PVRL1encode Nectin-1, 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-1 also functions as alpha herpes virus epithelial receptor.
Pathophysiologic mechanism
Biallelic loss-of-function variants in PVRL1reduce or abolish nectin-1 at adherens junctions (AJs), disrupting cis/trans nectin interactions and the nectin–afadin–F-actin scaffold. This weakens cooperation with cadherins, perturbs Rac1/Cdc42 signaling, and delays AJ assembly/remodeling during craniofacial, limb, and ectodermal development, mechanistically accounting for cleft lip/palate, partial cutaneous syndactyly, and hair/dental anomalies. Many pathogenic alleles are truncating and remove the transmembrane/cytoplasmic domains required for junctional anchoring and afadin binding.
In addition, nectin-1 is a principal HSV-1/HSV-2 entry receptor; the high carrier rate of the p.W185X founder allele on Margarita Island is consistent with selection favoring heterozygotes, potentially owing to reduced alpha-herpesvirus infectivity.
Diagnostic testing
Mutations in PVRL1can be identified using molecular genetic testing, either directly by sanger sequencing or by exome/genome sequencing.
PVRL1