title: Mutations in the planar cell polarity genes CELSR1 and SCRIB are associated with the severe neural tube defect craniorachischisis.
abstract: 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.
authors.affiliation: UCL Institute of Child Health, London WC1N 1EH, United Kingdom.
authors.forename: Alexis
authors.initials: A
authors.lastname: Robinson
authors.forename: Sarah
authors.initials: S
authors.lastname: Escuin
authors.forename: Kit
authors.initials: K
authors.lastname: Doudney
authors.forename: Michel
authors.initials: M
authors.lastname: Vekemans
authors.forename: Roger E
authors.initials: RE
authors.lastname: Stevenson
authors.forename: Nicholas D E
authors.initials: ND
authors.lastname: Greene
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Copp
authors.forename: Philip
authors.initials: P
authors.lastname: Stanier
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004285:Dogs; D005333:Fetus; D023061:Gene Order; D020022:Genetic Predisposition to Disease; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D020125:Mutation, Missense; D009436:Neural Tube Defects / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C454220:CELSR1 cadherin, human; D015820:Cadherins; D008565:Membrane Proteins; C480591:SCRIB protein, human; D025521:Tumor Suppressor Proteins
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