Human Genetics

, Volume 137, Issue 3, pp 195–202 | Cite as

Genetic and functional analysis of SHROOM1-4 in a Chinese neural tube defect cohort

  • Zhongzhong Chen
  • Lele Kuang
  • Richard H. Finnell
  • Hongyan Wang
Original Investigation


Neural tube defects (NTDs), which include spina bifida and anencephaly, are the second most common form of human structural congenital malformations. While it is well established that SHROOM3 plays a pivotal role in the complex morphogenetic processes involved in neural tube closure (NTC), the underlying genetic contributions of SHROOM gene family members in the etiology of human NTDs remain poorly understood. Herein, we systematically investigated the mutation patterns of SHROOM1-4 in a Chinese population composed of 343 NTD cases and 206 controls, using targeted next-generation sequencing. Functional variants were further confirmed by western blot and the mammalian two-hybrid assays. Loss of function (LoF) variants were identified in SHROOM3. We observed 1.56 times as many rare [minor allele frequency (MAF) < 0.01] coding variants (p = 2.9 × 10−3) in SHROOM genes, and 4.5 times as many rare D-Mis (deleterious missense) variants in SHROOM2 genes in the NTD cases compared with the controls. D-Mis variants of SHROOM2 (p.A1331S; p.R1557H) were confirmed by Sanger sequencing, and these variants were determined to have profound effects on gene function that disrupted their binding with ROCK1 in vitro. These findings provide genetic and molecular insights into the effects of rare damaging variants in SHROOM2, indicating that such variants of SHROOM2 might contribute to the risk of human NTDs. This research enhances our understanding of the genetic contribution of the SHROOM gene family to the etiology of human NTDs.



This work was supported by Grants from the 973 Program (2013CB945403), the National Natural Science Foundation of China (81430005, 31521003), National key research and development program (2016YFC1000502), and the Commission for Science and Technology of Shanghai Municipality (17JC1400902) to H. Wang. Finnell was supported by Changjiang Scholar award.

Author contributions

HW and ZC directed and designed the study. ZC performed statistical and bioinformatics analysis. LK performed functional validation. HW, ZC, RF, and LK prepared the manuscript; all authors reviewed the manuscript.

Compliance with ethical standards

Conflict of interest

The author declares no competing financial interests.

Supplementary material

439_2017_1864_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 14 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Zhongzhong Chen
    • 1
    • 2
  • Lele Kuang
    • 1
    • 2
  • Richard H. Finnell
    • 1
    • 2
    • 3
    • 4
  • Hongyan Wang
    • 1
    • 2
    • 5
  1. 1.Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and DevelopmentFudan UniversityShanghaiChina
  2. 2.Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center of Genetics and DevelopmentFudan UniversityShanghaiChina
  3. 3.Departments of Molecular and Cellular Biology and MedicineBaylor College of MedicineHoustonUSA
  4. 4.Collaborative Innovation Center for Genetics and Development, School of Life SciencesFudan UniversityShanghaiChina
  5. 5.Children’s Hospital and Institutes of Biomedical Sciences of Fudan UniversityShanghaiChina

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