Alternative titles; symbols
HGNC Approved Gene Symbol: F8A1
Cytogenetic location: Xq28 Genomic coordinates (GRCh38): X:154,886,355-154,888,061 (from NCBI)
Levinson et al. (1990) found a curious example of a gene within a gene. While looking for transcripts from the Xq28 region, they found one that hybridized to a region in exon 22 of the factor VIII gene (F8; 300841). The transcribed region was in reverse orientation to the F8 exons and was contained entirely within intron 22. Computer analysis of the sequence suggested that it codes for a protein, with the complication that codon usage analysis suggested a frameshift halfway through the gene. The transcript cDNA also bound to mouse, monkey, and rat genomic DNA in a zoo blot. Probably significantly, human intron 22 is hypomethylated on the active X and methylated on the inactive X.
In the mouse, Levinson et al. (1992) found that the F8a gene has no introns and codes for 380 amino acids with 85% identity to the predicted human sequence. Like the human gene, the mouse F8a gene is highly expressed in a wide variety of tissues.
Levinson et al. (1990) determined that the F8A1 gene spans less than 2 kb, contains no introns, and is GC rich.
Levinson et al. (1990) determined that the F8A1 gene maps to chromosome Xq28. It is located within intron 22 of the F8 gene in the reverse orientation.
Levinson et al. (1992) reported that the mouse F8a1 is linked to the factor VIII locus; however, physical mapping suggested that it lies outside the factor VIII gene.
Peters and Ross (2001) showed that huntingtin (HTT; 613004), the protein that is mutant in Huntington disease (HD; 143100), copurifies with a single novel 40-kD protein termed HAP40. They showed that HAP40 is encoded by the open reading frame F8A gene located within intron 22 of the factor VIII gene. Recombinant HAP40 is cytoplasmic in the presence of huntingtin but is actively targeted to the nucleus in the absence of huntingtin. These data indicated that HAP40 is likely to contribute to the function of normal huntingtin and is a candidate for involvement in the aberrant nuclear localization of mutant huntingtin found in degenerating neurons in Huntington disease.
Cryoelectron Microscopy
Guo et al. (2018) used cryoelectron microscopy to determine the structure of full-length human HTT in a complex with HAP40 (encoded by three F8A genes in humans) to an overall resolution of 4 angstroms. HTT is largely alpha-helical and consists of 3 major domains. The amino- and carboxy-terminal domains contain multiple HEAT repeats arranged in a solenoid fashion. These domains are connected by a smaller bridge domain containing different types of tandem repeats. HAP40 is also largely alpha-helical and has a tetratricopeptide repeat-like organization. HAP40 binds in a cleft and contacts the 3 HTT domains by hydrophobic and electrostatic interactions, thereby stabilizing the conformation of HTT.
Inaba et al. (1990) described an MspI RFLP in intron 22 of the F8 gene. Japanese showed 45% heterozygosity and Asian Indians showed 13%; polymorphism was not found in American blacks or Caucasians.
Guo, Q., Huang, B., Cheng, J., Seefelder, M., Engler, T., Pfeifer, G., Oeckl, P., Otto, M., Moser, F., Maurer, M., Pautsch, A., Baumeister, W., Fernandez-Busnadiego, R., Kochanek, S. The cryo-electron microscopy structure of huntingtin. Nature 555: 117-120, 2018. [PubMed: 29466333] [Full Text: https://doi.org/10.1038/nature25502]
Inaba, H., Fujimaki, M., Kazazian, H. H., Jr., Antonarakis, S. E. MspI polymorphic site in intron 22 of the factor VIII gene in the Japanese population. Hum. Genet. 84: 214-215, 1990. [PubMed: 1688823] [Full Text: https://doi.org/10.1007/BF00208947]
Levinson, B., Bermingham, J. R., Jr., Metzenberg, A., Kenwrick, S., Chapman, V., Gitschier, J. Sequence of the human factor VIII-associated gene is conserved in mouse. Genomics 13: 862-865, 1992. [PubMed: 1639415] [Full Text: https://doi.org/10.1016/0888-7543(92)90170-w]
Levinson, B., Kenwrick, S., Lakich, D., Hammonds, G., Gitschier, J. A transcribed gene in an intron of the human factor VIII gene. Genomics 7: 1-11, 1990. [PubMed: 2110545] [Full Text: https://doi.org/10.1016/0888-7543(90)90512-s]
Peters, M. F., Ross, C. A. Isolation of a 40-kDa huntingtin-associated protein. J. Biol. Chem. 276: 3188-3194, 2001. [PubMed: 11035034] [Full Text: https://doi.org/10.1074/jbc.M008099200]