RESUMO
Costello syndrome (CS) is a RASopathy characterized by a wide range of cardiac, musculoskeletal, dermatological, and developmental abnormalities. The RASopathies are defined as a group of syndromes caused by activated Ras/mitogen-activated protein kinase (MAPK) signaling. Specifically, CS is caused by activating mutations in HRAS. Although receptor tyrosine kinase (RTK) signaling, which is upstream of Ras/MAPK, is known to play a critical role in craniofacial and dental development, the craniofacial and dental features of CS have not been systematically defined in a large group of individuals. In order to address this gap in our understanding and fully characterize the CS phenotype, we evaluated the craniofacial and dental phenotype in a large cohort (n = 41) of CS individuals. We confirmed that the craniofacial features common in CS include macrocephaly, bitemporal narrowing, convex facial profile, full cheeks, and large mouth. Additionally, CS patients have a characteristic dental phenotype that includes malocclusion with anterior open bite and posterior crossbite, enamel hypo-mineralization, delayed tooth development and eruption, gingival hyperplasia, thickening of the alveolar ridge, and high palate. Comparison of the craniofacial and dental phenotype in CS with other RASopathies, such as cardio-facio-cutaneous syndrome (CFC), provides insight into the complexities of Ras/MAPK signaling in human craniofacial and dental development.
Assuntos
Síndrome de Costello/genética , Anormalidades Craniofaciais/embriologia , Anormalidades Craniofaciais/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Hipoplasia do Esmalte Dentário/embriologia , Hipoplasia do Esmalte Dentário/genética , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/genética , Fácies , Insuficiência de Crescimento/embriologia , Insuficiência de Crescimento/genética , Feminino , Hiperplasia Gengival/embriologia , Hiperplasia Gengival/genética , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/genética , Humanos , Masculino , Má Oclusão/embriologia , Má Oclusão/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , Dente/embriologia , Anormalidades Dentárias/embriologia , Anormalidades Dentárias/genética , Adulto JovemRESUMO
Cardio-facio-cutaneous (CFC) syndrome is caused by germline mutations in KRAS, BRAF and MEK1/2. The highly selective and potent MEK inhibitors that have been developed as anti-cancer agents hold potential as therapeutics for CFC syndrome. We have previously shown that the effects of CFC mutations on zebrafish gastrulation can be prevented by a 1-hour treatment with MEK inhibitors within a specific developmental time-window. However, MEK activity is essential for normal development and PD0325901 treatment outside this treatment window leads to additional developmental defects in MEK-dependent tissues. We now test ten different doses of PD0325901 at six developmental time points and assess the effects on body axis length, heart development and craniofacial structures in zebrafish embryos. Notably, we find that a continuous low-level dose of PD0325901 that has only minor inhibition of MEK activity can prevent the action of both the common CFC BRAF(Q257R) kinase-active allele and the BRAF(G596V) kinase-impaired mutant allele through the first 5 days of development. These results provide a detailed study of the effects of PD0325901 in development and show that, unlike in cancer, which requires robust inhibition of MAPK signalling, a partial reduction in phospho-ERK1/2 activity is sufficient to moderate the developmental effects of BRAF(CFC) mutations.