PVRL1 variants contribute to non-syndromic cleft lip and palate in multiple populations
PVRL1 variants contribute to non-syndromic cleft lip and palate in multiple populations
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DOI：
10.1002/ajmg.a.31367
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发表时间：
2006-12-01
影响因子：
2
通讯作者：
Murray, Jeffrey C.
中科院分区：
文献类型：
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作者：
Avila, Joseph R.;Jezewski, Peter A.;Murray, Jeffrey C.
脊髓灰质炎病毒受体样蛋白-1（PVRL 1）是免疫球蛋白超家族的一个成员，在上皮粘附连接的启动和维持中起作用，并在唇腭裂/外胚层发育不良1型综合征（CLPED 1，OMIM #225000）中发生突变。此外，在先前的病例对照研究中，在委内瑞拉北方的非综合征性散发性唇腭裂病例中更常发现PVRL 1的一种常见无义突变。本研究试图确定PVRL 1在多个人群中零星形式的口面裂中的作用。来自所有三种剪接异构体的多种罕见和常见变体最初通过对92个爱荷华州病例和86个菲律宾病例以及CEPH对照进行测序来确定。使用基于家族的分析来检查这些变体，G361 V编码变体的常见甘氨酸等位基因在所有口面裂表型中显著过度传递（P=0.005）。这代表了来自800多个爱荷华州、丹麦和菲律宾家庭的G361 V基因分型。在V1和C1结构域中发现的四种罕见氨基酸变化中，发现S112 T和T131 A邻近VI可变结构域中的关键氨基酸位置，这些区域先前显示介导细胞与细胞和细胞与病毒的粘附。在1,300多个未受影响的对照样品中没有发现T131 A变体，尽管在其他物种中发现了丙氨酸。S112 T变体位置的丝氨酸在所有已知的PVRL 1序列中是保守的。总之，这些数据表明，PVRL 1内的罕见和常见突变对破坏细胞间粘附的启动和调节以及胚胎面部的下游形态发生都有微小的贡献。(c)2006威利-利斯公司
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 VI 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. (c) 2006 Wiley-Liss, Inc.