Mutations in planar cell polarity gene SCRIB are associated with spina bifida.
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.
Dell Pediatric Research Institute, Department of Nutritional Sciences, the University of Texas at Austin, Austin, Texas, United States of America.
Yunping
Y
Lei
Huiping
H
Zhu
Cody
C
Duhon
Wei
W
Yang
M Elizabeth
ME
Ross
Gary M
GM
Shaw
Richard H
RH
Finnell
D000595:Amino Acid Sequence; D000818:Animals; D016764:Cell Polarity / Q000235:genetics*; D017124:Conserved Sequence / Q000235:genetics; D004285:Dogs; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense; D016366:Open Reading Frames / Q000235:genetics; D011485:Protein Binding; D021381:Protein Transport; D016135:Spinal Dysraphism / Q000235:genetics* / Q000473:pathology*; D013347:Subcellular Fractions / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C480591:SCRIB protein, human; D025521:Tumor Suppressor Proteins; C468513:VANGL2 protein, human