Abstract
Fragile X-associated primary ovarian insufficiency (FXPOI) is characterized by oligo/amenorrhea and hypergonadotropic hypogonadism and is caused by the expansion of the CGG repeat in the 5′UTR of Fragile X Mental Retardation 1 (FMR1). Approximately 20% of women carrying an FMR1 premutation (PM) allele (55–200 CGG repeat) develop FXPOI. Repeat Associated Non-AUG (RAN)-translation dependent on the variable CGG-repeat length is thought to cause FXPOI, due to the production of a polyglycine-containing FMR1 protein, FMRpolyG. Peripheral blood monocyte cells (PBMCs) and granulosa cells (GCs) were collected to detect FMRpolyG and its cell type-specific expression in FMR1 PM carriers by immunofluorescence staining (IF), Western blotting (WB), and flow cytometric analysis (FACS). For the first time, FMRpolyG aggregates were detected as ubiquitin-positive inclusions in PBMCs from PM carriers, whereas only a weak signal without inclusions was detected in the controls. The expression pattern of FMRpolyG in GCs was comparable to that in the lymphocytes. We detected FMRpolyG as a 15- to 25-kDa protein in the PBMCs from two FMR1 PM carriers, with 124 and 81 CGG repeats. Flow cytometric analysis revealed that FMRpolyG was significantly higher in the T cells from PM carriers than in those from non-PM carriers. The detection of FMRpolyG aggregates in the peripheral blood and granulosa cells of PM carriers suggests that it may have a toxic potential and an immunological role in ovarian damage in the development of FXPOI.
Highlights
Premature ovarian insufficiency (POI) is a common endocrine reproductive disorder defined as a loss of ovarian activity before the age of 40 [1]
Blood samples and granulosa cells from follicular punctures made during invitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment were obtained from 10 control participants and five Fragile X mental retardation 1 (FMR1) PM carriers who were still men
We found that FMRpolyG expression levels were significantly higher in the FMR1 PM carriers than they were in the group without PM (3.5-7foolfd1,3 p = 0.03, Figure 3A)
Summary
Premature ovarian insufficiency (POI) is a common endocrine reproductive disorder defined as a loss of ovarian activity before the age of 40 [1]. Fragile X-associated primary ovarian insufficiency (FXPOI), one of the most common genetic forms, is caused by the expansion of a CGG repeat in the 5 -untranslated region of the Fragile X mental retardation 1 (FMR1) gene [4]. Women with a PM with approximately 70–100 CGG repeats have the highest risk of FXPOI [6–8]. FXPOI is not observed in women with full mutations, occurring only in PM and, expanded CGG repeats in FMR1 PM have been proposed as a pathogenic mechanism [4]. Several studies support this hypothesis by demonstrating increased FMR1 mRNA levels in carriers of PM [9] and toxicity of the expanded CCG repeats [10–12]
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