HGNC Approved Gene Symbol: PLCD1
Cytogenetic location: 3p22.2 Genomic coordinates (GRCh38): 3:38,007,496-38,029,642 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p22.2 | Nail disorder, nonsyndromic congenital, 3, (leukonychia) | 151600 | Autosomal dominant; Autosomal recessive | 3 |
Phosphoinositide-specific phospholipase C (PLC) acts as a signal transducer that generates 2 second messengers, diacylglycerol and inositol 1,4,5-trisphosphate, by hydrolyzing inositol phospholipids. PLC comprises a diverse family of enzymes that differ in structure and tissue distribution (Berridge, 1993).
By screening a human aortic smooth muscle cDNA library with a probe derived from a rat C6 glioma cell PLC-delta-1 cDNA, Cheng et al. (1995) cloned a PLCD1 cDNA. The deduced 756-amino acid protein shares 95% sequence homology with the rat protein. It contains a pleckstrin homology (PH) domain and the conserved X and Y domains of PLC proteins. It is distinguished from PLC-gamma (see 172420) by lack of the SH2 and SH3 domains that are essential for activation of PLC-gamma by tyrosine protein kinases, and from PLC-beta (see 600810) by lack of the C-terminal region of PLC-beta that is responsible for binding and activation by G proteins. Northern blot analysis detected ubiquitous expression of a 3.8-kb transcript, with highest expression in lung, heart, pancreas, skeletal muscle, and kidney. An additional 7.5-kb transcript was detected in skeletal muscle.
Kiuru et al. (2011) performed immunohistochemical analysis of human fetal nail sections and detected prominent localization of PLCD1 in the nail matrix and nail bed. In addition, real-time quantitative PCR analysis demonstrated expression of PLCD1 mRNA in human skin and hair follicles.
Lyu et al. (1996) mapped the PLCD1 gene to chromosome 3 by means of a human/rodent somatic cell panel.
In the course of a large-scale sequencing analysis of genomic DNA in the vicinity of a homozygous deletion on chromosome 3p found in a lung cancer cell line, Ishikawa et al. (1997) found that the PLCD1 was located just distal to the region removed by the deletion. By fluorescence in situ hybridization, they localized the PLCD1 gene to 3p22-p21.3.
Ishikawa et al. (1997) determined that the PLCD1 gene contains 15 exons and spans about 22 kb.
When human PLCD1 was expressed in E. coli, the recombinant enzyme displayed high phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolyzing activity in a Ca(2+)-dependent manner (Cheng et al., 1995).
Using semiquantitative RT-PCR, Hu et al. (2009) found that expression of PLCD1 was silenced or reduced in a significant number of gastric cancer cell lines compared with normal gastric tissues. Methylation-specific PCR showed that silenced or reduced PLCD1 expression was associated with methylation of the PLCD1 CpG island. In 98 primary gastric cancers, PLCD1 methylation significantly correlated with high-stage tumors. Immunohistochemical analysis confirmed reduced PLCD1 protein levels in primary gastric carcinomas compared with normal gastric mucosa. Transfection of PLCD1 into gastric tumor cell lines had no effect on cell proliferation or cell cycle arrest, but it suppressed colony formation and cell migration and reduced cytoskeletal changes associated with cell migration. Expression of PLCD1 also reduced the metastatic potential of a gastric cancer cell line following injection into nude mice. Hu et al. (2009) concluded that PLCD1 functions as a tumor suppressor involved in gastric cancers.
Shimohama et al. (1998) examined the entire sequences corresponding to protein-coding exons 2-15 of the hamster PLC-delta-1 gene in genomic DNA derived from the leukocytes of 13 unrelated patients with early-onset sporadic Alzheimer disease (104300). In 1 of these patients whose clinical features and course did not differ from those of the other 12 cases, they found a change of codon CGC (arg) to CAC (his), located in the pleckstrin homology domain of the PLCD1 gene. They stated that this was the first mutation found in the human PLC genes. Site-directed mutagenesis of the glutathione-S-transferase (GST/PLCD1) fusion protein changing arg105 to his resulted in a 4-fold decrease in the affinity of specific binding and a reduction in hydrolyzing activity to about 40% of that of the wildtype enzyme. This remarkable loss of function could be interpreted in terms of a conformational change in the pleckstrin homology domain. Shimohama et al. (1998) found that the arg105-to-his mutation was present in heterozygous state in the patient with AD. The mutation was not found in DNA extracted from leukocytes of 23 unrelated patients with familial AD, 23 unrelated patients with early-onset sporadic AD, 46 unrelated patients with late-onset sporadic AD, and 456 nondemented control subjects. Thus the change did not appear to be a common polymorphism. However, determination of the possible pathologic role required transgenic studies of the mutant gene to determine the role of the enzyme and the mutation and a search for other mutations in the pleckstrin homology domain of PLC genes in human subjects with genetic disorders. They pointed out that mutations in the pleckstrin homology domain of the BTK gene (300300) occur in patients with Bruton agammaglobulinemia (300755).
Nonsyndromic Congenital Nail Disorder 3
In 4 Pakistani families with leukonychia totalis, also referred to as nonsyndromic congenital nail disorder-3 (NDNC3; 151600), mapping to chromosome 3p22-p21.3, 2 of which demonstrated autosomal recessive inheritance and 2 of which were consistent with autosomal dominant inheritance, Kiuru et al. (2011) analyzed candidate genes and identified homozygosity or heterozygosity for nonsense, splice site, and missense mutations in the PLCD1 gene (602142.0001-602142.0004). Kiuru et al. (2011) noted that the phenomenon of recessive and dominant mutations in the same gene resulting in a similar phenotype is very rare.
In affected members of a consanguineous Pakistani family with leukonychia totalis (151600), Kiuru et al. (2011) identified homozygosity for a 1309C-T transition in the PLCD1 gene, resulting in an arg437-to-ter (R437X) substitution. The mutation was not found in 130 unrelated population-matched controls. In vitro functional analysis in HEK293 cells showed significant reduction of enzymatic activity with the R437X mutant protein compared to wildtype.
In affected members of a consanguineous Pakistani family with leukonychia totalis (151600), Kiuru et al. (2011) identified homozygosity for a 10-bp deletion spanning the splice junction of intron 11 and exon 12 (1792-10delTGTAGTGGCC) in the PLCD1 gene, predicted to result in a premature termination codon due to a frameshift or missplicing. The mutation was not found in 130 unrelated population-matched controls.
In affected members of a nonconsanguineous Pakistani family segregating leukonychia totalis (151600) in an autosomal dominant fashion, Kiuru et al. (2011) identified heterozygosity for a 1720C-T transition in the PLCD1 gene, resulting in an ala574-to-thr (A574T) substitution at a highly conserved residue. The mutation was not found in 130 unrelated population-matched controls.
In affected members of a nonconsanguineous Pakistani family segregating leukonychia totalis (151600) in an autosomal dominant fashion, Kiuru et al. (2011) identified heterozygosity for a 625T-C transition in the PLCD1 gene, resulting in a cys209-to-arg (C209R) substitution at a highly conserved residue. The mutation was not found in 130 unrelated population-matched controls.
Berridge, M. J. Inositol trisphosphate and calcium signalling. Nature 361: 315-325, 1993. [PubMed: 8381210] [Full Text: https://doi.org/10.1038/361315a0]
Cheng, H. F., Jiang, M. J., Chen, C. L., Liu, S. M., Wong, L. P., Lomasney, J. W., King, K. Cloning and identification of amino acid residues of human phospholipase C delta 1 essential for catalysis. J. Biol. Chem. 270: 5495-5505, 1995. [PubMed: 7890667] [Full Text: https://doi.org/10.1074/jbc.270.10.5495]
Hu, X.-T., Zhang, F.-B., Fan, Y.-C., Shu, X.-S., Wong, A. H. Y., Zhou, W., Shi, Q.-L., Tang, H.-M., Fu, L., Guan, X.-Y., Rha, S. Y., Tao, Q., He, C. Phospholipase C delta 1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer. Oncogene 28: 2466-2475, 2009. [PubMed: 19448674] [Full Text: https://doi.org/10.1038/onc.2009.92]
Ishikawa, S., Takahashi, T., Ogawa, M., Nakamura, Y. Genomic structure of the human PLCD1 (phospholipase C delta 1) locus on 3p22-p21.3. Cytogenet. Cell Genet. 78: 58-60, 1997. [PubMed: 9345909] [Full Text: https://doi.org/10.1159/000134629]
Kiuru, M., Kurban, M., Itoh, M., Petukhova, L., Shimomura, Y., Wajid, M., Christiano, A. M. Hereditary leukonychia, or porcelain nails, resulting from mutations in PLCD1. Am. J. Hum. Genet. 88: 839-844, 2011. [PubMed: 21665001] [Full Text: https://doi.org/10.1016/j.ajhg.2011.05.014]
Lyu, M. S., Park, D. J., Rhee, S. G., Kozak, C. A. Genetic mapping of the human and mouse phospholipase C genes. Mammalian Genome 7: 501-504, 1996. [PubMed: 8672127] [Full Text: https://doi.org/10.1007/s003359900151]
Shimohama, S., Kamiya, S., Fujii, M., Ogawa, T., Kanamori, M., Kawamata, J., Imura, T., Taniguchi, T., Yagisawa, H. Mutation in the pleckstrin homology domain of the human phospholipase C-delta-1 gene is associated with loss of function. Biochem. Biophys. Res. Commun. 245: 722-728, 1998. [PubMed: 9588182] [Full Text: https://doi.org/10.1006/bbrc.1998.8307]