Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigenetic reprogramming of RAS-MAPK pathway genes

Oliver A. Kent (), Manipa Saha, Etienne Coyaud, Helen E. Burston, Napoleon Law, Keith Dadson, Sujun Chen, Estelle M. Laurent, Jonathan St-Germain, Ren X. Sun, Yoshinori Matsumoto, Justin Cowen, Aaryn Montgomery-Song, Kevin R. Brown, Charles Ishak, Jose La Rose, Daniel D. Carvalho, Housheng Hansen He, Brian Raught, Filio Billia, Peter Kannu and Robert Rottapel ()
Additional contact information
Oliver A. Kent: University Health Network
Manipa Saha: University Health Network
Etienne Coyaud: University Health Network
Helen E. Burston: University Health Network
Napoleon Law: University Health Network
Keith Dadson: Toronto General Research Institute
Sujun Chen: University Health Network
Estelle M. Laurent: University Health Network
Jonathan St-Germain: University Health Network
Ren X. Sun: University Health Network
Yoshinori Matsumoto: Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Justin Cowen: University Health Network
Aaryn Montgomery-Song: University Health Network
Kevin R. Brown: University Health Network
Charles Ishak: University Health Network
Jose La Rose: University Health Network
Daniel D. Carvalho: University Health Network
Housheng Hansen He: University Health Network
Brian Raught: University Health Network
Filio Billia: Toronto General Research Institute
Peter Kannu: Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children
Robert Rottapel: University Health Network

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract RAS-MAPK signaling mediates processes critical to normal development including cell proliferation, survival, and differentiation. Germline mutation of RAS-MAPK genes lead to the Noonan-spectrum of syndromes. Here, we present a patient affected by a 6p-interstitial microdeletion with unknown underlying molecular etiology. Examination of 6p-interstitial microdeletion cases reveals shared clinical features consistent with Noonan-spectrum disorders including short stature, facial dysmorphia and cardiovascular abnormalities. We find the RAS-responsive element binding protein-1 (RREB1) is the common deleted gene in multiple 6p-interstitial microdeletion cases. Rreb1 hemizygous mice display orbital hypertelorism and cardiac hypertrophy phenocopying the human syndrome. Rreb1 haploinsufficiency leads to sensitization of MAPK signaling. Rreb1 recruits Sin3a and Kdm1a to control H3K4 methylation at MAPK pathway gene promoters. Haploinsufficiency of SIN3A and mutations in KDM1A cause syndromes similar to RREB1 haploinsufficiency suggesting genetic perturbation of the RREB1-SIN3A-KDM1A complex represents a new category of RASopathy-like syndromes arising through epigenetic reprogramming of MAPK pathway genes.

Date: 2020
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DOI: 10.1038/s41467-020-18483-9

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