RESUMO
FEZF2 encodes a transcription factor critical to neurodevelopment that regulates other neurodevelopment genes. Rare variants in FEZF2 have previously been suggested to play a role in autism, and cases of 3p14 microdeletions that include FEZF2 share a neurodevelopmental phenotype including mild dysmorphic features and intellectual disability. We identified seven heterozygous predicted deleterious variants in FEZF2 (three frameshifts, one recurrent missense in two independent cases, one nonsense, and one complete gene deletion) in unrelated individuals with neurodevelopmental disorders including developmental delay/intellectual disability, autism, and/or attention-deficit/hyperactivity. Variants were confirmed to be de novo in five of seven cases and paternally inherited from an affected father in one. Predicted deleterious variants in FEZF2 may affect the expression of genes that are involved in fate choice pathways in developing neurons, and thus contribute to the neurodevelopmental phenotype. Future studies are needed to clarify the mechanism by which FEZF2 leads to this neurodevelopmental disorder.
Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Fenótipo , Humanos , Masculino , Feminino , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Criança , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Pré-Escolar , Adolescente , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas do Tecido Nervoso/genética , Fatores de TranscriçãoRESUMO
P(5) ATPases (ATP13A1 through ATP13A5) are found in all eukaryotes. They are currently poorly characterized and have unknown substrate specificity. Recent evidence has linked two P(5) ATPases to diseases of the nervous system, suggesting possible importance of these proteins within the nervous system. In this study we determined the relative expression of mouse P5 ATPases in development using quantitative real time PCR. We have shown that ATP13A1 and ATP13A2 were both expressed similarly during development, with the highest expression levels at the peak of neurogenesis. ATP13A3 was expressed highly during organogenesis with one of its isoforms playing a more predominant role during the period of neuronal development. ATP13A5 was expressed most highly in the adult mouse brain. We also assessed the expression of these genes in various regions of the adult mouse brain. ATP13A1 to ATP13A4 were expressed differentially in the cerebral cortex, hippocampus, brainstem and cerebellum while levels of ATP13A5 were fairly constant between these brain regions. Moreover, we demonstrated expression of the ATP13A4 protein in the corresponding brain regions using immunohistochemistry. In summary, this study furthers our knowledge of P(5)-type ATPases and their potentially important role in the nervous system.