Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome.

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.

Risk factors for mother-to-child transmission of hepatitis C virus: Maternal high viral load and fetal exposure in the birth canal.

AIM: Mother-to-child transmission (MTCT) is the major transmission pathway of hepatitis C virus (HCV) in children. However, its risk factors remain unsettled for introduction of putative intervention. METHODS: Pregnant women screened for HCV and MTCT in children born to antibody-positive mothers were prospectively studied in Tottori, Japan. RESULTS: Among 41 856 screened women, 188 (0.45%) were HCV antibody-positive, of whom 61% had detectable HCV RNA. While 10 of the 34 children (29%) born to high viral load (HVL: ≥6.0 × 10(5) IU/mL) mothers were infected, none born to RNA-detectable but non-HVL mothers were infected (P < 0.001). MTCT among vaginally delivered children born to HVL mothers was analyzed. Children delivered after 4 h or more of labor were more frequently infected than were those born within 4 h of labor (P = 0.019). Premature rupture of fetal membranes was significantly more common in infected children than in uninfected children (P < 0.001). Durations of membrane rupture and labor were longer in infected children than in uninfected children (P = 0.008 and P = 0.040, respectively). Elective cesarean section that eliminates these risk factors, other than HVL, significantly reduced MTCT from nine of 22 (41%) to none of nine children (0%) (P = 0.032). CONCLUSION: Our data suggest that contamination of the fetus in the birth canal with infected maternal blood is a major risk factor for HCV MTCT, in addition to maternal HVL. To rationalize intervention by elective cesarean section, the natural history of infected children should be carefully evaluated.