Gain-of-Function Mutations in RIT1 Cause Noonan Syndrome, a RAS/MAPK Pathway Syndrome

Abstract

RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes.

Growth references for Japanese individuals with Noonan syndrome

“…The protein is expressed throughout the body and plays a crucial role in cellular response to growth factors, hormones, cytokines, and cell adhesion molecules. There is increasing evidence that germline mutations in the genes involved in the Ras/mitogen-activated protein kinase signaling pathway cause NS and Noonan-related syndrome (9). While mutations in such genes were identified in ~60-70% of patients with NS phenotype (10,11), the diagnosis of NS remains clinical (2,12).…”

Neuropsychological Functioning in Individuals with Noonan Syndrome: a Systematic Literature Review with Educational and Treatment Recommendations

“…Rarer gene mutations, including those in NRAS, KRAS, RIT1, RAF1, SCHOC2, and CBL, account for relatively few cases of NS (Aoki et al 2013;Roberts et al 2013). Studies reporting on individuals with RAF1 mutations typically find that intellectual and adaptive functioning is commensurate with individuals with other NS gene mutations (Cesarini et al 2009;Pierpont et al 2010b;Alfieri et al 2014).…”

“…This signal transduction pathway plays an essential role in embryonic and postnatal development. NS is caused by germline mutations in one of several genes that encode protein components or regulators within the RAS-MAPK pathway (Tartaglia et al 2011;Aoki et al 2013). Notably, gene mutations affecting other components of the RAS-MAPK pathway are known to cause several related genetic disorders, including neurofibromatosis type 1 (NF1), Legius syndrome, Costello syndrome, and cardiofaciocutaneous (CFC) syndrome.…”

Co‐occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death

“…PTPN11 mutations (40%‐50%), SOS1 mutations (10%‐20%), RAF1 (3%‐17%), and RIT1 (9%) are common, followed by KRAS , NRAS , BRAF , SHOC2 , MAP2K1 , CBL, LZTR1, SOS2, RRAS, and CDC42 1, 2, 3, 4, 5, 6, 7, 8, 9…”