Abstract
BackgroundFragile X premutation (Amplification of CGG number 55–200) is associated with increased risk for fragile X-Associated Premature Ovarian Insufficiency (FXPOI) in females and fragile X-associated tremor/ataxia syndrome (FXTAS) predominantly in males. Recently, it has been shown that CGG repeats trigger repeat associated non-AUG initiated translation (RAN) of a cryptic polyglycine-containing protein, FMRpolyG. This protein accumulates in ubiquitin-positive inclusions in neuronal brain cells of FXTAS patients and may lead to protein-mediated neurodegeneration. FMRpolyG inclusions were also found in ovary stromal cells of a FXPOI patient. The role of FMRpolyG expression has not been thoroughly examined in folliculogenesis related cells. The main goal of this study is to evaluate whether FMRpolyG accumulates in mural granulosa cells of FMR1 premutation carriers. Following FMRpolyG detection, we aim to examine premutation transfected COV434 as a suitable model used to identify RAN translation functions in FXPOI pathogenesis.ResultsFMRpolyG and ubiquitin immunostained mural granulosa cells from six FMR1 premutation carriers demonstrated FMRpolyG aggregates. However, co-localization of FMRpolyG and ubiquitin appeared to vary within the FMR1 premutation carriers’ group as three exhibited partial ubiquitin and FMRpolyG double staining and three premutation carriers demonstrated FMRpolyG single staining. None of the granulosa cells from the five control women expressed FMRpolyG. Additionally, human ovarian granulosa tumor, COV434, were transfected with two plasmids; both expressing 99CGG repeats but only one enables FMRpolyG expression. Like in granulosa cells from FMR1 premutation carriers, FMRpolyG aggregates were found only in COV434 transfected with expended CGG repeats and the ability to express FMRpolyG.ConclusionsCorresponding with previous studies in FXTAS, we demonstrated accumulation of FMRpolyG in mural granulosa cells of FMR1 premutation carriers. We also suggest that following further investigation, the premutation transfected COV434 might be an appropriate model for RAN translation studies. Detecting FMRpolyG accumulation in folliculogenesis related cells supports previous observations and imply a possible common protein-mediated toxic mechanism for both FXPOI and FXTAS.
Highlights
Fragile X Syndrome (FXS) is the most common form of inherited mental retardation caused by a trinucleotide repeat expansion (CGG) in the 5′-untranslated region of the fragile X mental retardation 1 (FMR1) gene located at Xq27.3
We aimed to examine whether FMRpolyG is expressed in mural granulosa cells from FMR1 premutation carriers and evaluate premutation transfected COV434 as a disease model, to examine FMRpolyG presence and possible role in the pathogenesis of fragile X-Associated Premature Ovarian Insufficiency (FXPOI)
In contrast to the perpetual co-localization of ubiquitinand FMRpolyG-positive inclusions seen in our positive control slides with brain section of fragile X-associated tremor/ataxia syndrome (FXTAS) transgenic mice (Fig. 2.), the intra-cytoplasmic FMRpolyG aggregates in mural granulosa cells were not consistently colocalized with ubiquitin within the individuals
Summary
Fragile X Syndrome (FXS) is the most common form of inherited mental retardation caused by a trinucleotide repeat expansion (CGG) in the 5′-untranslated region of the fragile X mental retardation 1 (FMR1) gene located at Xq27.3. Expansion of the CGG triplet number above the normal range (n > 55) towards the premutation status (n = 55– 200) is associated with increased risk for fragile Xassociated premature ovarian insufficiency (FXPOI) in females [2, 3], and fragile X-associated tremor/ ataxia syndrome (FXTAS). Fragile X premutation (Amplification of CGG number 55–200) is associated with increased risk for fragile X-Associated Premature Ovarian Insufficiency (FXPOI) in females and fragile X-associated tremor/ataxia syndrome (FXTAS) predominantly in males. It has been shown that CGG repeats trigger repeat associated non-AUG initiated translation (RAN) of a cryptic polyglycine-containing protein, FMRpolyG This protein accumulates in ubiquitin-positive inclusions in neuronal brain cells of FXTAS patients and may lead to protein-mediated neurodegeneration. Following FMRpolyG detection, we aim to examine premutation transfected COV434 as a suitable model used to identify RAN translation functions in FXPOI pathogenesis
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