Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked FMR1 Gene.
Sarah L NolinEleonora NapoliAmanda FloresRandi J HagermanCecilia GiuliviPublished in: International journal of molecular sciences (2021)
Fifty-five to two hundred CGG repeats (called a premutation, or PM) in the 5'-UTR of the FMR1 gene are generally unstable, often expanding to a full mutation (>200) in one generation through maternal inheritance, leading to fragile X syndrome, a condition associated with autism and other intellectual disabilities. To uncover the early mechanisms of pathogenesis, we performed metabolomics and proteomics on amniotic fluids from PM carriers, pregnant with male fetuses, who had undergone amniocentesis for fragile X prenatal diagnosis. The prenatal metabolic footprint identified mitochondrial deficits, which were further validated by using internal and external cohorts. Deficits in the anaplerosis of the Krebs cycle were noted at the level of serine biosynthesis, which was confirmed by rescuing the mitochondrial dysfunction in the carriers' umbilical cord fibroblasts using alpha-ketoglutarate precursors. Maternal administration of serine and its precursors has the potential to decrease the risk of developing energy shortages associated with mitochondrial dysfunction and linked comorbidities.
Keyphrases
- umbilical cord
- mesenchymal stem cells
- pregnant women
- traumatic brain injury
- particulate matter
- autism spectrum disorder
- protein kinase
- air pollution
- birth weight
- intellectual disability
- copy number
- mass spectrometry
- pregnancy outcomes
- genome wide
- mitochondrial dna
- gestational age
- polycyclic aromatic hydrocarbons
- heavy metals
- oxidative stress
- genome wide identification
- cell wall
- water soluble
- case report
- extracellular matrix
- human health
- climate change
- genome wide analysis
- body mass index