RESUMEN
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.
Asunto(s)
Mutación Missense , Trastornos del Neurodesarrollo , Ubiquitina-Proteína Ligasas , Animales , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Ratones , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Mutación Missense/genética , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , Neuronas/metabolismo , Neuronas/patología , Fenotipo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Mabry syndrome is a glycophosphatidylinositol (GPI) deficiency characterized by intellectual disability, distinctive facial features, intractable seizures, and hyperphosphatasia. We expand the phenotypic spectrum of inherited GPI deficiencies with novel bi-allelic phosphatidylinositol glycan anchor biosynthesis class O (PIGO) variants in a neonate who presented with intractable epilepsy and complex gastrointestinal and urogenital malformations.
Asunto(s)
Anomalías Múltiples/genética , Epilepsia Refractaria/genética , Glicosilfosfatidilinositoles/deficiencia , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Trastornos del Metabolismo del Fósforo/genética , Anomalías Urogenitales/genética , Femenino , Tracto Gastrointestinal/anomalías , Variación Genética , Humanos , Recién Nacido , FenotipoRESUMEN
Dominant spinocerebellar ataxias are a rare clinically and genetically heterogeneous group of neurodegenerative disorders. They are characterized by progressive cerebellar ataxia resulting in unsteady gait, clumsiness, dysarthria, and swallowing difficulty. The onset of symptoms is usually in the third or fourth decade of life; however, more subtle clinical manifestations can start in early childhood. Spinocerebellar ataxia type 5, a dominant spinocerebellar ataxia associated with mutations involving ß-III spectrin (SPTBN2), has been described in 3 families. It typically consists of a slowly progressive spinocerebellar ataxia with onset in the third decade. The authors present the first case of infantile-onset spinocerebellar ataxia associated with a novel SPTBN2 mutation (transition C>T at nucleotide position 1438), the proband having a much more severe phenotype with global developmental delay, hypotonia, tremor, nystagmus, and facial myokymia.