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

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

doi:10.3390/ijms22115886

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

¹,

²,

^2,3,

^4,5

and

Cecilia Giulivi

^2,5,*

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

Medical Sciences Campus, Department of Biochemistry, University of Puerto Rico, San Juan PR00936, Puerto Rico

⁴

Department of Pediatrics, University of California Davis Medical Center, Sacramento, CA 95817, USA

⁵

The MIND Institute, University of California Davis Medical Center, Sacramento, CA 95817, USA

Author to whom correspondence should be addressed.

Academic Editor: Asher Ornoy

Int. J. Mol. Sci. 2021, 22(11), 5886; https://doi.org/10.3390/ijms22115886

Received: 23 April 2021 / Revised: 25 May 2021 / Accepted: 27 May 2021 / Published: 30 May 2021

(This article belongs to the Section Molecular Neurobiology)

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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 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. View Full-Text

Keywords: amniotic fluid; premutation; CGG repeats; FMR1; metabolomics; proteomics

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MDPI and ACS Style

Nolin, S.L.; Napoli, E.; Flores, A.; Hagerman, R.J.; Giulivi, C. Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked FMR1 Gene. Int. J. Mol. Sci. 2021, 22, 5886. https://doi.org/10.3390/ijms22115886

AMA Style

Nolin SL, Napoli E, Flores A, Hagerman RJ, Giulivi C. Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked FMR1 Gene. International Journal of Molecular Sciences. 2021; 22(11):5886. https://doi.org/10.3390/ijms22115886

Chicago/Turabian Style

Nolin, Sarah L., Eleonora Napoli, Amanda Flores, Randi J. Hagerman, and Cecilia Giulivi. 2021. "Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked FMR1 Gene" International Journal of Molecular Sciences 22, no. 11: 5886. https://doi.org/10.3390/ijms22115886

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

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