期刊
HUMAN MUTATION
卷 33, 期 2, 页码 440-447出版社
WILEY-BLACKWELL
DOI: 10.1002/humu.21662
关键词
neural tube defects; craniorachischisis; planar cell polarity; CELSR1; SCRIB
资金
- SPARKS [06ICH06]
- Wellcome Trust [087525]
- Medical Research Council [G0801124]
- Great Ormond Street Hospital Children's Charity
- Great Ormond Street Hospital Childrens Charity [V1241] Funding Source: researchfish
- Medical Research Council [G0801124] Funding Source: researchfish
- MRC [G0801124] Funding Source: UKRI
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. Hum Mutat 33:440-447, 2012. (C) 2011 Wiley Periodicals, Inc.
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