Somatic mutations in planar cell polarity genes in neural tissue from human fetuses with neural tube defects
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ORIGINAL INVESTIGATION
Somatic mutations in planar cell polarity genes in neural tissue from human fetuses with neural tube defects Tian Tian1,2 · Yunping Lei3 · Yongyan Chen1,2 · Menuka Karki3 · Lei Jin1,2 · Richard H. Finnell3,4 · Linlin Wang1,2 · Aiguo Ren1,2 Received: 30 January 2020 / Accepted: 25 April 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Extensive studies that have sought causative mutation(s) for neural tube defects (NTDs) have yielded limited positive findings to date. One possible reason for this is that many studies have been confined to analyses of germline mutations and so may have missed other, non-germline mutations in NTD cases. We hypothesize that somatic mutations of planar polarity pathway (PCP) genes may play a role in the development of NTDs. Torrent™ Personal Genome Machine™ (PGM) sequencing was designed for selected PCP genes in paired DNA samples extracted from the tissues of lesion sites and umbilical cord from 48 cases. Sanger sequencing was used to validate the detected mutations. The source and distribution of the validated mutations in tissues from different germ layers were investigated. Subcellular location, western blotting, and luciferase assays were performed to better understand the effects of the mutations on protein localization, protein level, and pathway signaling. ix somatic mutations were identified and validated, which showed diverse distributions in different tissues. Three somatic mutations were novel/rare: CELSR1 p.Gln2125His, FZD6 p.Gln88Glu, and VANGL1 p.Arg374His. FZD6 p.Gln88Glu caused mislocalization of its protein from the cytoplasm to the nucleus, and disrupted the colocalization of CELSR1 and FZD6. This mutation affected non-canonical WNT signaling in luciferase assays. VANGL1 p.Arg374His impaired the co-localization of CELSR1 and VANGL1, increased the protein levels of VANGL1, and influenced cell migration. In all, 7/48 (14.5%) of the studied NTD cases contained somatic PCP mutations. Somatic mutations in PCP genes (e.g., FZD6 and VANGL1) are associated with human NTDs, and they may occur in different stages and regions during embryonic development, resulting in a varied distribution in fetal tissues/organs. Tian Tian and Yunping Lei contributed equally to the manuscript.
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00439-020-02172-0) contains supplementary material, which is available to authorized users.
Neural tube defects (NTDs) are congenital malformations of the central nervous system that result from a failure of the neural tube to close during the third and fourth weeks post-fertilization (Wallingford et al. 2013). This term encompasses a number of distinct clinical entities, including anencephaly, spina bifida, craniorachischisis, encephalocele, iniencephaly, and others. Although NTDs are considered a multifactorial disorder, arising from complex interactions of genetic and environmental factors, the genetic components are the dominant factor
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