HGNC Approved Gene Symbol: FRG1
Cytogenetic location: 4q35.2 Genomic coordinates (GRCh38) : 4:189,940,872-189,963,192 (from NCBI)
Van Deutekom et al. (1996) identified a novel gene, which they referred to as FRG1, that mapped 100 kb centromeric of the repeated units on chromosome 4q35 that are deleted in facioscapulohumeral muscular dystrophy (FSHD; 158900). The FRG1 gene detected a transcript of 1.1 kb on Northern blot analysis of adult muscle and lymphocytes and of fetal brain, muscle, and placenta. DNA sequence analysis did not reveal any homology to known genes. The FRG1 gene was found to be evolutionarily conserved and to have related sequences on multiple human chromosomes. Van Deutekom et al. (1996) identified a polymorphism in exon 1 of this gene and used RT-PCR to amplify reverse transcribed mRNA from lymphocytes and muscle biopsies of patients and controls. These studies indicated that both alleles were transcribed and gave no evidence of position effect variegation leading to repression of allelic transcription.
Almost all patients with FSHD carry deletions of an integral number of tandem 3.3-kb repeats, termed D4Z4, on chromosome 4q35. Gabellini et al. (2002) found that in FSHD muscle, genes located upstream of D4Z4 on 4q35, including FRG1 (601278), FRG2 (609032), and ANT1 (103220), are inappropriately overexpressed. They showed that an element within D4Z4 specifically binds a multiprotein complex that mediates transcriptional repression of 4q35 genes. Gabellini et al. (2002) proposed that deletion of D4Z4 leads to the inappropriate transcriptional derepression of 4q35 genes, resulting in disease.
Within the D4Z4 locus, Petrov et al. (2006) identified 2 DNA loop domains anchored to the nuclear matrix via nuclear scaffold/matrix attached regions (S/MARs). Myoblasts derived from patients with FSHD showed a significant decrease in association of S/MARs with the nuclear matrix compared to control myoblasts. Biochemical mapping showed that in normal myoblasts the D4Z4 array was located in a DNA loop domain distinct from the DNA loop domain where FRG1 and FRG2 were located, whereas in damaged FSHD chromosome, the partially deleted D4Z4 array and FRG1 and FRG2 were located within the same DNA loop domain. Petrov et al. (2006) suggested that S/MARs regulate chromatin accessibility and expression of genes implicated in FSHD.
To identify the gene responsible for FSHD pathogenesis, Gabellini et al. (2006) generated transgenic mice selectively overexpressing in skeletal muscle the 4q35 genes FRG1, FRG2 (609032), or ANT1 (103220). They found that FRG1 transgenic mice developed a muscular dystrophy with features characteristic of the human disease; by contrast, FRG2 and ANT1 transgenic mice seemed normal. FRG1 is a nuclear protein and several lines of evidence suggest it is involved in pre-mRNA splicing. Gabellini et al. (2006) found changes in the alternative splicing pattern of the pre-mRNAs of TNNT3 (600692) and myotubularin related-protein 1 (MTMR1; 300171) in muscle of FRG1 transgenic mice and FSHD patients. Collectively, the results suggested that FSHD results from inappropriate overexpression of FRG1 in skeletal muscle, which leads to abnormal alternative splicing of specific pre-mRNAs.
Gabellini, D., D'Antona, G., Moggio, M., Prelle, A., Zecca, C., Adami, R., Angeletti, B., Ciscato, P., Pellegrino, M. A., Bottinelli, R., Green, M. R., Tupler, R. Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1. Nature 439: 973-977, 2006. [PubMed: 16341202] [Full Text: https://doi.org/10.1038/nature04422]
Gabellini, D., Green, M. R., Tupler, R. Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle. Cell 110: 339-348, 2002. [PubMed: 12176321] [Full Text: https://doi.org/10.1016/s0092-8674(02)00826-7]
Petrov, A., Pirozhkova, I., Carnac, G., Laoudj, D., Lipinski, M., Vassetzky, Y. S. Chromatin loop domain organization within the 4q35 locus in facioscapulohumeral dystrophy patients versus normal human myoblasts. Proc. Nat. Acad. Sci. 103: 6982-6987, 2006. [PubMed: 16632607] [Full Text: https://doi.org/10.1073/pnas.0511235103]
van Deutekom, J. C. T., Lemmers, R. J. L. F., Grewal, P. K., van Geel, M., Romberg, S., Dauwerse, H. G., Wright, T. J., Padberg, G. W., Hofker, M. H., Hewitt, J. E., Frants, R. R. Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q35. Hum. Molec. Genet. 5: 581-590, 1996. [PubMed: 8733123] [Full Text: https://doi.org/10.1093/hmg/5.5.581]