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RET and NRG1 interplay in Hirschsprung disease

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An Erratum to this article was published on 15 February 2014

Abstract

Hirschsprung disease (HSCR, aganglionic megacolon) is a complex genetic disorder of the enteric nervous system (ENS) characterized by the absence of enteric neurons along a variable length of the intestine. While rare variants (RVs) in the coding sequence (CDS) of several genes involved in ENS development lead to disease, the association of common variants (CVs) with HSCR has only been reported for RET (the major HSCR gene) and NRG1. Importantly, RVs in the CDS of these two genes are also associated with the disorder. To assess independent and joint effects between the different types of RET and NRG1 variants identified in HSCR patients, we used 254 Chinese sporadic HSCR patients and 143 ethnically matched controls for whom the RET and/or NRG1 variants genotypes (rare and common) were available. Four genetic risk factors were defined and interaction effects were modeled using conditional logistic regression analyses and pair-wise Kendall correlations. Our analysis revealed a joint effect of RET CVs with RET RVs, NRG1 CVs or NRG1 RVs. To assess whether the genetic interaction translated into functional interaction, mouse neural crest cells (NCCs; enteric neuron precursors) isolated from embryonic guts were treated with NRG1 (ErbB2 ligand) or/and GDNF (Ret ligand) and monitored during the subsequent neural differentiation process. Nrg1 inhibited the Gdnf-induced neuronal differentiation and Gdnf negatively regulated Nrg1-signaling by down-regulating the expression of its receptor, ErbB2. This preliminary data suggest that the balance neurogenesis/gliogenesis is critical for ENS development.

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Acknowledgments

This work was supported by the research grant from the Hong Kong Research Grants Council HKU 778610 to P.K.T. and HKU775710 to E.S.W.N. Support was also received from the University of Hong Kong Strategic Research Theme on Genomics.

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Authors and Affiliations

  1. Department of Psychiatry, The University of Hong Kong, Hong Kong SAR, China

    Hongsheng Gui, Petroola Proitsi, Pak C. Sham & Stacey S. Cherny

  2. Department of Surgery, The University of Hong Kong, Hong Kong SAR, China

    Wai-Kiu Tang, Man-Ting So, Paul K. Tam, Elly Sau-Wai Ngan & Maria-Mercè Garcia-Barceló

  3. Centre for Reproduction, Development and Growth, The University of Hong Kong, Hong Kong SAR, China

    Pak C. Sham, Paul K. Tam, Elly Sau-Wai Ngan & Maria-Mercè Garcia-Barceló

  4. Center for Genomic Sciences Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Pak C. Sham

  5. State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong SAR, China

    Pak C. Sham & Stacey S. Cherny

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  1. Hongsheng Gui
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  2. Wai-Kiu Tang
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  4. Petroola Proitsi
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  6. Paul K. Tam
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  7. Elly Sau-Wai Ngan
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  8. Stacey S. Cherny
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  9. Maria-Mercè Garcia-Barceló
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Correspondence to Elly Sau-Wai Ngan, Stacey S. Cherny or Maria-Mercè Garcia-Barceló.

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H. Gui and W.-K. Tang contributed equally to this work.

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Gui, H., Tang, WK., So, MT. et al. RET and NRG1 interplay in Hirschsprung disease. Hum Genet 132, 591–600 (2013). https://doi.org/10.1007/s00439-013-1272-9

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