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

Tytuł:: Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked FMR1 Gene.
Autorzy:: Nolin SL; Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Napoli E; Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
Flores A; 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, PR00936 San Juan, Puerto Rico.
Hagerman RJ; Department of Pediatrics, University of California Davis Medical Center, Sacramento, CA 95817, USA.; The MIND Institute, University of California Davis Medical Center, Sacramento, CA 95817, USA.
Giulivi C; Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.; The MIND Institute, University of California Davis Medical Center, Sacramento, CA 95817, USA.
Źródło:: International journal of molecular sciences [Int J Mol Sci] 2021 May 30; Vol. 22 (11). Date of Electronic Publication: 2021 May 30.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Original Publication: Basel, Switzerland : MDPI, [2000-
MeSH Terms:: Mutation*
Autistic Disorder/*genetics
Fragile X Mental Retardation Protein/*genetics
Fragile X Syndrome/*genetics
Mitochondria/*genetics
Serine/*deficiency
5' Untranslated Regions ; Adult ; Amniocentesis ; Amniotic Fluid/chemistry ; Autistic Disorder/diagnosis ; Autistic Disorder/metabolism ; Autistic Disorder/pathology ; Citric Acid Cycle/genetics ; Female ; Fetus ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Fragile X Mental Retardation Protein/metabolism ; Fragile X Syndrome/diagnosis ; Fragile X Syndrome/metabolism ; Fragile X Syndrome/pathology ; Gene Expression ; Genetic Complementation Test ; Heterozygote ; Humans ; Male ; Metabolomics/methods ; Mitochondria/metabolism ; Mitochondria/pathology ; Pregnancy ; Primary Cell Culture ; Proteomics/methods ; Serine/biosynthesis ; Trinucleotide Repeats
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Grant Information:: HD036071 National Institute of Child Health and Human Development
Contributed Indexing:: Keywords: CGG repeats; FMR1; amniotic fluid; metabolomics; premutation; proteomics
Substance Nomenclature:: 0 (5' Untranslated Regions)
0 (FMR1 protein, human)
139135-51-6 (Fragile X Mental Retardation Protein)
452VLY9402 (Serine)
Entry Date(s):: Date Created: 20210602 Date Completed: 20210623 Latest Revision: 20210623
Update Code:: 20240104
PubMed Central ID:: PMC8198117
DOI:: 10.3390/ijms22115886
PMID:: 34070950
: Czasopismo naukowe

Pełny tekst

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.

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