HGNC Approved Gene Symbol: RFX4
Cytogenetic location: 12q23.3 Genomic coordinates (GRCh38) : 12:106,583,004-106,762,803 (from NCBI)
The RFX4 gene encodes a transcription factor with a highly conserved DNA-binding domain (summary by Harris et al., 2021).
Some human breast tumors appear to contain abnormal estrogen receptor (ESR1; 133430) protein. Dotzlaw et al. (1992) characterized variant ESR1 cDNAs from human breast cancer biopsy samples. One cDNA, clone 24, contained the first 3 exons of the ESR1 gene followed by a unique sequence. RNase protection studies indicated that clone 24 mRNA was present in only 1 of 61 breast cancer biopsy samples tested. Reith et al. (1994) determined that the sequence fused to ESR1 in clone 24 shows homology to the DNA-binding domain of RFX proteins (see RFX1; 600006). Emery et al. (1996) assigned the designation RFX4 to the gene corresponding to the non-ESR1 region of clone 24. They reported that the predicted DNA-binding domain of RFX4 shares 57 to 78% identity with those of other RFX family members in organisms ranging from yeast to mammals.
Harris et al. (2021) noted that RFX4 is expressed in outer radial glia and astrocytes in the cortex of the developing human brain.
Cheng et al. (2007) found that mouse Rfx4, which is highly expressed in suprachiasmatic nuclei, was downregulated by miR132 (MIRN132; 610016).
Associations Pending Confirmation
Harris et al. (2021) reported 3 unrelated patients with a neurodevelopmental disorder with behavioral abnormalities associated with de novo heterozygous variants in the RFX4 gene identified by exome sequencing through the GeneMatcher Program. There was 1 in-frame deletion in the C-terminal domain (Tyr639_Ser643del) and 2 missense variants (R79S and T362A) affecting highly conserved residues. In addition, 3 affected sibs (family RFX4-3) were homozygous for a missense variant (T247M) that was inherited from the unaffected parents in an autosomal recessive manner. None of the variants were present in the gnomAD database. Functional studies of the variants and studies of patient cells were not performed, but the authors postulated a loss-of-function effect. The patients, who ranged from 8 to 31 years of age, had global developmental delay with impaired intellectual development; most had language delay. All had autism spectrum disorder (ASD) and variable behavioral abnormalities, including sensitivity to noise, impulsivity, mood swings, and ADHD. Two patients with de novo mutations had epilepsy, including 1 with intractable seizures. One patient had microcephaly, cleft lip and palate, and absent pituitary on brain imaging.
Cheng, H.-Y. M., Papp, J. W., Varlamova, O., Dziema, H., Russell, B., Curfman, J. P., Nakazawa, T., Shimizu, K., Okamura, H., Impey, S., Obrietan, K. microRNA modulation of circadian-clock period and entrainment. Neuron 54: 813-829, 2007. [PubMed: 17553428] [Full Text: https://doi.org/10.1016/j.neuron.2007.05.017]
Dotzlaw, H., Alkhalaf, M., Murphy, L. C. Characterization of estrogen receptor variant mRNAs from human breast cancers. Molec. Endocr. 6: 773-785, 1992. [PubMed: 1603086] [Full Text: https://doi.org/10.1210/mend.6.5.1603086]
Emery, P., Durand, B., Mach, B., Reith, W. RFX proteins, a novel family of DNA binding proteins conserved in the eukaryotic kingdom. Nucleic Acids Res. 24: 803-807, 1996. [PubMed: 8600444] [Full Text: https://doi.org/10.1093/nar/24.5.803]
Harris, H. K., Nakayama, T., Lai, J., Zhao, B., Argyrou, N., Gubbels, C. S., Soucy, A., Genetti, C. A., Suslovitch, V., Rodan, L. H., Tiller, G. E., Lesca, G., and 69 others. Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior. Genet. Med. 23: 1028-1040, 2021. [PubMed: 33658631] [Full Text: https://doi.org/10.1038/s41436-021-01114-z]
Reith, W., Ucla, C., Barras, E., Gaud, A., Durand, B., Herrero-Sanchez, C., Kobr, M., Mach, B. RFX1, a transactivator of hepatitis B virus enhancer I, belongs to a novel family of homodimeric and heterodimeric DNA-binding proteins. Molec. Cell. Biol. 14: 1230-1244, 1994. [PubMed: 8289803] [Full Text: https://doi.org/10.1128/mcb.14.2.1230-1244.1994]