ASFMR1splice variant

ObjectiveTo explore the association of a splice variant of theantisense fragile X mental retardation 1(ASFMR1) gene, loss offragile X mental retardation 1(FMR1) AGG interspersions andFMR1CGG repeat size with manifestation, and severity of clinical symptoms of fragile X-associated tremor/ataxia syndrome (FXTAS).MethodsPremutation carriers (PMCs) with FXTAS, without FXTAS, and normal controls (NCs) had a neurologic evaluation and collection of skin and blood samples. Expression ofASFMR1transcript/splice variant 2 (ASFMR1-TV2), nonsplicedASFMR1, totalASFMR1, andFMR1messenger RNA were quantified and compared using analysis of variance. Least absolute shrinkage and selection operator (LASSO) logistic regression and receiver operating characteristic analyses were performed.ResultsPremutation men and women both with and without FXTAS had higherASFMR1-TV2 levels compared with NC men and women (n = 135,135,p< 0.0001), andASFMR1-TV2 had good discriminating power for FXTAS compared with NCs but not for FXTAS from PMC. After adjusting for age, loss of AGG, larger CGG repeat size (in men), and elevatedASFMR1-TV2 level (in women) were strongly associated with FXTAS compared with NC and PMC (combined).ConclusionsThis study found elevated levels ofASFMR1-TV2and loss of AGG interruptions in both men and women with FXTAS. Future studies will be needed to determine whether these variables can provide useful diagnostic or predictive information.

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Hypermobile Ehlers-Danlos syndrome (hEDS) phenotype in fragile X premutation carriers: case series

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107609 ◽

2021 ◽

pp. jmedgenet-2020-107609

Author(s):

Nattaporn Tassanakijpanich ◽

Forrest McKenzie ◽

Yingratana A McLennan ◽

Elisabeth Makhoul ◽

Flora Tassone ◽

...

Keyword(s):

Mental Retardation ◽

Connective Tissue ◽

Messenger Rna ◽

Fragile X ◽

Case Series ◽

Ehlers Danlos Syndrome ◽

Cgg Repeat ◽

Fragile X Mental Retardation ◽

Fragile X Premutation ◽

Danlos Syndrome

BackgroundWhile an association between full mutation CGG-repeat expansions of the Fragile X Mental Retardation 1 (FMR1) gene and connective tissue problems are clearly described, problems in fragile X premutation carriers (fXPCs) CGG-repeat range (55–200 repeats) of the FMR1 gene may be overlooked.ObjectiveTo report five FMR1 fXPCs cases with the hypermobile Ehlers-Danlos syndrome (hEDS) phenotype.MethodsWe collected medical histories and FMR1 molecular measures from five cases who presented with joint hypermobility and loose connective tissue and met inclusion criteria for hEDS.ResultsFive cases were female and ranged between 16 and 49 years. The range of CGG-repeat allele sizes ranged from 66 to 150 repeats. All had symptoms of hEDS since early childhood. Commonalities in molecular pathogenesis and coexisting conditions between the fXPCs and hEDS are also presented. The premutation can lead to a reduction of fragile X mental retardation protein, which is crucial in maintaining functions of the extracellular matrix-related proteins, particularly matrix metallopeptidase 9 and elastin. Moreover, elevated FMR1 messenger RNA causes sequestration of proteins, which results in RNA toxicity.ConclusionBoth hEDS phenotype and premutation involvement may co-occur because of related commonalities in pathogenesis.

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FMRP Levels in Human Peripheral Blood Leukocytes Correlates with Intellectual Disability

Diagnostics ◽

10.3390/diagnostics11101780 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1780

Author(s):

Mark Roth ◽

Lucienne Ronco ◽

Diego Cadavid ◽

Blythe Durbin-Johnson ◽

Randi J. Hagerman ◽

...

Keyword(s):

Mental Retardation ◽

Intellectual Disability ◽

Peripheral Blood ◽

Fragile X ◽

Repeat Expansion ◽

Repeat Number ◽

Cgg Repeat ◽

Fragile X Mental Retardation ◽

Cgg Repeats ◽

Fmr1 Mrna

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. FXS is an X-linked, neurodevelopmental disorder caused by a CGG trinucleotide repeat expansion in the 5′ untranslated region (UTR) of the Fragile X Mental Retardation gene, FMR1. Greater than 200 CGG repeats results in epigenetic silencing of the gene leading to the deficiency or absence of Fragile X mental retardation protein (FMRP). The loss of FMRP is considered the root cause of FXS. The relationship between neurological function and FMRP expression in peripheral blood mononuclear cells (PBMCs) has not been well established. Assays to detect and measure FMR1 and FMRP have been described; however, none are sufficiently sensitive, precise, or quantitative to properly characterize the relationships between cognitive ability and CGG repeat number, FMR1 mRNA expression, or FMRP expression measured in PBMCs. To address these limitations, two novel immunoassays were developed and optimized, an electro-chemiluminescence immunoassay and a multiparameter flow cytometry assay. Both assays were performed on PMBCs isolated from 27 study participants with FMR1 CGG repeats ranging from normal to full mutation. After correcting for methylation, a significant positive correlation between CGG repeat number and FMR1 mRNA expression levels and a significant negative correlation between FMRP levels and CGG repeat expansion was observed. Importantly, a high positive correlation was observed between intellectual quotient (IQ) and FMRP expression measured in PBMCs.

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Triplet-Repeat Primed PCR and Capillary Electrophoresis for Characterizing the Fragile X Mental Retardation 1 CGG Repeat Hyperexpansions

Methods in Molecular Biology - Clinical Applications of Capillary Electrophoresis ◽

10.1007/978-1-4939-9213-3_14 ◽

2019 ◽

pp. 199-210

Author(s):

Indhu-Shree Rajan-Babu ◽

Samuel S. Chong

Keyword(s):

Capillary Electrophoresis ◽

Mental Retardation ◽

Fragile X ◽

Triplet Repeat ◽

Cgg Repeat ◽

Fragile X Mental Retardation

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Macroorchidism in FMR1 Knockout Mice Is Caused by Increased Sertoli Cell Proliferation during Testicular Development*

Endocrinology ◽

10.1210/endo.139.1.5706 ◽

1998 ◽

Vol 139 (1) ◽

pp. 156-162 ◽

Cited By ~ 49

Author(s):

Karin E. Slegtenhorst-Eegdeman ◽

Dirk G. de Rooij ◽

Miriam Verhoef-Post ◽

Henk J. G. van de Kant ◽

Cathy E. Bakker ◽

...

Keyword(s):

Signal Transduction ◽

Cell Proliferation ◽

Mental Retardation ◽

Fragile X Syndrome ◽

Sertoli Cell ◽

Knockout Mice ◽

Messenger Rna ◽

Fragile X ◽

Fsh Receptor ◽

Cgg Repeat

Abstract The fragile X syndrome is the most frequent hereditary form of mental retardation. This X-linked disorder is, in most cases, caused by an unstable and expanding trinucleotide CGG repeat located in the 5′-untranslated region of the gene involved, the fragile X mental retardation 1 (FMR1) gene. Expansion of the CGG repeat to a length of more than 200 trinucleotides results in silencing of the FMR1 gene promoter and, thus, in an inactive gene. The clinical features of male fragile X patients include mental retardation, autistiform behavior, and characteristic facial features. In addition, macroorchidism is observed. To study the role of Sertoli cell proliferation and FSH signal transduction in the occurrence of macroorchidism in fragile X males, we made use of an animal model for the fragile X syndrome, an Fmr1 knockout mouse. The results indicate that in male Fmr1 knockout mice, the rate of Sertoli cell proliferation is increased from embryonic day 12 to 15 days postnatally. The onset and length of the period of Sertoli cell proliferation were not changed compared with those in the control males. Serum levels of FSH, FSH receptor messenger RNA expression, and short term effects of FSH on Sertoli cell function, as measured by down-regulation of FSH receptor messenger RNA, were not changed. We conclude that macroorchidism in Fmr1 knockout male mice is caused by an increased rate of Sertoli cell proliferation. This increase does not appear to be the result of a major change in FSH signal transduction in Fmr1 knockout mice.

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