RESUMO
Autism spectrum disorder (ASD) is a heritable, common neurodevelopmental disorder with diverse genetic causes. Several studies have implicated protein synthesis as one among several of its potential convergent mechanisms. We originally identified Janus kinase and microtubule-interacting protein 1 (JAKMIP1) as differentially expressed in patients with distinct syndromic forms of ASD, fragile X syndrome, and 15q duplication syndrome. Here, we provide multiple lines of evidence that JAKMIP1 is a component of polyribosomes and an RNP translational regulatory complex that includes fragile X mental retardation protein, DEAD box helicase 5, and the poly(A) binding protein cytoplasmic 1. JAKMIP1 loss dysregulates neuronal translation during synaptic development, affecting glutamatergic NMDAR signaling, and results in social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors in the mouse. These findings define an important and novel role for JAKMIP1 in neural development and further highlight pathways regulating mRNA translation during synaptogenesis in the genesis of neurodevelopmental disorders.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Redes Reguladoras de Genes/fisiologia , Biossíntese de Proteínas/fisiologia , Proteínas de Ligação a RNA/fisiologia , Sinapses/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/fisiologia , Proteômica/métodosRESUMO
Advances in genetics and genomics have improved our understanding of autism spectrum disorders. As many genes have been implicated, we look to points of convergence among these genes across biological systems to better understand and treat these disorders.
