LARP1 haploinsufficiency is associated with an autosomal dominant neurodevelopmental disorder
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.
Authors
- Megan Li (ORCID: https://orcid.org/0000-0003-0302-8474)
- Robert G. Best (ORCID: https://orcid.org/0000-0002-9691-125X)
- Anna K. Childers (ORCID: https://orcid.org/0000-0002-0747-8539)
- Kent Carter
- Danielle Monteil (ORCID: https://orcid.org/0000-0002-9844-7817)
- Blake Vuocolo
- Kévin Uguen (ORCID: https://orcid.org/0000-0002-6744-2837)
- Anne M. Comi (ORCID: https://orcid.org/0000-0001-7915-6881)
- Aviva Eliyahu
- Zinaida Dedeić (ORCID: https://orcid.org/0000-0002-7046-3815)
- Ingrid M. Wentzensen (ORCID: https://orcid.org/0000-0001-6994-1640)
- Thomas Besnard (ORCID: https://orcid.org/0000-0003-4804-5147)
- Sébastien Küry (ORCID: https://orcid.org/0000-0001-5497-0465)
- Olivia Larner
- Roberta Sierra
- Nofar Mor
- Raymond J. Louie (ORCID: https://orcid.org/0000-0002-6788-1151)
- Stephan Sanders (ORCID: https://orcid.org/0000-0001-9112-5148)
- Lori Berry
- Alyssa Blesson (ORCID: https://orcid.org/0000-0002-8954-9387)
- Bertrand Isidor (ORCID: https://orcid.org/0000-0001-6480-126X)
- Cindy Skinner (ORCID: https://orcid.org/0000-0002-7841-8277)
- Sarah P. Blagden (ORCID: https://orcid.org/0000-0001-8783-3491)
- Lior Greenbaum (ORCID: https://orcid.org/0000-0001-6176-0941)
- Kevin Chen (ORCID: https://orcid.org/0000-0003-3330-8717)
- Josephine Morris
- Benjamin Cogné (ORCID: https://orcid.org/0000-0002-5503-6292)
- Seema R. Lalani
- James Chettle
- Barbara R. DuPont
- R. Curtis Rogers
- Marc Planes
Institutions
- Centre National de la Recherche Scientifique (FR)
- Kennedy Krieger Institute (US)
- Naval Medical Center Portsmouth (US)
- Inserm (FR)
- University of South Carolina (US)
- Tel Aviv University (IL)
- University of California, San Francisco (US)
- Baylor College of Medicine (US)
- California Institute for Regenerative Medicine (US)
- Sheba Medical Center (IL)
- The University of Texas Rio Grande Valley (US)
- Yale University (US)
- University of Oxford (GB)
- Centre Hospitalier Régional Universitaire de Brest (FR)
- Institut du Thorax (FR)
- Greenwood Genetic Center (US)
- Invitae (United States) (US)
- Nantes Université (FR)
Publication Details
- Journal
- Human Genetics and Genomics Advances
- Published
- 2024-08-30
- DOI
- https://doi.org/10.1016/j.xhgg.2024.100345
- Citations
- 5
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.17
Funders
- BioMarin Pharmaceutical
- National Institutes of Health
- National Institute of Mental Health