PVRL1 variants contribute to non‐syndromic cleft lip and palate in multiple populations

Abstract

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 nonsense 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.

Cooperation between the transcription factors p63 and IRF6 is essential to prevent cleft palate in mice

“…Moreover, variation within IRF6, TBX22, PVRL1, and MSX1 is a contributing factor to nonsyndromic forms of cleft lip and cleft palate (41)(42)(43)(44)(45)(46). Despite these successes, the molecular pathways in which the proteins encoded by these genes function during development of the lip and palate remain poorly characterized, as such studies are not feasible in human embryos.…”

Mutation analysis of PVRL1 in patients with non-syndromic cleft of the lip and/or palate in Guangdong

“…Scapoli et al (2004Scapoli et al ( , 2006 did not find the W185X mutation in the populations studied, but instead found R199Q, R210H, and R212H mutations, affecting conserved amino acids (Avila et al, 2006). In Norway, the Philippines, and South America, 23 people carrying NSCLP-related mutations were identified; these mutations included 11 in the coding region, 7 in introns, and another 7 in the CpG islands.…”

Mutation Analysis of thePVRL1Gene in Caucasians with Nonsyndromic Cleft Lip/Palate

“…Several subsequent studies have supported (Turhani et al, 2005;Avila et al, 2006;Neiswanger et al, 2006;Scapoli et al, 2006) or not supported (Scapoli et al, 2004;Ichikawa et al, 2006;Tseng et al, 2006) a role for PVRL1 in risk of nsCL=P. Two other genes of the nectin family, PVR and PVRL2, have also been considered as possible candidate genes for nsCL=P (Neiswanger et al, 2006;Warrington et al, 2006;Pezzetti et al, 2007), due to their paralogy with PVRL1 and their location in chromosome segment 19q13.2, which corresponds to a linkage region for nsCL=P, OFC3 (MIM 600757; Stein et al, 1995).…”