Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked FMR1 Gene

International Journal of Molecular Sciences

SarahL. Nolin¹  Cecilia Giulivi²  Amanda Flores²  Eleonora Napoli²  RandiJ. Hagerman³ 

[1] Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA;Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA;Department of Pediatrics, University of California Davis Medical Center, Sacramento, CA 95817, USA;

关键词: amniotic fluid;    premutation;    CGG repeats;    FMR1;    metabolomics;    proteomics;   

DOI  :  10.3390/ijms22115886

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown