scholarly journals Expanded alleles of the FMR1 gene are related to unexplained recurrent miscarriages

2017 ◽  
Vol 37 (6) ◽  
Author(s):  
Xin-hua Wang ◽  
Xiao-hua Song ◽  
Yan-lin Wang ◽  
Xing-hua Diao ◽  
Tong Li ◽  
...  
Keyword(s):  
Recurrent Miscarriage ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Case Group ◽  
Cgg Repeat ◽  
Recurrent Miscarriages ◽  
Future Studies ◽  
Expanded Allele ◽  
The Impact ◽  
Control Study

Up to 50% of recurrent miscarriage cases in women occur without an underlying etiology. In the current prospective case–control study, we determined the impact of CGG trinucleotide expansions of the fragile-X mental retardation 1 (FMR1) gene in 49 women with unexplained recurrent miscarriages. Case group consisted of women with two or more unexplained consecutive miscarriages. Blood samples were obtained and checked for the presence of expanded alleles of the FMR1 gene using PCR. Patients harboring the expanded allele, with a threshold set to 40 repeats, were further evaluated by sequencing. The number of abortions each woman had, was not associated with her respective CGG repeat number (P=0.255). The repeat sizes of CGG expansion in the FMR1 gene were significantly different in the two population groups (P=0.027). All the positive cases involved intermediate zone carriers. Hence, the CGG expanded allele of the FMR1 gene might be associated with unexplained multiple miscarriages; whether such an association is coincidental or causal can be confirmed by future studies using a larger patient cohort.

P–514 RAN-Translation in Fragile X associated Premature Ovarian Insufficiency (FXPOI): FMRpolyG as a predictive tool

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
X P Nguyen ◽  
B Messmer ◽  
J E Dietrich ◽  
K Hinderhofer ◽  
T Strowitzki ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Fragile X ◽  
Human Lymphocytes ◽  
Predictive Tool ◽  
Ovarian Insufficiency ◽  
Glass Coverslip ◽  
Cgg Repeat ◽  
Fmr1 Premutation ◽  
The Impact ◽  
Ran Translation

Abstract Study question Does repeat-associated non-AUG (RAN) translation lead to accumulation of polyglycine- containing protein (FMRpolyG) in human lymphocytes and mural granulosa cells of FMR1 premutation carriers? Summary answer Lymphocytes and granulosa cells from FMR1 premutation carriers contain intracellular inclusions that stain positive for both FMRpolyG and ubiquitin. What is known already: Fragile-X-associated-Primary-Ovarian-Insufficiency (FXPOI) is characterized by oligo/amenorrhea and hypergonadotropic hypogonadism associated with the expansion of CGG-repeats in the 5’UTR of FMR1, called premutation (PM) (n: 55–200). Approximately 20% of women carrying a FMR1-premutation (PM) allele develop FXPOI. RAN-translation dependent on variable CGG-repeat length is hypothesized to cause FXPOI due to the production of a polyglycine-containing FMR1-protein, FMRpolyG. Recently, FMRpolyG inclusions were found in neuronal brain cells of FXTAS patients and stromal cells of the ovary of an FXPOI patient. Study design, size, duration: Lymphocytes and granulosa cells (GCs) from women with PM (6) and women without PM (10) (controls) were analyzed by immunofluorescence (IF) staining for the presence of inclusions positive for ubiquitin and FMRpolyG. Cell lysis and protein extraction samples were subjected to Fluorescent Western Blot (WB) analysis to detect FMRP and FMRpolyG Participants/materials, setting, methods Human GCs were obtained from follicular fluid after oocyte retrieval and lymphocytes were isolated from peripheral blood using Ficoll-Paque. Cells suspended in PBS were adhered to a glass-coverslip placed at the bottom of the 6-well culture plate, via gravity sedimentation. Adhered cells were fixed, IF staining for FMRpolyG and ubiquitin was performed and analyzed by fluorescence microscopy. Fluorescent WB was used to demonstrate the expression of FMRP, FMRpolyG in extracted protein from lymphocytes and GCs. Main results and the role of chance FMRP was successfully detected by fluorescence WB in both lymphocytes and GCs. FMRP is mainly present in cytoplasm and was expressed in greater amount in GCs than in leukocytes. Moreover, FMRP expression was significantly decreased in GCs from FMR1-PM compared with controls. Lymphocytes from PM-carriers and controls were immunostained for FMRpolyG and ubiquitin. In PM-carriers, FMRpolyG was present as aggregates, whereas in controls only a weak signal without inclusions was detectable. The expression pattern of FMRpolyG in GCs was similar to that in lymphocytes with a significant increase in PM-carriers. There, the FMRpolyG-aggregates additionally demonstrated as ubiquitin-positive inclusions. These may resemble the toxic potential of these protein fractions involved the ovarian damage in developing FXPOI. Limitations, reasons for caution More patients are needed to support the present findings. Further investigation into the possible consequences of these FMRpolyG-positive inclusions in PM-carriers is also advisable. Wider implications of the findings: We found for the first time FMRpolyG-accumulation in lymphocytes and GCs from FMR1-PM-carriers in ubiquitin-positive inclusions. Future experiments evaluating consistency in more patients and elucidating the impact on fertility and prospective value for individual ovarian reserve are therefore in preparation. Trial registration number Not applicable

scholarly journals Secondary Structure and Dynamics of the r(CGG) Repeat in the mRNA of the Fragile X Mental Retardation 1(FMR1)Gene

RNA Biology ◽  
2007 ◽  
Vol 4 (2) ◽  
pp. 93-100 ◽  
Author(s):  
Marta Zumwalt ◽  
Anna Ludwig ◽  
Paul J. Hagerman ◽  
Thorsten Dieckmann
Keyword(s):  
Mental Retardation ◽  
Secondary Structure ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Cgg Repeat ◽  
Fragile X Mental Retardation ◽  
Structure And Dynamics

scholarly journals Clostridium difficileInfection Worsens the Prognosis of Ulcerative Colitis

2014 ◽  
Vol 28 (7) ◽  
pp. 373-380 ◽  
Author(s):  
María E Negrón ◽  
Herman W Barkema ◽  
Kevin Rioux ◽  
Jeroen De Buck ◽  
Sylvia Checkley ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Postoperative Complications ◽  
Population Based ◽  
Infectious Complications ◽  
Future Studies ◽  
Laboratory Services ◽  
Increased Risk ◽  
Health Zone ◽  
The Impact ◽  
Control Study

BACKGROUND: The impact ofClostridium difficileinfections among ulcerative colitis (UC) patients is well characterized. However, there is little knowledge regarding the association betweenC difficileinfections and postoperative complications among UC patients.OBJECTIVE: To determine whetherC difficileinfection is associated with undergoing an emergent colectomy and experiencing postoperative complications.METHODS: The present population-based case-control study identified UC patients admitted to Calgary Health Zone hospitals for a flare between 2000 and 2009.C difficiletoxin tests ordered in hospital or 90 days before hospital admission were provided by Calgary Laboratory Services (Calgary, Alberta). Hospital records were reviewed to confirm diagnoses and to extract clinical data. Multivariate logistic regression analyses were performed among individuals tested forC difficileto examine the association betweenC difficileinfection and emergent colectomy and diagnosis of any postoperative complications and, secondarily, an infectious postoperative complication. Estimates were presented as adjusted ORs with 95% CIs.RESULTS:C difficilewas tested in 278 (58%) UC patients and 6.1% were positive.C difficileinfection was associated with an increased risk for emergent colectomy (adjusted OR 3.39 [95% CI 1.02 to 11.23]). Additionally, a preoperative diagnosis ofC difficilewas significantly associated with the development of postoperative infectious complications (OR 4.76 [95% CI 1.10 to 20.63]).CONCLUSION:C difficilediagnosis worsened the prognosis of UC by increasing the risk of colectomy and postoperative infectious complications following colectomy. Future studies are needed to explore whether early detection and aggressive management ofC difficileinfection will improve UC outcomes.

scholarly journals Enhanced detection of nucleotide repeat mRNA with hybridization chain reaction

2021 ◽  
Author(s):  
Mary Rebecca Glineburg ◽  
Yuan Zhang ◽  
Elizabeth M Tank ◽  
Sami Barmada ◽  
Peter Todd
Keyword(s):  
Fragile X ◽  
Data Interpretation ◽  
Repeat Expansion ◽  
Hybridization Chain Reaction ◽  
Chain Reaction ◽  
Cgg Repeat ◽  
Hexanucleotide Repeat ◽  
Rna Foci ◽  
Repeat Expansions ◽  
The Impact

RNAs derived from expanded nucleotide repeats form detectable foci in patient cells and these foci are thought to contribute to disease pathogenesis. The most widely used method for detecting RNA foci is fluorescence in situ hybridization (FISH). However, FISH is prone to low sensitivity and photo-bleaching that can complicate data interpretation. Here we applied hybridization chain reaction (HCR) as an alternative approach to repeat RNA foci detection of GC-rich repeats in two neurodegenerative disorders: GGGGCC (G4C2) hexanucleotide repeat expansions in C9orf72 that cause amyotrophic lateral sclerosis and frontotemporal dementia (C9 ALS/FTD) and CGG repeat expansions in FMR1 that cause Fragile X-associated tremor/ataxia syndrome. We found that HCR of both G4C2 and CGG repeats has comparable specificity to traditional FISH, but is >40x more sensitive and shows repeat-length dependence in its intensity. HCR is better than FISH at detecting both nuclear and cytoplasmic foci in human C9 ALS/FTD fibroblasts, patient iPSC derived neurons, and patient brain samples. We used HCR to determine the impact of integrated stress response (ISR) activation on RNA foci number and distribution. G4C2 repeat RNA did not readily co-localize with the stress granule marker G3BP1, but ISR induction increased both the number of detectible nuclear RNA foci and the nuclear/cytoplasmic foci ratio in patient fibroblasts and patient derived neurons. Taken together, these data suggest that HCR can be a useful tool for detecting repeat expansion mRNA in C9 ALS/FTD and other repeat expansion disorders.

scholarly journals The impact of individual lifestyle and status on the acquisition of COVID-19: A case—Control study

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0241540
Author(s):  
Chang Gao ◽  
Zhi Zhao ◽  
Fengyuan Li ◽  
Jia-lin Liu ◽  
Hongyang Xu ◽  
...  
Keyword(s):  
Case Control Study ◽  
Case Control ◽  
Physical Activities ◽  
Control Group ◽  
Case Group ◽  
Lifestyle Behaviors ◽  
Lack Of Sleep ◽  
Independent Risk Factors ◽  
The Impact ◽  
Control Study

Background Coronavirus disease 2019 (COVID-19) has spread to the world. Whether there is an association between lifestyle behaviors and the acquisition of COVID-19 remains unclear. Methods In this case-control study, we recruited 105 patients with SARS-CoV-2 infection as a case group from the Wuhan Tongji Hospital (Wuhan, China). For each case two control subjects were recruited. Participants were randomly selected from communities in Wuhan and matched for sex, age (± 2yrs), and pre-existing comorbidities (hypertension and diabetes). Results A total of 105 patients diagnosed with COVID-19 and 210 controls were included. Compared with control group, the case group had higher proportions of lack of sleep (30.5% vs. 14.8%, P = 0.001) and increased physical activities (56.2% vs. 32.9%, P < 0.001). And patients in the case group were more likely to have alopecia (28.6% vs. 10.0%, P < 0.001) than people from the control group. Overall, we found that lack of sleep [adjusted odds ratio (OR) 1.56, 95% confidence interval (CI) 1.03–2.39)], physical activities (≥ 5 times a week) (adjusted OR 2.05, 95%CI 1.39–3.02) and alopecia (adjusted OR 1.73, 95%CI 1.13–2.66) were independent risk factors for COVID-19 infection. Conversely, low-dose alcohol intake (<100g alcohol per week), hand hygiene, and fruits intake (daily) were significantly associated with a decrease in morbidity. Conclusions Individual lifestyle behaviors and health status can affect the occurrence of COVID-19.

scholarly journals Screening for FMR1 CGG Repeat Expansion in Thai Patients with Autism Spectrum Disorder

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Areerat Hnoonual ◽  
Charunee Jankittunpaiboon ◽  
Pornprot Limprasert
Keyword(s):  
Autism Spectrum Disorder ◽  
Fragile X ◽  
Single Gene ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Fmr1 Gene ◽  
Normal Male ◽  
Cgg Repeat ◽  
Cgg Repeats ◽  
Normal Controls

Autism spectrum disorder (ASD) is a complex disorder with a heterogeneous etiology. Fragile X syndrome (FXS) is recognized as the most common single gene mutation associated with ASD. FXS patients show some autistic behaviors and may be difficult to distinguish at a young age from autistic children. However, there have been no published reports on the prevalence of FXS in ASD patients in Thailand. In this study, we present a pilot study to analyze the CGG repeat sizes of the FMR1 gene in Thai autistic patients. We screened 202 unrelated Thai patients (168 males and 34 females) with nonsyndromic ASD and 212 normal controls using standard FXS molecular diagnosis techniques. The distributions of FMR1 CGG repeat sizes in the ASD and normal control groups were similar, with the two most common alleles having 29 and 30 CGG repeats, followed by an allele with 36 CGG repeats. No FMR1 full mutations or premutations were found in either ASD individuals or the normal controls. Interestingly, three ASD male patients with high normal CGG and intermediate CGG repeats (44, 46, and 53 CGG repeats) were identified, indicating that the prevalence of FMR1 intermediate alleles in Thai ASD patients was approximately 1% while these alleles were absent in the normal male controls. Our study indicates that CGG repeat expansions of the FMR1 gene may not be a common genetic cause of nonsyndromic ASD in Thai patients. However, further studies for mutations other than the CGG expansion in the FMR1 gene are required to get a better information on FXS prevalence in Thai ASD patients.

A Novel Polymorphism in the FMR1 Gene: Implications for Clinical Testing of Fragile X Syndrome

2008 ◽  
Vol 132 (1) ◽  
pp. 95-98
Author(s):  
Bharat Thyagarajan ◽  
Matthew Bower ◽  
Michael Berger ◽  
Sidney Jones ◽  
Michelle Dolan ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Southern Blot ◽  
Trinucleotide Repeat ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Chain Reaction ◽  
Cgg Repeat ◽  
Polymerase Chain

Abstract Fragile X syndrome is the most common cause of inherited mental retardation among males. In most cases, the molecular basis of fragile X syndrome is the expansion and subsequent methylation of a CGG trinucleotide repeat in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene. Laboratory diagnosis usually relies on a combination of Southern blot and polymerase chain reaction analyses. In this case report we describe an unusual Southern blot result in a patient who presented with developmental delay and had a normal CGG repeat number by polymerase chain reaction analysis. Further investigation revealed a novel G3310C transversion in the FMR1 gene resulting in a new recognition site for the BssHII restriction enzyme. This novel restriction site could potentially mimic a partial deletion of the FMR1 gene on Southern blot analysis and thus represents a possible pitfall in the diagnosis of fragile X syndrome.

scholarly journals Repeat Instability in the Fragile X-Related Disorders: Lessons from a Mouse Model

2019 ◽  
Vol 9 (3) ◽  
pp. 52 ◽  
Author(s):  
Xiaonan Zhao ◽  
Inbal Gazy ◽  
Bruce Hayward ◽  
Elizabeth Pintado ◽  
Ye Hwang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mouse Models ◽  
Molecular Basis ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Repeat Instability ◽  
Cgg Repeat ◽  
Repeat Tract ◽  
Exon 1 ◽  
Clinical Conditions

The fragile X-related disorders (FXDs) are a group of clinical conditions that result primarily from an unusual mutation, the expansion of a CGG-repeat tract in exon 1 of the FMR1 gene. Mouse models are proving useful for understanding many aspects of disease pathology in these disorders. There is also reason to think that such models may be useful for understanding the molecular basis of the unusual mutation responsible for these disorders. This review will discuss what has been learnt to date about mechanisms of repeat instability from a knock-in FXD mouse model and what the implications of these findings may be for humans carrying expansion-prone FMR1 alleles.

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