Presence of inclusions positive for polyglycine containing protein, FMRpolyG, indicates that repeat-associated non-AUG translation plays a role in fragile X-associated primary ovarian insufficiency

Buijsen, Ronald A.M.; Visser, Jenny A.; Kramer, P.; Severijnen, E. A W F M; Gearing, Marla; Charlet‐Berguerand, Nicolas; Sherman, Stephanie L.; Berman, Robert F.; Willemsen, Rob; Hukema, Renate K.

doi:10.1093/humrep/dev280

Cited by 90 publications

(76 citation statements)

References 47 publications

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“…In an inducible mouse model of FXTAS that expresses the FMR1 5'UTR with 90 CGG repeats, turning off transgene expression reverses the formation of neuronal FMRpolyG-positive inclusions and repeat-elicited behavioral deficits (Hukema et al ., 2015). Finally, FMRpolyG-positive inclusions have been found in ovarian stromal cells in FXTAS mouse models and a FXPOI patient, suggesting FMRpolyG expression is linked to other Fragile X-related clinical phenotypes (Buijsen et al , 2016). …”

Section: Ran Translation Of Cgg Repeats In Fxtasmentioning

confidence: 96%

RAN translation—What makes it run?

2016

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Nucleotide-repeat expansions underlie a heterogeneous group of neurodegenerative and neuromuscular disorders for which there are currently no effective therapies. Recently, it was discovered that such repetitive RNA motifs can support translation initiation in the absence of an AUG start codon across a wide variety of sequence contexts, and that the products of these atypical translation initiation events contribute to neuronal toxicity. This review examines what we currently know and don’t know about repeat associated non-AUG (RAN) translation in the context of established canonical and non-canonical mechanisms of translation initiation. We highlight recent findings related to RAN translation in three repeat expansion disorders: CGG repeats in fragile X-associated tremor ataxia syndrome (FXTAS), GGGGCC repeats in C9orf72 associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and CAG repeats in Huntington disease. These studies suggest that mechanistic differences may exist for RAN translation dependent on repeat type, repeat reading frame, and the surrounding sequence context, but that for at least some repeats, RAN translation retains a dependence on some of the canonical translational initiation machinery.

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Section: Ran Translation Of Cgg Repeats In Fxtasmentioning

confidence: 96%

RAN translation—What makes it run?

2016

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“…The pathobiology of FXPOI still remains unclear, but a recent study reports detection of FMRpolyG-positive inclusions in the ovarian stromal cells of a subject with FXPOI, suggesting a possible role for RAN translation in FXPOI pathogenesis [48]. …”

Section: Molecular Determinants Of Fxpoimentioning

confidence: 99%

Molecular Correlates and Recent Advancements in the Diagnosis and Screening of FMR1-Related Disorders

Rajan‐Babu

Chong

2016

Genes

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Fragile X syndrome (FXS) is the most common monogenic cause of intellectual disability and autism. Molecular diagnostic testing of FXS and related disorders (fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS)) relies on a combination of polymerase chain reaction (PCR) and Southern blot (SB) for the fragile X mental retardation 1 (FMR1) CGG-repeat expansion and methylation analyses. Recent advancements in PCR-based technologies have enabled the characterization of the complete spectrum of CGG-repeat mutation, with or without methylation assessment, and, as a result, have reduced our reliance on the labor- and time-intensive SB, which is the gold standard FXS diagnostic test. The newer and more robust triplet-primed PCR or TP-PCR assays allow the mapping of AGG interruptions and enable the predictive analysis of the risks of unstable CGG expansion during mother-to-child transmission. In this review, we have summarized the correlation between several molecular elements, including CGG-repeat size, methylation, mosaicism and skewed X-chromosome inactivation, and the extent of clinical involvement in patients with FMR1-related disorders, and reviewed key developments in PCR-based methodologies for the molecular diagnosis of FXS, FXTAS and FXPOI, and large-scale (CGG)n expansion screening in newborns, women of reproductive age and high-risk populations.

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“…It is possible that the FMR1 premutation is associated with a multi-system pathological process, with the same or similar mechanisms occurring in different organ systems. Previous studies identifying intranuclear inclusions across multiple systems are in keeping with this theory [19,20,21,22]. Alternatively, it is possible that the health problems faced by PMCs are mediated by endocrine dysfunction and are not a direct effect of the premutation.…”

Section: Discussionmentioning

confidence: 61%

“…As both the brain and gonads are regions in the body where FMRP is highly expressed (and therefore FMR1 highly transcribed) [10,18], cell toxicity could account for the heightened risk within female PMCs to develop both a neurological and a gonadal condition. Consistent with this, post-mortem studies of PMCs have documented the presence of intranuclear inclusions in non-central nervous system tissues, including, but not limited to, the gonads, thyroid, pituitary, and adrenal glands [19,20,21,22]. Endocrine disorders, such as premature ovarian insufficiency (POI) and thyroid dysfunction, may therefore represent markers of multi-system pathology in female PMCs, similar to the findings for FXTAS.…”

Section: Introductionmentioning

confidence: 57%

Endocrine Dysfunction in Female FMR1 Premutation Carriers: Characteristics and Association with Ill Health

Campbell

Eley

McKechanie

et al. 2016

Genes

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Female FMR1 premutation carriers (PMC) have been suggested to be at greater risk of ill health, in particular endocrine dysfunction, compared to the general population. We set out to review the literature relating to endocrine dysfunction, including premature ovarian insufficiency (POI), in female PMCs, and then to consider whether endocrine dysfunction in itself may be predictive of other illnesses in female PMCs. A systematic review and pilot data from a semi-structured health questionnaire were used. Medline, Embase, and PsycInfo were searched for papers concerning PMCs and endocrine dysfunction. For the pilot study, self-reported diagnoses in females were compared between PMCs with endocrine dysfunction (n = 18), PMCs without endocrine dysfunction (n = 14), and individuals without the premutation (n = 15). Twenty-nine papers were identified in the review; the majority concerned POI and reduced fertility, which are consistently found to be more common in PMCs than controls. There was some evidence that thyroid dysfunction may occur more frequently in subgroups of PMCs and that those with endocrine difficulties have poorer health than those without. In the pilot study, PMCs with endocrine problems reported higher levels of fibromyalgia (p = 0.03), tremor (p = 0.03), headache (p = 0.01) and obsessive–compulsive disorder (p = 0.009) than either comparison group. Further larger scale research is warranted to determine whether female PMCs are at risk of endocrine disorders other than those associated with reproduction and whether endocrine dysfunction identifies a high-risk group for the presence of other health conditions.

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Presence of inclusions positive for polyglycine containing protein, FMRpolyG, indicates that repeat-associated non-AUG translation plays a role in fragile X-associated primary ovarian insufficiency

Abstract: This study was supported by grants from NFXF, ZonMW, the Netherlands Brain Foundation and NIH. The authors have no conflict of interest to declare.

Cited by 90 publications

References 47 publications

RAN translation—What makes it run?

RAN translation—What makes it run?

Molecular Correlates and Recent Advancements in the Diagnosis and Screening of FMR1-Related Disorders

Endocrine Dysfunction in Female FMR1 Premutation Carriers: Characteristics and Association with Ill Health

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