (2021) identified de novo heterozygous mutations in the POU4F1 gene (601632.0001-601632.0004). The mutations were found by exome sequencing. Three patients had frameshift mutations, predicted to result in a loss of function and haploinsufficiency, and 1 had a missense variant at a conserved residue (Q306R; 601632.0001) that was demonstrated to have decreased transcriptional activity in vitro. Functional studies of the frameshift variants were not performed, but the authors noted that homozygous-null Pou4f1 mice have uncoordinated movements consistent with the ataxia phenotype seen in their patients, as well as behavioral and anatomic defects (see ANIMAL MODEL).
Xiang et al. (1996) generated heterozygous and homozygous Pou4f1-mutant mice. While heterozygous-null (Pou4f1 +/-) mice were indistinguishable from wildtype in both growth and behavior, Pou4f1 -/- mice showed uncoordinated limb and truncal movement, as well as decreased suckling, leading to death by 24 hours of age. Additionally, Pou4f1 -/- mice had loss of neurons in the trigeminal ganglia, medial habenula, red nucleus, inferior olivary nucleus, and nucleus ambiguus.
Using alkaline phosphatase staining, Badea et al. (2009) showed that populations of Brn3a- and Brn3b-expressing RGCs had overlapping but distinct distributions of dendritic stratification in mice. Deletion of Brn3a led to an increase in the ratio of bistratified to monostratified RGCs, with only modest RGC loss and little effect on central projections. In contrast, deletion of Brn3b led to greater RGC loss, disorganization of axonal structure in eye and brain, and differential loss and/or dysfunction of central projections, resulting in visual-driven behavioral deficits in mutant mice.
Maskell et al. (2017) found that Brn3a repressed Brn3b in cardiomyocytes of mice by reducing Brn3b promoter activity. Knockout of Brn3a upregulated Brn3b expression, which increased expression of the Brn3b target genes cyclin D1 (CCND1; 168461) and Bax (600040), resulting in cardiomyocyte apoptosis and heart morphologic defects that likely caused death of Brn3a -/- mice soon after birth. Brn3a -/- and Brn3b -/- double-knockout mice suffered early embryonic lethality, indicating the essential and partially overlapping roles of these genes during early embryogenesis. The authors also found that brn3a and brn3b were expressed during zebrafish heart development, and that knockdown of brn3a and brn3b in zebrafish embryos resulted in cardiac defects.
Mele et al. (2019) found that treatment with angiotensin II (ANGII; 106150) induced hypertrophic responses in mouse heart and stimulated Brn3b expression in cardiomyocytes by activating the Brn3b promoter through hypertrophic signaling pathways. Brn3b expression in response to AngII further triggered time-dependent, differential regulation of distinct Brn3b target genes in cardiomyocytes. Hearts from male Brn3b -/- mice had altered contractile efficiency at baseline and reduced hypertrophic responses following AngII treatment. The reduced cardiac function in response to AngII treatment correlated with increased fibrosis and adverse remodeling in Brn3b -/- hearts, suggesting that mutant hearts were unable to adapt to stress.
In a 3.5-year-old girl (patient 1) with childhood-onset ataxia, intention tremor, and hypotonia syndrome (ATITHS; 619352), Webb et al. (2021) identified a de novo heterozygous c.917A-G transition (c.917A-G, NM_006237.3) in the POU4F1 gene, resulting in a gln306-to-arg (Q306R) substitution at a highly conserved residue in the POU-specific domain. The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. In vitro functional expression studies showed that the Q306R mutation leads to production of a stable protein that has decreased transcriptional activity compared to that of controls.
In a 3.8-year-old boy (patient 2) with childhood-onset ataxia, intention tremor, and hypotonia syndrome (ATITHS; 619352), Webb et al. (2021) identified a de novo heterozygous 4-bp duplication (c.158_161dup, NM_006237.3) in the POU4F1 gene, resulting in a frameshift and premature termination (Leu55AlafsTer295). The mutation was found by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function and haploinsufficiency.
In a 4-year-old boy (patient 3) with childhood-onset ataxia, intention tremor, and hypotonia syndrome (ATITHS; 619352), Webb et al. (2021) identified a de novo heterozygous 8-bp deletion (c.283_290del, NM_006237.3) in the POU4F1 gene, resulting in a frameshift and premature termination (Thr95SerfsTer251). The mutation was found by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function and haploinsufficiency.
In a 22-year-old woman (patient 4) with childhood-onset ataxia, intention tremor, and hypotonia syndrome (ATITHS; 619352), Webb et al. (2021) identified a de novo heterozygous 11-bp deletion (c.271_281del, NM_006237.3) in the POU4F1 gene, resulting in a frameshift and premature termination (Thr91HisfsTer254). The mutation was found by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function and haploinsufficiency.
Badea, T. C., Cahill, H., Ecker, J., Hattar, S., Nathans, J. Distinct roles of transcription factors Brn3a and Brn3b in controlling the development, morphology, and function of retinal ganglion cells. Neuron 61: 852-864, 2009. [PubMed: 19323995] [Full Text: https://doi.org/10.1016/j.neuron.2009.01.020]
Calissano, M., Latchman, D. S. Functional interaction between the small GTP-binding protein Rin and the N-terminal of Brn-3a transcription factor. Oncogene 22: 5408-5414, 2003. [PubMed: 12934100] [Full Text: https://doi.org/10.1038/sj.onc.1206635]
Collum, R. G., Fisher, P. E., Datta, M., Mellis, S., Thiele, C., Huebner, K., Croce, C. M., Israel, M. A., Theil, T. Moroy, T.; DePinho, R.; Alt, F. W.: A novel POU homeodomain gene specifically expressed in cells of the developing mammalian nervous system. Nucleic Acids Res. 20: 4919-4925, 1992. [PubMed: 1357630] [Full Text: https://doi.org/10.1093/nar/20.18.4919]
Gerrero, M. R., McEvilly, R. J., Turner, E., Lin, C. R., O'Connell, S., Jenne, K. J., Hobbs, M. V., Rosenfeld, M. G. Brn-3.0: a POU-domain protein expressed in the sensory immune and endocrine systems that functions on elements distinct from known octamer motifs. Proc. Nat. Acad. Sci. 90: 10841-10845, 1993. [PubMed: 8248179] [Full Text: https://doi.org/10.1073/pnas.90.22.10841]
Liu, Y. Z., Dawson, S. J., Latchman, D. S. Alternative splicing of the Brn-3a and Brn-3b transcription factor RNAs is regulated in neuronal cells. J. Molec. Neurosci. 7: 77-85, 1996. [PubMed: 8835784] [Full Text: https://doi.org/10.1007/BF02736850]
Maskell, L. J., Qamar, K., Babakr, A. A., Hawkins, T. A., Heads, R. J., Budhram-Machadeo, V. S. Essential but partially redundant roles for POU4F1/Brn-3a and POU4F2/Brn-3b transcription factors in the developing heart. Cell Death Dis. 8: e2861, 2017. Note: Electronic Article. [PubMed: 28594399] [Full Text: https://doi.org/10.1038/cddis.2017.185]
Mele, L., Maskell, L. J., Stuckey, D. J., Clark, J. E., Heads, R. J., Budhram-Mahadeo, V. S. The POU4F2/Brn-3b transcription factor is required for the hypertrophic response to angiotensin II in the heart. Cell Death Dis. 10: 621, 2019. Note: Electronic Article. [PubMed: 31413277] [Full Text: https://doi.org/10.1038/s41419-019-1848-y]
Sajgo, S., Ghinia, M. G., Brooks, M., Kretschumer, F., Chuang, K., Hiriyanna, S., Wu, Z., Popescu, O., Badea, T. C. Molecular codes for cell type specification in Brn3 retinal ganglion cells. Proc. Nat. Acad. Sci. 114: E3974-E3983, 2017. Note: Electronic Article. [PubMed: 28465430] [Full Text: https://doi.org/10.1073/pnas.1618551114]
Smith, M. D., Dawson, S. J., Latchman, D. S. Inhibition of neuronal process outgrowth and neuronal specific gene activation by the Brn-3b transcription factor. J. Biol. Chem. 272: 1382-1388, 1997. [PubMed: 8995448] [Full Text: https://doi.org/10.1074/jbc.272.2.1382]
Still, I. H., Cowell, J. The Brn-3a transcription factor gene (POU4F1) maps close to the locus for the variant late infantile form of neuronal ceroid-lipofuscinosis. Cytogenet. Cell Genet. 74: 225-226, 1996. [PubMed: 8941380] [Full Text: https://doi.org/10.1159/000134422]
Stumpf, A. M. Personal Communication. Baltimore, Md. 06/08/2021.
Webb, B. D., Evans, A., Naidich, T. P., Bird, L. M., Parikh, S., Fernandez Garcia, M., Henderson, L. B., Millan, F., Si, Y., Brennand, K. J., Hung, P., Rucker, J. C., Wheeler, P. G., Schadt, E. E. Haploinsufficiency of POU4F1 causes an ataxia syndrome with hypotonia and intention tremor. Hum. Mutat. 42: 685-693, 2021. [PubMed: 33783914] [Full Text: https://doi.org/10.1002/humu.24201]
Xiang, M., Gan, L., Zhou, L., Klein, W. H., Nathans, J. Targeted deletion of the mouse POU domain gene Brn-3a causes selective loss of neurons in the brainstem and trigeminal ganglion, uncoordinated limb movement, and impaired suckling. Proc. Nat. Acad. Sci. 93: 11950-11955, 1996. [PubMed: 8876243] [Full Text: https://doi.org/10.1073/pnas.93.21.11950]
Xiang, M., Zhou, L., Macke, J. P., Yoshioka, T., Hendry, S. H. C., Eddy, R. L., Shows, T. B., Nathans, J. The Brn-3 family of POU-domain factors: primary structure, binding specificity, and expression in subsets of retinal ganglion cells and somatosensory neurons. J. Neurosci. 15: 4762-4785, 1995. [PubMed: 7623109] [Full Text: https://doi.org/10.1523/JNEUROSCI.15-07-04762.1995]