Alternative titles; symbols
HGNC Approved Gene Symbol: PLP2
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38): X:49,171,898-49,175,235 (from NCBI)
Oliva et al. (1993) cloned a cDNA encoding the A4 differentiation-dependent protein from a human colon cell line.
Fisher et al. (1997) determined that the product of the A4 gene is an integral membrane protein, containing 4 putative transmembrane domains. The protein may play a role in cell differentiation in the intestinal epithelium.
In a study of the gene-rich region Xp11.23-p11.22, Fisher et al. (1997) identified the promoter and complete coding sequence of the A4 gene, which has 5 exons spanning approximately 3.5 kb of DNA.
Fisher et al. (1997) identified the A4 gene on chromosome Xp11.23-p11.22.
Using an X-chromosome cDNA microarray (XCA) to survey the expression profile of X-linked genes in lymphoblasts of males with X-linked mental retardation (XLMR), Zhang et al. (2007) identified 2 unrelated patients with approximately 4-fold decreased expression of the PLP2 gene. Sequencing analysis in both patients revealed a promoter variant, -113C-A, that altered the core-binding site of the transcription factor ELK1 (311040). Using a luciferase reporter system, Zhang et al. (2007) showed that the variant was sufficient to cause reduced expression. The variant was found to be enriched in a cohort of males with probable XLMR (14 of 239, 5.85%) as compared to normal males (9 of 577, 1.56%) (chi square = 11.07, p less than 0.001). The authors noted that additional studies were required to understand the role of PLP2 in the development of human cognitive function.
Zhang et al. (2015) found that cultured human fibroblasts harboring the PLP2 -113C-A promoter variant showed increased basal endoplasmic reticulum (ER) stress, exaggerated response to ER stressors, and defective ER trafficking, similar to findings in mouse Plp2-null fibroblasts and neurons (see ANIMAL MODEL). Overexpression of PLP2 protected HEK293 cells from ER stress-induced apoptosis. Zhang et al. (2015) concluded that PLP2 promotes resistance to ER stress. They hypothesized that reduced PLP2 expression in conjunction with perinatal ER stress may increase neuronal cell death and contribute to risk of intellectual disability in humans.
Zhang et al. (2015) found that Plp2-null mice were obtained at the expected mendelian ratio and had normal growth, appearance, ambulatory activity, and mating behavior. Fibroblasts from male Plp2-null embryos showed defective ER trafficking, increased basal ER stress, and exaggerated susceptibility to inducers of ER stress. Cortical neurons from Plp2-null embryos showed increased sensitivity and death in response to ischemic conditions. Hypoxic-ischemic injury to common carotid artery of Plp2-null neonatal pups significantly reduced hippocampal volume compared with wildtype.
Fisher, S. E., Ciccodicola, A., Tanaka, K., Curci, A., Desicato, S., D'Urso, M., Craig, I. W. Sequence-based exon prediction around the synaptophysin locus reveals a gene-rich area containing novel genes in human proximal Xp. Genomics 45: 340-347, 1997. [PubMed: 9344658] [Full Text: https://doi.org/10.1006/geno.1997.4941]
Oliva, M. M., Wu, T. C., Yang, V. W. Isolation and characterization of a differentiation-dependent gene in the human colonic cell line HT29-18. Arch. Biochem. Biophys. 302: 183-192, 1993. [PubMed: 8470895] [Full Text: https://doi.org/10.1006/abbi.1993.1197]
Zhang, L., Jie, C., Obie, C., Abidi, F., Schwartz, C. E., Stevenson, R. E., Valle, D., Wang, T. X chromosome cDNA microarray screening identifies a functional PLP2 promoter polymorphism enriched in patients with X-linked mental retardation. Genome Res. 17: 641-648, 2007. [PubMed: 17416750] [Full Text: https://doi.org/10.1101/gr.5336307]
Zhang, L., Wang, T., Valle, D. Reduced PLP2 expression increases ER-stress-induced neuronal apoptosis and risk for adverse neurological outcomes after hypoxia ischemia injury. Hum. Molec. Genet. 24: 7221-7226, 2015. [PubMed: 26512060] [Full Text: https://doi.org/10.1093/hmg/ddv422]