Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease

Loïc De Pontual; Norann A. Zaghloul; Sophie Thomas; Erica Ellen Davis; David M. Mcgaughey; Hélène Dollfus; Clarisse Baumann; Seneca L. Bessling; Candice Babarit; Anna Pelet; Cecilia Gascue; Philip Beales; Arnold Munnich; Stanislas Lyonnet; Heather Etchevers; Tania Attie-Bitach; Jose L. Badano; Andrew S. McCallion; Elias Nicholas Katsanis; Jeanne Amiel

doi:10.1073/pnas.0901219106

Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease

Loïc De Pontual, Norann A. Zaghloul, Sophie Thomas, Erica Ellen Davis, David M. Mcgaughey, Hélène Dollfus, Clarisse Baumann, Seneca L. Bessling, Candice Babarit, Anna Pelet, Cecilia Gascue, Philip Beales, Arnold Munnich, Stanislas Lyonnet, Heather Etchevers, Tania Attie-Bitach, Jose L. Badano, Andrew S. McCallion, Elias Nicholas Katsanis^*, Jeanne Amiel

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

Abstract

Hirschsprung disease (HSCR) is a common, multigenic neurocristopathy characterized by incomplete innervation along a variable length of the gut. The pivotal gene in isolated HSCR cases, either sporadic or familial, is RET. HSCR also presents in various syndromes, including Shah-Waardenburg syndrome (WS), Down (DS), and Bardet-Biedl (BBS). Here, we report 3 families with BBS and HSCR with concomitant mutations in BBS genes and regulatory RET elements, whose functionality is tested in physiologically relevant assays. Our data suggest that BBS mutations can potentiate HSCR predisposing RET alleles, which by themselves are insufficient to cause disease. We also demonstrate that these genes interact genetically in vivo to modulate gut innervation, and that this interaction likely occurs through complementary, yet independent, pathways that converge on the same biological process.

Original language	English (US)
Pages (from-to)	13921-13926
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	106
Issue number	33
DOIs	https://doi.org/10.1073/pnas.0901219106
State	Published - Aug 18 2009

Keywords

Bardet-Biedl
Genetic interaction
Neural crest cells
Zebrafish

ASJC Scopus subject areas

General

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10.1073/pnas.0901219106

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De Pontual, L., Zaghloul, N. A., Thomas, S., Davis, E. E., Mcgaughey, D. M., Dollfus, H., Baumann, C., Bessling, S. L., Babarit, C., Pelet, A., Gascue, C., Beales, P., Munnich, A., Lyonnet, S., Etchevers, H., Attie-Bitach, T., Badano, J. L., McCallion, A. S., Katsanis, E. N., & Amiel, J. (2009). Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease. Proceedings of the National Academy of Sciences of the United States of America, 106(33), 13921-13926. https://doi.org/10.1073/pnas.0901219106

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title = "Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease",

abstract = "Hirschsprung disease (HSCR) is a common, multigenic neurocristopathy characterized by incomplete innervation along a variable length of the gut. The pivotal gene in isolated HSCR cases, either sporadic or familial, is RET. HSCR also presents in various syndromes, including Shah-Waardenburg syndrome (WS), Down (DS), and Bardet-Biedl (BBS). Here, we report 3 families with BBS and HSCR with concomitant mutations in BBS genes and regulatory RET elements, whose functionality is tested in physiologically relevant assays. Our data suggest that BBS mutations can potentiate HSCR predisposing RET alleles, which by themselves are insufficient to cause disease. We also demonstrate that these genes interact genetically in vivo to modulate gut innervation, and that this interaction likely occurs through complementary, yet independent, pathways that converge on the same biological process.",

keywords = "Bardet-Biedl, Genetic interaction, Neural crest cells, Zebrafish",

author = "{De Pontual}, Lo{\"i}c and Zaghloul, {Norann A.} and Sophie Thomas and Davis, {Erica Ellen} and Mcgaughey, {David M.} and H{\'e}l{\`e}ne Dollfus and Clarisse Baumann and Bessling, {Seneca L.} and Candice Babarit and Anna Pelet and Cecilia Gascue and Philip Beales and Arnold Munnich and Stanislas Lyonnet and Heather Etchevers and Tania Attie-Bitach and Badano, {Jose L.} and McCallion, {Andrew S.} and Katsanis, {Elias Nicholas} and Jeanne Amiel",

year = "2009",

month = aug,

day = "18",

doi = "10.1073/pnas.0901219106",

language = "English (US)",

volume = "106",

pages = "13921--13926",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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De Pontual, L, Zaghloul, NA, Thomas, S, Davis, EE, Mcgaughey, DM, Dollfus, H, Baumann, C, Bessling, SL, Babarit, C, Pelet, A, Gascue, C, Beales, P, Munnich, A, Lyonnet, S, Etchevers, H, Attie-Bitach, T, Badano, JL, McCallion, AS, Katsanis, EN & Amiel, J 2009, 'Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 33, pp. 13921-13926. https://doi.org/10.1073/pnas.0901219106

Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease. / De Pontual, Loïc; Zaghloul, Norann A.; Thomas, Sophie et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 33, 18.08.2009, p. 13921-13926.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease

AU - De Pontual, Loïc

AU - Zaghloul, Norann A.

AU - Thomas, Sophie

AU - Davis, Erica Ellen

AU - Mcgaughey, David M.

AU - Dollfus, Hélène

AU - Baumann, Clarisse

AU - Bessling, Seneca L.

AU - Babarit, Candice

AU - Pelet, Anna

AU - Gascue, Cecilia

AU - Beales, Philip

AU - Munnich, Arnold

AU - Lyonnet, Stanislas

AU - Etchevers, Heather

AU - Attie-Bitach, Tania

AU - Badano, Jose L.

AU - McCallion, Andrew S.

AU - Katsanis, Elias Nicholas

AU - Amiel, Jeanne

PY - 2009/8/18

Y1 - 2009/8/18

N2 - Hirschsprung disease (HSCR) is a common, multigenic neurocristopathy characterized by incomplete innervation along a variable length of the gut. The pivotal gene in isolated HSCR cases, either sporadic or familial, is RET. HSCR also presents in various syndromes, including Shah-Waardenburg syndrome (WS), Down (DS), and Bardet-Biedl (BBS). Here, we report 3 families with BBS and HSCR with concomitant mutations in BBS genes and regulatory RET elements, whose functionality is tested in physiologically relevant assays. Our data suggest that BBS mutations can potentiate HSCR predisposing RET alleles, which by themselves are insufficient to cause disease. We also demonstrate that these genes interact genetically in vivo to modulate gut innervation, and that this interaction likely occurs through complementary, yet independent, pathways that converge on the same biological process.

AB - Hirschsprung disease (HSCR) is a common, multigenic neurocristopathy characterized by incomplete innervation along a variable length of the gut. The pivotal gene in isolated HSCR cases, either sporadic or familial, is RET. HSCR also presents in various syndromes, including Shah-Waardenburg syndrome (WS), Down (DS), and Bardet-Biedl (BBS). Here, we report 3 families with BBS and HSCR with concomitant mutations in BBS genes and regulatory RET elements, whose functionality is tested in physiologically relevant assays. Our data suggest that BBS mutations can potentiate HSCR predisposing RET alleles, which by themselves are insufficient to cause disease. We also demonstrate that these genes interact genetically in vivo to modulate gut innervation, and that this interaction likely occurs through complementary, yet independent, pathways that converge on the same biological process.

KW - Bardet-Biedl

KW - Genetic interaction

KW - Neural crest cells

KW - Zebrafish

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U2 - 10.1073/pnas.0901219106

DO - 10.1073/pnas.0901219106

M3 - Article

C2 - 19666486

AN - SCOPUS:69549085026

SN - 0027-8424

VL - 106

SP - 13921

EP - 13926

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 33

ER -

Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease

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Keywords

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