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

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