Deficits in prenatal serine biosynthesis underlie the mitochondrial dysfunction associated with the autism-linked fmr1 gene

Sarah L. Nolin, Eleonora Napoli, Amanda Flores, Randi J. Hagerman, Cecilia R Giulivi

Research output: Contribution to journalArticlepeer-review

Abstract

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 co-horts. 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 fi-broblasts 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.

Original languageEnglish (US)
Article number5886
JournalInternational journal of molecular sciences
Volume22
Issue number11
DOIs
StatePublished - Jun 1 2021

Keywords

  • Amniotic fluid
  • CGG repeats
  • FMR1
  • Metabolomics
  • Premutation
  • Proteomics

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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