Publication Date
10-10-2024
Journal
Human Genetics and Genomics Advances
DOI
10.1016/j.xhgg.2024.100345
PMID
39182167
PMCID
PMC11418108
PubMedCentral® Posted Date
8-30-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Adolescent, Adult, Child, Child, Preschool, Female, Humans, Male, Autism Spectrum Disorder, Haploinsufficiency, Neurodevelopmental Disorders, Ribonucleoproteins, RNA Recognition Motif Proteins, LARP1, autism, ASD, NDD, neurodevelopmental, metabolism, plasticity, proband, RBP, RNA binding protein
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 (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.
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