Poliovirus Receptor Like-1 (
PVRL1) is a member of the
immunoglobulin super family that acts in the initiation and maintenance of epithelial adherens junctions and is mutated in the
cleft lip and palate/
ectodermal dysplasia 1 syndrome (
CLPED1, OMIM #225000). In addition, a common non-sense mutation in
PVRL1 was discovered more often among non-syndromic sporadic clefting cases in Northern Venezuela in a previous case-control study. The present work sought to ascertain the role of
PVRL1 in the sporadic forms of orofacial clefting in multiple populations. Multiple rare and common variants from all three splice
isoforms were initially ascertained by sequencing 92 Iowan and 86 Filipino cases and CEPH controls. Using a family-based analysis to examine these variants, the common
glycine allele of the G361V coding variant was significantly overtransmitted among all orofacial clefting phenotypes (P = 0.005). This represented G361V genotyping from over 800 Iowan, Danish, and Filipino families. Among four rare
amino acid changes found within the V1 and C1 domains, S112T and T131A were found adjacent to critical
amino acid positions within the V1 variable domain, regions previously shown to mediate cell-to-cell and cell-to-virus adhesion. The T131A variant was not found in over 1,300 non-affected control samples although the
alanine is found in other species. The
serine of the S112T variant position is conserved across all known
PVRL1 sequences. Together these data suggest that both rare and common mutations within
PVRL1 make a minor contribution to disrupting the initiation and regulation of cell-to-cell adhesion and downstream morphogenesis of the embryonic face.