Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked <i>FMR1</i> Gene
Fifty-five to two hundred CGG repeats (called a premutation, or PM) in the 5′-UTR of the <i>FMR1</i> 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...
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| Format: | Article |
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MDPI AG
2021-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/11/5886 |
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| author | Sarah L. Nolin Eleonora Napoli Amanda Flores Randi J. Hagerman Cecilia Giulivi |
| author_facet | Sarah L. Nolin Eleonora Napoli Amanda Flores Randi J. Hagerman Cecilia Giulivi |
| author_sort | Sarah L. Nolin |
| collection | DOAJ |
| description | Fifty-five to two hundred CGG repeats (called a premutation, or PM) in the 5′-UTR of the <i>FMR1</i> 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. |
| first_indexed | 2024-03-10T10:52:04Z |
| format | Article |
| id | doaj.art-ca7ee5557efb4ba0ab8476f2d0e7ca5c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T10:52:04Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ca7ee5557efb4ba0ab8476f2d0e7ca5c2023-11-21T22:09:07ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-012211588610.3390/ijms22115886Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked <i>FMR1</i> GeneSarah L. Nolin0Eleonora Napoli1Amanda Flores2Randi J. Hagerman3Cecilia Giulivi4Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USADepartment of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USADepartment of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USADepartment of Pediatrics, University of California Davis Medical Center, Sacramento, CA 95817, USADepartment of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USAFifty-five to two hundred CGG repeats (called a premutation, or PM) in the 5′-UTR of the <i>FMR1</i> 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.https://www.mdpi.com/1422-0067/22/11/5886amniotic fluidpremutationCGG repeats<i>FMR1</i>metabolomicsproteomics |
| spellingShingle | Sarah L. Nolin Eleonora Napoli Amanda Flores Randi J. Hagerman Cecilia Giulivi Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked <i>FMR1</i> Gene International Journal of Molecular Sciences amniotic fluid premutation CGG repeats <i>FMR1</i> metabolomics proteomics |
| title | Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked <i>FMR1</i> Gene |
| title_full | Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked <i>FMR1</i> Gene |
| title_fullStr | Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked <i>FMR1</i> Gene |
| title_full_unstemmed | Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked <i>FMR1</i> Gene |
| title_short | Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked <i>FMR1</i> Gene |
| title_sort | deficits in prenatal serine biosynthesis underlie the mitochondrial dysfunction associated with the autism linked i fmr1 i gene |
| topic | amniotic fluid premutation CGG repeats <i>FMR1</i> metabolomics proteomics |
| url | https://www.mdpi.com/1422-0067/22/11/5886 |
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