School of Medicine Publications and Presentations
Document Type
Article
Publication Date
8-23-2024
Abstract
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. 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 lower cellular levels of LARP1 protein causing 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.
Recommended Citation
Chettle, J., Louie, R. J., Larner, O., Best, R., Chen, K., Morris, J., Dedeic, Z., Childers, A., Rogers, R. C., DuPont, B. R., Skinner, C., Küry, S., Uguen, K., Planes, M., Monteil, D., Li, M., Eliyahu, A., Greenbaum, L., Mor, N., Besnard, T., … Blagden, S. P. (2024). LARP1 haploinsufficiency is associated with an autosomal dominant neurodevelopmental disorder. HGG advances, 100345. Advance online publication. https://doi.org/10.1016/j.xhgg.2024.100345
Publication Title
Human Genetics and Genomics Advances
DOI
https://doi.org/10.1016/j.xhgg.2024.100345
Academic Level
faculty
Comments
Original published version available at https://doi.org/10.1016/j.xhgg.2024.100345