RESUMO
PURPOSE: Fem1 homolog B (FEM1B) acts as a substrate recognition subunit for ubiquitin ligase complexes belonging to the CULLIN 2-based E3 family. Several biological functions have been proposed for FEM1B, including a structurally resolved function as a sensor for redox cell status by controlling mitochondrial activity, but its implication in human disease remains elusive. METHODS: To understand the involvement of FEM1B in human disease, we made use of Matchmaker exchange platforms to identify individuals with de novo variants in FEM1B and performed their clinical evaluation. We performed functional validation using primary neuronal cultures and in utero electroporation assays, as well as experiments on patient's cells. RESULTS: Five individuals with a recurrent de novo missense variant in FEM1B were identified: NM_015322.5:c.377G>A NP_056137.1:p.(Arg126Gln) (FEM1BR126Q). Affected individuals shared a severe neurodevelopmental disorder with behavioral phenotypes and a variable set of malformations, including brain anomalies, clubfeet, skeletal abnormalities, and facial dysmorphism. Overexpression of the FEM1BR126Q variant but not FEM1B wild-type protein, during mouse brain development, resulted in delayed neuronal migration of the target cells. In addition, the individuals' cells exhibited signs of oxidative stress and induction of type I interferon signaling. CONCLUSION: Overall, our data indicate that p.(Arg126Gln) induces aberrant FEM1B activation, resulting in a gain-of-function mechanism associated with a severe syndromic developmental disorder in humans.
Assuntos
Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento , Ubiquitina-Proteína Ligases , Humanos , Mutação de Sentido Incorreto/genética , Feminino , Camundongos , Masculino , Animais , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Ubiquitina-Proteína Ligases/genética , Criança , Pré-Escolar , Fenótipo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Neurônios/metabolismo , Neurônios/patologia , LactenteRESUMO
The association of long QT syndrome and left ventricular noncompaction is uncommon, with only a handful of previous reports, and only one reported case in association with a mutation in KCNQ1. Here we present genetic and phenotypic data for 4 family members across 2 generations who all have evidence of prolonged QT interval and left ventricular noncompaction in association with a pathogenic mutation in KCNQ1, and discuss the potential mechanisms of this association. In conclusion, we suggest that it may be helpful to consider looking for mutations in KCNQ1 in similar patients.