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Mutations in the planar cell polarity genes CELSR1 and SCRIB are associated with the severe neural tube defect craniorachischisis
Open accessAbstract
Craniorachischisis (CRN) is a severe neural tube defect (NTD) resulting from failure to initiate closure, leaving the hindbrain and spinal neural tube entirely open. Clues to the genetic basis of this condition come from several mouse models, which harbor mutations in core members of the planar cell polarity (PCP) signaling pathway. Previous studies of humans with CRN failed to identify mutations in the core PCP genes, VANGL1 and VANGL2. Here, we analyzed other key PCP genes: CELSR1, PRICKLE1, PTK7, and SCRIB, with the finding of eight potentially causative mutations in both CELSR1 and SCRIB. Functional effects of these unique or rare human variants were evaluated using known protein-protein interactions as well as subcellular protein localization. While protein interactions were not affected, variants from five of the 36 patients exhibited a profound alteration in subcellular protein localization, with diminution or abolition of trafficking to the plasma membrane. Comparable effects were seen in the crash and spin cycle mouse Celsr1 mutants, and the line-90 mouse Scrib mutant. We conclude that missense variants in CELSR1 and SCRIB may represent a cause of CRN in humans, as in mice, with defective PCP protein trafficking to the plasma membrane a likely pathogenic mechanism.
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Human SCRIBBLE mutations are found in some patients with neural tube defects.
“The role of Scribble in neural tube closure is clinically relevant, as human SCRIBBLE mutations are found in some patients with neural tube defects (Robinson et al., 2012; Kharfallah et al., 2017).”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Robinson et al., 2012
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Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation
Bonello, T. T., & Peifer, M. (2019) · Journal of Cell Biology · doi:10.1083/jcb.201810103 · Cited by 127
“The role of Scribble in neural tube closure is clinically relevant, as human SCR IBB LE mutations are found in some patients with neural tube defects (Robinson et al., 2012; Kharfallah et al., 2017).”
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Localization, Not Important in All Tumor-Suppressing Properties: A Lesson Learnt from Scribble
Elsum, I. A., & Humbert, P. O. (2013) · Cells Tissues Organs · doi:10.1159/000348423 · Cited by 27
Metadata
- Authors
- Robinson, A., Escuin, S., Doudney, K., Vekemans, M., Stevenson, R. E., Greene, N. D. E., Copp, A. J., & Stanier, P.
- Affiliations
- University College London (GB)
- Hôpital Necker-Enfants Malades (FR)
- Greenwood Genetic Center (US)
- Corresponding author
- Stanier, Philip
- ORCID
- Venue
- Human Mutation
- Publisher
- Hindawi Limited
- Published
- 2011-12-20
- Volume
- 33
- Issue
- 2
- Pages
- 440-447
- ISSN
- 1059-7794 (ISSN-L)
- PMC
- PMC4772123
- OpenAlex
- W1981393886
- Cited by
- 189
- References
- 39
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 10 · 2023: 10 · 2022: 15 · 2021: 14 · 2020: 16 · 2019: 12 · 2018: 8 · 2017: 16 · 2016: 16 · 2015: 7 · 2014: 16 · 2013: 18 · 2012: 14
- FWCI
- 15.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Human Mutation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- SPARKS (06ICH06)
- Wellcome Trust (087525)
- Medical Research Council (G0801124)
- Great Ormond Street Hospital Children's Charity (to P.S.)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Spinal Dysraphism and Malformations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Keywords
- craniorachischisis, neural tube defects, planar cell polarity, CELSR1, SCRIB, missense mutations, protein localization, plasma membrane trafficking, mouse model
- MeSH terms
- Animals, Cell Line, Dogs, Fetus, Humans, Membrane Proteins, Mutation, Neural Tube Defects, Cadherins, Genetic Predisposition to Disease, Mutation, Missense, Protein Transport, Gene Order, Tumor Suppressor Proteins, Immunoprecipitation
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