Alternative titles; symbols
HGNC Approved Gene Symbol: PCDH11Y
Cytogenetic location: Yp11.2 Genomic coordinates (GRCh38) : Y:5,000,296-5,742,228 (from NCBI)
Protocadherins are involved in cell-cell interactions critical in the development of the central nervous system. By genomic sequence analysis of a BAC clone from the X-Y homology region on Xq21.3, searching an EST database, and PCR, Blanco et al. (2000) obtained a cDNA encoding PCDHX (300246). Using PCR on a Y-only somatic cell hybrid and CEPH-Y YAC clones with primers based on the PCDHX sequence capable of amplifying Y exons, Blanco et al. (2000) obtained a cDNA encoding the Yp11 counterpart of PCDHX, which they termed PCDHY. PCDHX and PCDHY are 98.1% identical at the nucleotide level. The deduced 1,037-amino acid PCDHY protein is 98.3% identical to the PCDHX protein, and both have 7 extracellular cadherin domains followed by a transmembrane domain. However, PCDHY has a shorter cytoplasmic domain, and due to a 13-bp deletion, the PCDHY initiator methionine is located further upstream, resulting in an enlarged signal peptide sequence. Blanco et al. (2000) also identified a second initiator methionine further downstream that would exclude the signal peptide from the resulting protein. RT-PCR analysis detected expression of PCDHY and PCDHX in fetal brain and adult amygdala, hippocampus, caudate nucleus, corpus callosum, substantia nigra, and thalamus; expression was not detected in other tissues, except for a low level in testis. Nested RT-PCR analysis showed that low levels of PCDHX predominate in the cerebellum, and transcripts in the kidney, liver, muscle, and testis are predominantly PCDHY. Differential regulation of PCDHX and PCDHY was observed in a pluripotential cell line: PCDHX predominated before retinoic acid treatment, and PCDHY predominated after retinoic acid treatment.
By subtractive hybridization to identify genes preferentially expressed in apoptosis-resistant prostate cancer (LNCaP) cells, Chen et al. (2002) cloned PCDH11Y. They identified a serine-rich region similar to a beta-catenin (CTNNB1; 116806)-binding site near the C terminus of PCDH11Y. Northern blot analysis detected a 4.8-kb PCDH11Y transcript abundantly expressed in apoptosis-resistant LNCaP cells. Western blot analysis detected a 110-kD PCDH11Y protein, and cell fractionation showed that the protein was cytoplasmic.
Using subtractive hybridization, Chen et al. (2002) found that PCDH11Y was upregulated in LNCaP cells resistant to apoptosis caused by phorbol ester or serum starvation. Immunoprecipitation analysis showed that beta-catenin interacted with PCDH11Y in apoptosis-resistant LNCaP cells.
Yang et al. (2005) increased PCDHY expression in human prostate cancer cells by transfection with PCDHY cDNA or by using an androgen-free growth medium. Elevated PCDHY expression activated Wnt signaling as assessed by nuclear accumulation of beta-catenin, increased expression of a reporter gene driven by a promoter with TCF (see 189908)/LEF1 (153245)-binding elements, and increased expression of Wnt target genes. Moreover, elevated PCDHY expression in human prostate cancer cells led to their transdifferentiation into neuroendocrine-like cells with elevated expression of ENO2 (131360) and chromogranin A (118910). Transdifferentiation was also achieved by transfection with stabilized beta-catenin. PCDHY- or beta-catenin-specific short interfering RNAs or expression of dominant-negative TCF suppressed Wnt signaling and neuroendocrine transdifferentiation. Yang et al. (2005) concluded that increased PCDHY expression drives neuroendocrine transdifferentiation by activating Wnt signaling.
By genomic sequence analysis, Blanco et al. (2000) determined that the PCDHY gene, like PCDHX, contains 6 exons and spans approximately 100 kb.
Both the short and long arms of the X and Y chromosomes contain telomeric pseudoautosomal regions (PAR) that recombine in males during meiosis. The PAR at the short arm recombines at least once during each meiosis, whereas the PAR on the long arm has a recombination frequency of 2%, 6 times greater than the average for X-specific DNA (Ciccodicola et al., 2000). In contrast, homology regions on the sex chromosomes do not recombine during male meiosis. Mumm et al. (1997) identified homology regions at Xq21.3 and Yp11.1. Tilford et al. (2001) identified 2 homology regions on Yp and 4 homology regions on Yq. Schwartz et al. (1998) determined that the homology region on Yp consists of a 4-Mb span that is 99% identical to the region on Xq21. This X-Y homology region resulted from a LINE-mediated inversion and a single transposition event from Xq21 3 to 4 million years ago, after the divergence of hominid and chimpanzee lineages and near the emergence of Homo, but before the radiation of human populations.
Blanco et al. (2000) mapped the PCDH11Y gene to Yp11.2, within the X-Y homologous region, using detailed YAC and PAC contigs and fine STS marker order.
Using a combination of STS deletion mapping, binary marker and Y-short tandem repeat haplotyping, and TSPY (480100) copy number estimation, Jobling et al. (2007) identified 4 distinct classes of deletions affecting chromosome Yp in 45 males from 12 different populations. The most common deletion class was found in 41 Y chromosomes (91%) and appeared to be caused by nonallelic homologous recombination between the major TSPY repeat array and a single telomeric copy of the TSPY gene located over 3 Mb from the array. This deletion resulted in loss of the AMELY (410000), TBL1Y (400033), and PRKY (400008) genes, which lie in the region separating the single TSPY gene and the TSPY repeat array, as well as reduced TSPY copy number. The rarer deletion classes did not involve the major TSPY repeat array, but resulted in loss of the more telomeric PCDH11Y gene in addition to AMELY, TBL1Y, PRKY, and the single telomeric TSPY copy. The persistence and expansion of deletion lineages, together with phenotypic evidence, suggested that absence of these genes has no major deleterious effects.
By zoo blot analysis, Blanco et al. (2000) showed that the PCDHX/PCDHY gene is restricted to the X chromosome in marsupials, rodents, and New and Old World monkeys, but is X-Y homologous in higher primates such as orangutan, gorilla, and human. Blanco et al. (2000) proposed that a deletion event might account for the absence of PCDHY on the chimpanzee Y chromosome. They suggested that PCDHX/PCDHY may provide the basis for a dimorphic trait influencing brain phenotype.
Mendez et al. (2016) compared approximately 120 kb of exome-captured Y-chromosome DNA from a Neandertal male from Spain with orthologous chimpanzee and modern human sequences. They found support for a model that placed the Neandertal lineage as an outgroup to modern human Y chromosomes, including A00, the highly divergent basal haplogroup. The authors estimated that the time to the most recent common ancestor (TMRCA) of Neandertal and modern human Y chromosomes was approximately 588,000 years ago, approximately 2 times longer than the TMRCA of A00 and other extant modern human Y-chromosome lineages. The estimate suggested that the Y-chromosome divergence mirrored the population divergence of Neandertals, whose Y sequence is not found in modern humans, and modern human ancestors. Notable coding differences between Neandertal and modern human Y chromosomes included potentially damaging changes to PCDH11Y, TMSB4Y (400017), USP9Y (400005), and KDM5D (426000). Three of these changes occurred in genes that produce male-specific minor histocompatibility (H-Y) antigens that may elicit a maternal immune response during gestation. The authors hypothesized that the incompatibilities at 1 or more of these genes may have played a role in the reproductive isolation of the 2 groups.
Blanco, P., Sargent, C. A., Boucher, C. A., Mitchell, M., Affara, N. A. Conservation of PCDHX in mammals; expression of X/Y genes predominantly in brain. Mammalian Genome 11: 906-914, 2000. [PubMed: 11003707] [Full Text: https://doi.org/10.1007/s003350010177]
Chen, M.-W., Vacherot, F., de la Taille, A., Gil-Diez-de-Medina, S., Shen, R., Friedman, R. A., Burchardt, M., Chopin, D. K., Buttyan, R. The emergence of protocadherin-PC expression during the acquisition of apoptosis-resistance by prostate cancer cells. Oncogene 21: 7861-7871, 2002. [PubMed: 12420223] [Full Text: https://doi.org/10.1038/sj.onc.1205991]
Ciccodicola, A., D'Esposito, M., Esposito, T., Gianfrancesco, F., Migliaccio, C., Miano, M. G., Matarazzo, M. R., Vacca, M., Franze, A., Cuccurese, M., Cocchia, M., Curci, A., and 9 others. Differentially regulated and evolved genes in the fully sequenced Xq/Yq pseudoautosomal region. Hum. Molec. Genet. 9: 395-401, 2000. [PubMed: 10655549] [Full Text: https://doi.org/10.1093/hmg/9.3.395]
Jobling, M. A., Lo, I. C. C., Turner, D. J., Bowden, G. R., Lee, A. C., Xue, Y., Carvalho-Silva, D., Hurles, M. E., Adams, S. M., Chang, Y. M., Kraaijenbrink, T., Henke, J., Guanti, G., McKeown, B., van Oorschot, R. A. H., Mitchell, R. J., de Knijff, P., Tyler-Smith, C., Parkin, E. J. Structural variation on the short arm of the human Y chromosome: recurrent multigene deletions encompassing Amelogenin Y. Hum. Molec. Genet. 16: 307-316, 2007. [PubMed: 17189292] [Full Text: https://doi.org/10.1093/hmg/ddl465]
Mendez, F. L., Poznik, G. D., Castellano, S., Bustamante, C. D. The divergence of Neandertal and modern human Y chromosomes. Am. J. Hum. Genet. 98: 728-734, 2016. [PubMed: 27058445] [Full Text: https://doi.org/10.1016/j.ajhg.2016.02.023]
Mumm, S., Molini, B., Terrell, J., Srivastava, A., Schlessinger, D. Evolutionary features of the 4-Mb Xq21.3 XY homology region revealed by a map at 60-kb resolution. Genome Res. 7: 307-314, 1997. [PubMed: 9110170] [Full Text: https://doi.org/10.1101/gr.7.4.307]
Schwartz, A., Chan, D. C., Brown, L. G., Alagappan, R., Pettay, D., Disteche, C., McGillivray, B., de la Chapelle, A., Page, D. C. Reconstructing hominid Y evolution: X-homologous block, created by X-Y transposition, was disrupted by Yp inversion through LINE-LINE recombination. Hum. Molec. Genet. 7: 1-11, 1998. [PubMed: 9384598] [Full Text: https://doi.org/10.1093/hmg/7.1.1]
Tilford, C. A., Kuroda-Kawaguchi, T., Skaletsky, H., Rozen, S., Brown, L. G., Rosenberg, M., McPherson, J. D., Wylie, K., Sekhon, M., Kucaba, T. A., Waterston, R. H., Page, D. C. A physical map of the human Y chromosome. Nature 409: 943-945, 2001. [PubMed: 11237016] [Full Text: https://doi.org/10.1038/35057170]
Yang, X., Chen, M.-W., Terry, S., Vacherot, F., Chopin, D. K., Bemis, D. L., Kitajewski, J., Benson, M. C., Guo, Y., Buttyan, R. A human- and male-specific protocadherin that acts through the Wnt signaling pathway to induce neuroendocrine transdifferentiation of prostate cancer cells. Cancer Res. 65: 5263-5271, 2005. [PubMed: 15958572] [Full Text: https://doi.org/10.1158/0008-5472.CAN-05-0162]