Dell Pediatric Research Institute, Department of Nutritional Sciences, the University of Texas at Austin, Austin, Texas, United States of America.
PLoS One. 2013 Jul 26;8(7):e69262. doi: 10.1371/journal.pone.0069262. Print 2013.
Neural tube defects (NTDs) (OMIM #182940) including anencephaly, spina bifida and craniorachischisis, are severe congenital malformations that affect 0.5-1 in 1,000 live births in the United States, with varying prevalence around the world. Mutations in planar cell polarity (PCP) genes are believed to cause a variety of NTDs in both mice and humans. SCRIB is a PCP-associated gene. Mice that are homozygous for the Scrib p.I285K and circletail (Crc) mutations, present with the most severe form of NTDs, namely craniorachischisis. A recent study reported that mutations in SCRIB were associated with craniorachischisis in humans, but whether SCRIB mutations contribute to increased spina bifida risk is still unknown. We sequenced the SCRIB gene in 192 infants with spina bifida and 190 healthy controls. Among the spina bifida patients, we identified five novel missense mutations that were predicted-to-be-deleterious by the PolyPhen software. Of these five mutations, three of them (p.P1043L, p.P1332L, p.L1520R) significantly affected the subcellular localization of SCRIB. In addition, we demonstrated that the craniorachischisis mouse line-90 mutation I285K, also affected SCRIB subcellular localization. In contrast, only one novel missense mutation (p.A1257T) was detected in control samples, and it was predicted to be benign. This study demonstrated that rare deleterious mutations of SCRIB may contribute to the multifactorial risk for human spina bifida.
神经管缺陷（NTDs）（OMIM#182940）包括无脑畸形、脊柱裂和颅脊柱裂，是严重的先天性畸形，在美国每 1000 例活产中就有 0.5-1 例，世界各地的患病率也各不相同。平面细胞极性（PCP）基因突变被认为是导致小鼠和人类多种 NTD 的原因。SCRIB 是 PCP 相关基因。Scrib p.I285K 和 circletail（Crc）突变纯合的小鼠表现出最严重的 NTD 形式，即颅脊柱裂。最近的一项研究报告称，SCRIB 突变与人类颅脊柱裂有关，但 SCRIB 突变是否会增加脊柱裂的风险仍不清楚。我们对 192 例脊柱裂婴儿和 190 例健康对照者的 SCRIB 基因进行了测序。在脊柱裂患者中，我们鉴定了五个新的错义突变，这些突变被 PolyPhen 软件预测为有害突变。在这五个突变中，有三个（p.P1043L、p.P1332L、p.L1520R）显著影响了 SCRIB 的亚细胞定位。此外，我们证明了颅脊柱裂小鼠系 90 号突变 I285K 也影响了 SCRIB 的亚细胞定位。相比之下，在对照样本中仅检测到一个新的错义突变（p.A1257T），预测为良性。本研究表明，SCRIB 的罕见有害突变可能导致人类脊柱裂的多因素风险。
