RESUMEN
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.
Asunto(s)
Síndrome de Costello/genética , Anomalías Craneofaciales/embriología , Anomalías Craneofaciales/genética , Sistema de Señalización de MAP Quinasas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Anomalías Múltiples/embriología , Anomalías Múltiples/genética , Adolescente , Adulto , Niño , Hipoplasia del Esmalte Dental/embriología , Hipoplasia del Esmalte Dental/genética , Displasia Ectodérmica/embriología , Displasia Ectodérmica/genética , Facies , Insuficiencia de Crecimiento/embriología , Insuficiencia de Crecimiento/genética , Femenino , Hiperplasia Gingival/embriología , Hiperplasia Gingival/genética , Cardiopatías Congénitas/embriología , Cardiopatías Congénitas/genética , Humanos , Masculino , Maloclusión/embriología , Maloclusión/genética , Proteínas Quinasas Activadas por Mitógenos/genética , Mutación , Fosfatidilinositol 3-Quinasas/genética , Diente/embriología , Anomalías Dentarias/embriología , Anomalías Dentarias/genética , Adulto JovenRESUMEN
SPTBN1 encodes ßII-spectrin, the ubiquitously expressed ß-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal ßII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect ßII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of ßII-spectrin in the central nervous system.