RESUMEN
Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and metabolic plasticity. Using lymphocytes collected and immortalized from an index proband who carries a truncating variant in one allele of LARP1, we demonstrated that lower cellular levels of LARP1 protein cause reduced rates of aerobic respiration and glycolysis. As expression of LARP1 increases during neurodevelopment, with higher levels in neurons and astrocytes, we propose that LARP1 haploinsufficiency contributes to ASD or related NDDs through attenuated metabolic activity in the developing fetal brain.
RESUMEN
Autism spectrum disorder (ASD) is a highly prevalent and impairing neurodevelopmental disorder that affects 1 : 54 persons. Over the last several decades, the reported incidence of ASD in the US has increased potentially due to increased awareness and improved diagnostic measurement. Although ASD prevalence is increasing, the etiology of ASD remains relatively unknown. To better understand the neurological basis of ASD, rodent models of ASD have been developed for research. Currently, there is not a standardized set of behavioral tests to quantify ASD-like behavior in rodents. The goal of this review is to present an overview of the methodologies used to analyze ASD-like behaviors in rodents, focusing on the valproic acid (VPA) model, and illustrate inconsistencies between different approaches. Despite that the in utero VPA rodent model for ASD is widely used and extensively characterized, behaviors vary substantially between different researchers. Moving forward, consistency in behavioral method analytics would benefit progress in evaluating interventions for all models of ASD and help to uncover unique qualities underlying mechanisms causing ASD signs and symptoms.