PVRL4encode Nectin-4, a calcium-independent, Ig-like cell-adhesion molecule of the nectin family localized at adherens junctions (AJ). It mediates cell–cell adhesion via homo- and heterophilic cis/trans interactions through its extracellular Ig domains. It links to the actin cytoskeleton via afadin, influencing epithelial polarity, migration, and differentiation.
Nectin-4 also functions as a measles virus epithelial receptor (facilitating viral spread across airway epithelium).
In cancer, it is frequently overexpressed and can be released as a soluble ectodomain through ADAM17-mediated shedding.
Pathophysiologic mechanism
Biallelic loss-of-function variants in PVRL4lead to reduced, absent, or dysfunctional nectin-4 at adherens junctions (AJs). This disrupts cis/trans nectin interactions and the nectin–afadin–F-actin scaffold, weakening cadherin cooperation, altering Rac1 signaling, and delaying AJ assembly; this results in AJ dysfunction, impairs epidermal/periderm adhesion dynamics, epithelial remodelling, and placode morphogenesis, leading to persistent epithelial bridges and failure of normal interdigital separation (partial cutaneous syndactyly), and to hair and dental anomalies.
Diagnostic testing
Mutations in PVRL4can be identified using molecular genetic testing, either directly by Sanger sequencing or by exome/genome sequencing.
PVRL4