TY - JOUR
T1 - Characterization of the Metabolic, Clinical and Neuropsychological Phenotype of Female Carriers of the Premutation in the X-Linked FMR1 Gene
AU - Napoli, Eleonora
AU - McLennan, Yingratana Amabel
AU - Schneider, Andrea
AU - Tassone, Flora
AU - Hagerman, Randi J.
AU - Giulivi, Cecilia R
N1 - Funding Information:
We wish to thank all women who provided these samples making this study possible. Funding. This study was funded by the National Institutes of Health (HD036071). Support was also obtained from the MIND Institute Intellectual and Developmental Disabilities Research Center (U54 HD079125) and the Health and Human Administration of Developmental Disabilities grants 90DD0596 and UL1 TR001860.
PY - 2020/10/22
Y1 - 2020/10/22
N2 - The X-linked FMR1 premutation (PM) is characterized by a 55–200 CGG triplet expansion in the 5′-untranslated region (UTR). Carriers of the PM were originally thought to be asymptomatic; however, they may present general neuropsychiatric manifestations including learning disabilities, depression and anxiety, among others. With age, both sexes may also develop the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS). Among carriers, females are at higher risk for developing immune disorders, hypertension, seizures, endocrine disorders and chronic pain, among others. Some female carriers younger than 40 years old may develop fragile X-associated primary ovarian insufficiency (FXPOI). To date, no studies have addressed the metabolic footprint – that includes mitochondrial metabolism – of female carriers and its link to clinical/cognitive manifestations. To this end, we performed a comprehensive biochemical assessment of 42 female carriers (24–70 years old) compared to sex-matched non-carriers. By applying a multivariable correlation matrix, a generalized bioenergetics impairment was correlated with diagnoses of the PM, FXTAS and its severity, FXPOI and anxiety. Intellectual deficits were strongly correlated with both mitochondrial dysfunction and with CGG repeat length. A combined multi-omics approach identified a down-regulation of RNA and mRNA metabolism, translation, carbon and protein metabolism, unfolded protein response, and up-regulation of glycolysis and antioxidant response. The suboptimal activation of the unfolded protein response (UPR) and endoplasmic-reticulum-associated protein degradation (ERAD) response challenges and further compromises the PM genetic background to withstand other, more severe forms of stress. Mechanistically, some of the deficits were linked to an altered protein expression due to decreased protein translation, but others seemed secondary to oxidative stress originated from the accumulation of either toxic mRNA or RAN-derived protein products or as a result of a direct toxicity of accumulated metabolites from deficiencies in critical enzymes.
AB - The X-linked FMR1 premutation (PM) is characterized by a 55–200 CGG triplet expansion in the 5′-untranslated region (UTR). Carriers of the PM were originally thought to be asymptomatic; however, they may present general neuropsychiatric manifestations including learning disabilities, depression and anxiety, among others. With age, both sexes may also develop the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS). Among carriers, females are at higher risk for developing immune disorders, hypertension, seizures, endocrine disorders and chronic pain, among others. Some female carriers younger than 40 years old may develop fragile X-associated primary ovarian insufficiency (FXPOI). To date, no studies have addressed the metabolic footprint – that includes mitochondrial metabolism – of female carriers and its link to clinical/cognitive manifestations. To this end, we performed a comprehensive biochemical assessment of 42 female carriers (24–70 years old) compared to sex-matched non-carriers. By applying a multivariable correlation matrix, a generalized bioenergetics impairment was correlated with diagnoses of the PM, FXTAS and its severity, FXPOI and anxiety. Intellectual deficits were strongly correlated with both mitochondrial dysfunction and with CGG repeat length. A combined multi-omics approach identified a down-regulation of RNA and mRNA metabolism, translation, carbon and protein metabolism, unfolded protein response, and up-regulation of glycolysis and antioxidant response. The suboptimal activation of the unfolded protein response (UPR) and endoplasmic-reticulum-associated protein degradation (ERAD) response challenges and further compromises the PM genetic background to withstand other, more severe forms of stress. Mechanistically, some of the deficits were linked to an altered protein expression due to decreased protein translation, but others seemed secondary to oxidative stress originated from the accumulation of either toxic mRNA or RAN-derived protein products or as a result of a direct toxicity of accumulated metabolites from deficiencies in critical enzymes.
KW - cellular response to stress
KW - fragile X-associated primary ovarian insufficiency
KW - fragile X-associated tremor and ataxia syndrome
KW - glycolysis
KW - mitochondrial dysfunction
KW - omics
KW - oxidative phosphorylation
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U2 - 10.3389/fmolb.2020.578640
DO - 10.3389/fmolb.2020.578640
M3 - Article
AN - SCOPUS:85095683622
VL - 7
JO - Frontiers in Molecular Biosciences
JF - Frontiers in Molecular Biosciences
SN - 2296-889X
M1 - 578640
ER -