Alternative titles; symbols
HGNC Approved Gene Symbol: PCSK6
Cytogenetic location: 15q26.3 Genomic coordinates (GRCh38): 15:101,303,933-101,489,707 (from NCBI)
Using PCR methods, Kiefer et al. (1991) identified a human subtilisin-like protease gene, PCSK6, which they designated PACE4. PCR primers were designed to be specific for the subfamily of eukaryotic subtilisin-like proteases with specificity for paired basic amino acid residue processing motifs. The deduced 969-amino acid full-length prepro-PACE4 has a signal peptidase cleavage site after ala63, and a propeptide processing site after arg149. Mature PACE4 has an N-terminal subtilisin-like catalytic domain that includes active-site asp, his, asn, and ser residues. It has 3 N-glycosylation sites near the C terminus. A PACE4 splice variant encodes a C-terminally truncated isoform identical to full-length PACE4 up to lys471, after which it has 16 unique C-terminal amino acids. As with the product of the PACE gene (FURIN; 136950), the tissue distribution of PACE4 was widespread, with comparatively higher levels in liver.
Shore et al. (2016) identified a bidirectional promoter within the PCSK6 gene. In the sense direction, the promoter drives expression of a predicted 308-amino acid N-terminally truncated isoform that has the furin-like repeats and C-terminal PLAC domain of full-length PCSK6, but lacks the N-terminal convertase-like domain. In the antisense direction, the promoter drives expression of 2 splice variants of a long noncoding RNA. PCR analysis and reporter gene assays of human neuronal and nonneuronal cell lines confirmed expression of 1 sense and 2 antisense transcripts, with the sense transcript predominating.
Shore et al. (2016) identified a SNP, rs1185145, within the internal promoter region of the PCSK6 gene. The A allele of the SNP introduces a possible HOX (see 142955)-binding site. EMSA experiments confirmed that the internal promoter with the A allele, but not the T allele, bound protein in nuclear extracts of human neuronal and nonneuronal cell lines.
Shore et al. (2016) reported that the PCSK6 gene has at least 23 exons. They identified an internal bidirectional promoter around exons 15 and 16.
By in situ hybridization using isolated cosmid clones, Kiefer et al. (1991) mapped the PACE4 gene to chromosome 15 in close proximity to the PACE gene at 15q25-q26. Double labeling in situ hybridization suggested that the 2 genes are within 5 megabases of each other.
Mbikay et al. (1995) mapped the mouse Pace4 gene (Pcsk6) to chromosome 7 by RFLP analysis of a DNA panel from an interspecific backcross. It was located at a distance of 13 cM from the Pcsk3 locus, which specifies furin (136950), another member of the proprotein convertase subtilisin-like family of enzymes previously mapped to mouse chromosome 7. This is in concordance with the known close proximity of these 2 loci in the homologous region on human 15q25-qter. Pcsk3 and Pcsk6 map to a region of mouse chromosome 7 that has been associated cytogenetically with postnatal lethality in maternal disomy, suggesting that these genes may be imprinted.
Shore et al. (2016) reported that the PCSK6 gene maps to chromosome 15q26.3.
Kiefer, M. C., Tucker, J. E., Joh, R., Landsberg, K. E., Saltman, D., Barr, P. J. Identification of a second human subtilisin-like protease gene in the fes/fps region of chromosome 15. DNA Cell Biol. 10: 757-769, 1991. [PubMed: 1741956] [Full Text: https://doi.org/10.1089/dna.1991.10.757]
Mbikay, M., Seidah, N. G., Chretien, M., Simpson, E. M. Chromosomal assignment of the genes for proprotein convertases PC4, PC5, and PACE 4 in mouse and human. Genomics 26: 123-129, 1995. [PubMed: 7782070] [Full Text: https://doi.org/10.1016/0888-7543(95)80090-9]
Shore, R., Covill, L., Pettigrew, K. A., Brandler, W. M., Diaz, R., Xu, Y., Tello, J. A., Talcott, J. B., Newbury, D. F., Stein, J., Monaco, A. P., Paracchini, S. The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts. Hum. Molec. Genet. 25: 1771-1779, 2016. [PubMed: 26908617] [Full Text: https://doi.org/10.1093/hmg/ddw047]