PLCB4 gene

The PLCB4 gene (PLCB4 stands for: Phospholipase C Beta 4) is a protein coding gene located on chromosome 20p12.3-p12.2. An important paralog of this gene is PLCB1.

The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transmission of many extracellular signals in the retina. Several transcript variants encoding different isoforms have been found for this gene. Phospholipases are a group of enzymes that hydrolyze phospholipids into fatty acids and other lipophilic molecules. There are four main classes: phospholipase A, phospholipase B, phosphoinositide-specific phospholipase C and phospholipase D.

Diseases associated with PLCB4 include auriculocondylar syndrome. Auriculocondylar syndrome is a rare genetic dysostosis that affects craniofacial development. It is characterized by bilateral malformations of the outer ears, hypoplasia of the mandibular condyles, microstomia, micrognathia, microglossia and facial asymmetry. Other manifestations include hypotonia, ptosis, cleft palate, full cheeks, developmental delay, hearing impairment and respiratory distress. The condition includes malformed outer ears, including a pronounced question mark shape, cupped ears, narrow ear canals and rotated ears. Abnormalities of the lower jaw are common, with features such as micrognathia and dysfunction of the temporomandibular joint. Other features may include protruding cheeks, microstomia, facial asymmetry and cleft palate. Phenotypic variation can be considerable within and between families.

Blue nevus: GNAQ and GNA11 mutations are frequently found in blue nevi and choroidal melanomas. Recurrent CYSLTR2 and PLCB4 mutations have been found in uveal melanomas that do not have GNAQ or GNA11 mutations. All four genes (GNAQ, GNA11, CYSLTR2 and PLCB4) encode proteins that are involved in the same signaling pathway, which is activated by (activating) mutations in these genes (Möller I et al.2017).

Activated phosphatidylinositol-specific phospholipase C enzymes catalyze the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), which are involved in G protein-coupled receptor signaling pathways. PLCB4 is a direct effector of the endothelin receptor signaling pathway, which plays an essential role in the development of mandibular and middle ear structures (Kanai SM et al. 2022).

1. de la Fouchardiere A (2023). Blue naevi and the blue tumor spectrum. Pathology 55:187-195.
2. Kanai SM et al. (2022) Auriculocondylar syndrome 2 results from the dominant-negative action of PLCB4 variants. Dis Model Mech 15:dmm049320.
3. Möller I et al.(2017) Activating cysteinyl leukotriene receptor 2 (CYSLTR2) mutations in blue nevi. Mod Pathol 30: 350-356