RESUMEN
RhoA and RhoC GTPases are 92% identical but demonstrate unique regulation and function. Phosphorylation of Ser188 has widely been reported to inhibit RhoA activity. RhoC possesses Arg188 in place of Ser188 but retains a canonical upstream PKA recognition sequence. We report here that RhoC-R188S was a PKA substrate in vitro and exhibited less GTP loading compared to wild-type RhoC when expressed in cells. Transiently expressed RhoC was found to be significantly more membrane associated than RhoA. Membrane association of RhoC-R188S and RhoC-R188A were similar to each other and wild-type RhoA, suggesting that Arg188 directly promotes RhoC membrane binding. The positive influence of Arg188 on RhoC membrane association was evident in a constitutively active (Q63L) background. In accordance, RhoA-S188R was significantly more membrane associated than either RhoA or RhoA-S188A. Altogether, these data suggest that swapping residue 188 identity effectively flips the membrane binding profile of wild-type RhoA and RhoC through positive arginine contribution rather than negative phosphoserine regulation.
Asunto(s)
Arginina/metabolismo , Membrana Celular/metabolismo , Proteína rhoC de Unión a GTP/química , Proteína rhoC de Unión a GTP/metabolismo , Humanos , Mutación , Unión Proteica , Proteína rhoC de Unión a GTP/genéticaRESUMEN
Triple X syndrome (47, XXX) occurs in approximately 1:1,000 female births and has a variable phenotype of physical and psychological features. Prenatal diagnosis rates of 47, XXX are increasing due to non-invasive prenatal genetic testing. Previous studies suggest that prenatal diagnosed females have better neurodevelopmental outcomes. This cross-sectional study describes diagnosis, physical features, medical problems, and neurodevelopmental features in a large cohort of females with 47, XXX. Evaluation included review of medical and developmental history, physical exam, cognitive, and adaptive testing. Medical and developmental features were compared between the prenatal and postnatal diagnosis groups using rate calculations and Fisher's exact test. Cognitive and adaptive tests scores were compared using t-tests. Seventy-four females age 6 months-24 years (mean 8.3 years) participated. Forty-four (59.5%) females were in the prenatal diagnosis group. Mean age of postnatal diagnosis was 5.9 years; developmental delay was the most common indication for postnatal genetic testing. Common physical features included hypertelorism, epicanthal folds, clinodactyly, and hypotonia. Medical problems included dental disorders (44.4%), seizure disorders (16.2%), genitourinary malformations (12.2%). The prenatal diagnosis group had higher verbal (P < 0.001), general ability index (P = 0.004), and adaptive functioning scores (P < 0.001). Rates of ADHD (52.2% vs. 45.5%, P = 0.77) and learning disabilities (39.1% vs. 36.3%, P = 1.00) were similar between the two groups. These findings expand on the phenotypic features in females with Triple X syndrome and support that prenatally ascertained females have better cognitive and functional outcomes. However, prenatally diagnosed females are still at risk for neurodevelopmental disorders. Genetic counseling and treatment recommendations are summarized. © 2016 Wiley Periodicals, Inc.