Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia

Abstract

Noonan syndrome is a heterogeneous autosomal dominant disorder caused by mutations in at least eight genes involved in the RAS/MAPK signaling pathway. Recently, RIT1 (Ras-like without CAAX 1) has been shown to be involved in the pathogenesis of some patients. We report a series of 44 patients from 30 pedigrees (including nine multiplex families) with mutations in RIT1. These patients display a typical Noonan gestalt and facial phenotype. Among the probands, 8.7% showed postnatal growth retardation, 90% had congenital heart defects, 36% had hypertrophic cardiomyopathy (a lower incidence compared with previous report), 50% displayed speech delay and 52% had learning difficulties, but only 22% required special education. None had major skin anomalies. One child died perinatally of juvenile myelomonocytic leukemia. Compared with the canonical Noonan phenotype linked to PTPN11 mutations, patients with RIT1 mutations appear to be less severely growth retarded and more frequently affected by cardiomyopathy. Based on our experience, we estimate that RIT1 could be the cause of 5% of Noonan syndrome patients. Because mutations found constitutionally in Noonan syndrome are also found in several tumors in adulthood, we evaluated the potential contribution of RIT1 to leukemogenesis in Noonan syndrome. We screened 192 pediatric cases of acute lymphoblastic leukemias (96 B-ALL and 96 T-ALL) and 110 cases of juvenile myelomonocytic leukemias (JMML), but detected no variation in these tumoral samples, suggesting that Noonan patients with germline RIT1 mutations are not at high risk to developing JMML or ALL, and that RIT1 has at most a marginal role in these sporadic malignancies.

RIT1 controls actin dynamics via complex formation with RAC1/CDC42 and PAK1

“…We studied the signaling consequences of wild-type RIT1 (WT) and six NS-associated RIT1 mutations, including p.K23N and p.G31R in the P-loop, p.A57G in the switch I region, and p.F82L, p.M90V and p.G95A in the switch II region ( Fig 1A ) [ 14 , 16 – 18 , 27 ]. Serum stimulation promoted a sound ERK1/2 phosphorylation response in HEK293T cells expressing wild-type RIT1, which was increased compared to control cells ( Fig 1B ), indicating that RIT1 affects MEK-ERK signaling.…”

“…NS is a genetically heterogeneous, autosomal dominant disorder characterized by craniofacial dysmorphism, growth retardation, cardiac abnormalities, and learning difficulties [ 15 ]. Individuals with a RIT1 mutation have a higher prevalence of cardiovascular manifestations and lymphatic problems compared with other NS subtypes, and the frequency of RIT1 mutations in NS is at least 5% [ 14 , 16 – 18 ]. NS-associated RIT1 mutations reported to date particularly affect codons 57, 82 and 95 and result in amino acid changes in the switch I and II regions ( Fig 1A ) [ 14 , 16 – 30 ].…”

“…Individuals with a RIT1 mutation have a higher prevalence of cardiovascular manifestations and lymphatic problems compared with other NS subtypes, and the frequency of RIT1 mutations in NS is at least 5% [ 14 , 16 – 18 ]. NS-associated RIT1 mutations reported to date particularly affect codons 57, 82 and 95 and result in amino acid changes in the switch I and II regions ( Fig 1A ) [ 14 , 16 – 30 ]. These two protein motifs are involved in nucleotide, effector and regulator binding and thereby ensure molecular functioning of RIT1 [ 31 , 32 ].…”

Prenatal cases with rare RIT1 variants causing severe fetal hydrops and death

“…The RIT1 gene is located on chromosome 1q22. The protein coded by RIT1 is involved in MAPKdependent signaling pathways (involved in stress-mediated activation of p38-MK2-HSP27-AKT complex in cell-survival mechanism) and NGF (Nerve Growth Factor) dependent nerve growth and differentiation [3]. Proteins coded by a mutated RIT1 gene cause hyperactivation of MAPK-ERK or transactivation of ELK pathways, participating in NS pathogenesis [3].…”

“…The protein coded by RIT1 is involved in MAPKdependent signaling pathways (involved in stress-mediated activation of p38-MK2-HSP27-AKT complex in cell-survival mechanism) and NGF (Nerve Growth Factor) dependent nerve growth and differentiation [3]. Proteins coded by a mutated RIT1 gene cause hyperactivation of MAPK-ERK or transactivation of ELK pathways, participating in NS pathogenesis [3]. The gain-of-function mutations of RIT1 are responsible for around 5% of all NS cases, making RIT1 one of the most common genetic causes of NS [4].…”