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

Endocrinology ◽  
1998 ◽  
Vol 139 (1) ◽  
pp. 156-162 ◽  
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.

scholarly journals ASFMR1splice variant

2018 ◽  
Vol 4 (4) ◽  
pp. e246 ◽  
Author(s):  
Padmaja Vittal ◽  
Shrikant Pandya ◽  
Kevin Sharp ◽  
Elizabeth Berry-Kravis ◽  
Lili Zhou ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Splice Variant ◽  
Messenger Rna ◽  
Clinical Symptoms ◽  
Fragile X ◽  
Cgg Repeat ◽  
Men And Women ◽  
Fragile X Mental Retardation ◽  
Repeat Size ◽  
Ataxia Syndrome

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.

Learning-disabled Males With a Fragile X CGG Expansion in the Upper Premutation Size Range

PEDIATRICS ◽  
1996 ◽  
Vol 97 (1) ◽  
pp. 122-126
Author(s):  
Randi J. Hagerman ◽  
Louise W. Staley ◽  
Rebecca O'Conner ◽  
Kellie Lugenbeel ◽  
David Nelson ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Size Range ◽  
Cpg Island ◽  
Fragile X ◽  
Learning Disabled ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Responsible Gene ◽  
Repeat Segment

There is a broad spectrum of clinical involvement in both boys and girls affected by fragile X syndrome. Although this disorder is best known as the most common inherited cause of mental retardation, it also can manifest as learning disabilities in individuals with IQs in the broad range of normal. Boys are usually retarded, and girls are usually learning disabled with fragile X syndrome.1 The responsible gene, fragile X mental retardation 1 (FMR1), was isolated in 1991, and the mutation was found to involve expansion of a trinucleotide (CGG) repeat segment. Individuals with fragile X syndrome have a CGG expansion of more than 200 repeats associated with hypermethylation of both the expansion and an adjacent CpG island (full mutation).2,3

scholarly journals Alterations of Amino Acids and Monoamine Metabolism in Male Fmr1 Knockout Mice: A Putative Animal Model of the Human Fragile X Mental Retardation Syndrome

2001 ◽  
Vol 8 (4) ◽  
pp. 285-298 ◽  
Author(s):  
Michael Gruss ◽  
Katharina Braun
Keyword(s):  
Amino Acids ◽  
Animal Model ◽  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Knockout Mice ◽  
Fragile X ◽  
Fragile X Mental Retardation ◽  
Behavioral Abnormalities ◽  
Cortical Regions ◽  
Knockout Animals

The Fragile X syndrome, a common form of mental retardation in humans, is caused by silencing the fragile X mental retardation (FMR1) geneleading to the absence of the encoded fragile X mental retardation protein 1 (FMRP). We describe morphological and behavioral abnormalities for both affected humans and Fmr1 knockout mice, a putative animal model for the human Fragile X syndrome. The aim of the present study was to identify possible neurochemical abnormalities in Fmr1 knockout mice, with particular focus on neurotransmission. Significant region-specific differences: of basal neurotransmitter and metabolite levels were found between wildtype and Fmr1 knockout animals, predominantly in juveniles (post-natal days 28 to 31). Adults (postnatal days 209 to 221) showed only few abnormalities as compared with the wildtype. In juvenile knockout mice, aspartate and taurine were especially increased in cortical regions, striatum, hippocampus, cerebellum, and brainstem. In addition, juveniles showed an altered balance between excitatory and inhibitory amino acids in the caudal cortex, hippocampus, and brainstem. We detected very few differences in monoamine turnover in both age stages. The results presented here provide the first evidence that lack of FMRP expression in FMRP knockout mice is accompanied by age-dependent, region-specific alterations in neurotransmission.

scholarly journals BASES GENÉTICAS Y BIOLÓGICAS DEL SÍNDROME DE X FRÁGIL

2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Ruth Maribel Forero Castro ◽  
Edwin Javier Vergara Estupiñán ◽  
Jefer Iván Moreno Granados
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Messenger Rna ◽  
Fragile Site ◽  
Fragile X ◽  
Normal Population ◽  
Incomplete Penetrance ◽  
Racial Groups ◽  
Full Mutation ◽  
Mendelian Segregation

Después del síndrome de Down, el síndrome de X frágil es la causa más frecuente de retardo mental. Su distribución geográfica es universal y afecta a diferentes grupos raciales. Esta anomalía genética presenta un patrón de herencia ligado a X, dominante, con penetrancia incompleta y anticipación, por lo que revela una segregación no-mendeliana. En 1969, Lubs fue el primero en relacionar el retardo mental con la existencia de un sitio frágil, actualmente reconocido en el brazo largo del cromosoma X en la banda Xq27.3 denominada FRAXA. El gen involucrado en el síndrome de X frágil es el FMR 1, el cual fue identificado en 1991 y su defecto fue atribuido a una expansión del trinucleótido repetitivo CGG, localizado en el primer exón del gen. En la población normal, las repeticiones CGG varían<br />entre un rango de 6 a 54, en individuos portadores entre 43 a 200<br />repeticiones (premutación), mientras que en afectados la expansión de la secuencia CGG tiene más de 200 repeticiones (mutación  completa) y está asociada con la metilación e inactivación del gen. El clonaje del gen FMR 1 condujo a la caracterización de su producto de expresión: la proteína FMRP, involucrada en el metabolismo del RNA y en la función ribosomal. Cuando la región promotora está hipermetilada, se frena la producción del ARN mensajero (ARNm) del gen FMR 1 y, por ende, la producción de la proteína, causando retardo mental, macroorquidismo y otros rasgos físicos y comportamentales característicos del síndrome de X frágil. El diagnóstico del síndrome de X frágil se puede hacer a nivel clínico, citogenético, molecular e inmunohistoquímico, implicando el hallazgo de la fragilidad, la determinación de individuos normales, portadores y afectados, el<br />grado de metilación del gen FMR 1 y la expresión de la proteína FMRP. Aunque este síndrome no tiene cura, el tratamiento en la última década ha sido un foco de interés no solo para los genetistas y médicos generales sino también para otros profesionales, tales como pediatras, psicólogos, trabajadores sociales, logopedas y educadores. El presente artículo tiene como objetivo informar sobre las bases genéticas y biológicas del síndrome de X frágil, y la ruta diagnóstica que debe tenerse en cuenta en el seguimiento de los pacientes y familias afectadas.<br /><br /><strong>Palabras clave:</strong> Síndrome de X frágil, FMR 1, FMRP, retardo mental, premutación, mutación completa.<br /><br /><strong>Abstract</strong><br />Following the Down syndrome, Fragile X Syndrome is the most common cause of mental retardation. Its geographical distribution is universal and affects different racial groups. This genetic anomaly shows a pattern of inheritance linked to X, dominant, with incomplete penetrance and anticipation, so it reveals a non-Mendelian segregation. In 1969, Lubs was the first to link mental retardation with the existence of a fragile site, currently recognised by the long arm of the X chromosome in band Xq27.3 called FRAXA. The gene involved in Fragile X Syndrome is the FMR 1, which was identified in 1991 and its defect was attributed to an expansion of repetitive trinucleotide CGG, located in the first exon of the gene. In the normal population, the CGG repetitions vary from a range of 6 to 54, in carriers between 43 to 200 repetitions (Premutation) while in affected individuals the expansion of the sequence CGG has more than 200 repetitions (Full Mutation) and associated with methylation and gene inactivation. The cloning of the FMR 1 gene led to the characterization of its expression product: FMRP protein, involved in RNA metabolism and<br />ribosomal function. When the promoter region is hypermethylated, it<br />reduces the production of messenger RNA (mRNA) of FMR-1 gene<br />and, thus, the production of the protein, causing mental retardation,<br />macroorquidism and other physical and behavioral traits which are characteristic of Fragile X Syndrome. The diagnosis of Fragile X Syndrome can be made at clinical, cytogenetic, molecular and immunohistochemical level, involving the discovery of the fragility, the determination of normal individuals, carriers and affected persons, <br />the degree of methylation of the FMR-1 gene and expression of<br />FMRP protein. Although this syndrome has no cure, treatment in the<br />last decade has been a source of interest not only for geneticists<br />and general practitioners, but also for other professionals, such as<br />paediatricians, psychologists, social workers, speech therapists and<br />educators. This article aims to report on the biological and genetic<br />bases of the Fragile X Syndrome, and the diagnostic route to be<br />taken into account in the follow-up of patients and families affected.<br /><strong>Keywords:</strong> Fragile X Syndrome, FMR 1, FMRP, mental retardation,<br />premutation, full mutation.

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 The Feasibility and Utility of Hair Follicle Sampling To Measure FMRP and FMR1 mRNA in Children With or Without Fragile X Syndrome

2021 ◽  
Author(s):  
Isha Jalnapurkar ◽  
Jean A. Frazier ◽  
Mark Roth ◽  
David M. Cochran ◽  
Ann Foley ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Hair Follicle ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Hair Follicles ◽  
Buccal Swab ◽  
Typically Developing ◽  
Cgg Repeat ◽  
Fragile X Mental Retardation ◽  
Fmr1 Mrna

Abstract Background: Fragile X syndrome (FXS) is the most common cause inherited cause of intellectual disability in males and the most common single gene cause of autism. This X-linked disorder is caused by an expansion of a trinucleotide CGG repeat (>200 base pairs) on the promotor region of the fragile X mental retardation 1 gene (FMR1). This leads to the deficiency or absence of the encoded protein, Fragile X mental retardation protein (FMRP). FMRP has a central role in the translation of mRNAs involved in synaptic connections and plasticity. Recent studies have demonstrated the benefit of therapeutics focused on reactivation of the FMR1 locus towards improving key clinical phenotypes via restoration of FMRP and ultimately disease modification. A key step in future studies directed towards this effort is the establishment of proof of concept (POC) for FMRP reactivation in individuals with FXS. For this it is key to determine the feasibility of repeated collection of tissues or fluids to measure FMR1 and FMRP. Methods: Individuals, ages 3 to 22 years of age, with FXS and those who were typically developing participated in this single-site pilot clinical biomarker study. The repeated collection of hair follicles was compared with the collection of blood and buccal swabs for detection of FMR1 mRNA and FMRP and related molecules. Results: There were n = 15 participants, of whom 10 had a diagnosis of FXS (7.0 ± 3.56 years) and 5 were typically developing (8.2 ± 2.77 years). Absolute levels of FMRP and FMR1 mRNA were substantially higher in healthy participants compared to full mutation and mosaic FXS participants, and lowest in the FXS boys. Measurement of FMR1 and FMRP levels by any method did not show any notable variation by collection location at home versus office across the various sample collection methodologies of hair follicle, blood sample, and buccal swab. Conclusion: Findings demonstrated that repeated sampling of hair follicles in individuals with FXS, in both, home and office settings, is feasible, repeatable, and can be used for measurement of FMR1 and FMRP in longitudinal studies.

scholarly journals Fragile X Syndrome in Mentally Retarded Patients from Latvia

2009 ◽  
Vol 63 (1-2) ◽  
pp. 70-72
Author(s):  
Zanda Daneberga ◽  
Zita Krūmiņa ◽  
Baiba Lāce ◽  
Daiga Bauze ◽  
Natālija Proņina ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Detection Rate ◽  
Fragile X ◽  
Mentally Retarded ◽  
Normal Allele ◽  
Cgg Repeat ◽  
Repeat Structure ◽  
Cgg Repeats ◽  
Intermediate Alleles

Fragile X Syndrome in Mentally Retarded Patients from Latvia The aim of this study was to estimate the prevalence of FXS in Latvia and characterise the FMR1 CGG-repeat structure in Latvian patients exhibiting mental retardation. A group of 352 unrelated patients with mental retardation (MR) referred from clinical geneticists was screened by PCR for the normal allele. In a sample of 245 chromosomes the CGG repeat number was determined by Applied Biosystems protocol on ABI Prism 310. Prevalence of 29, 30, and 31 CGG repeats was found for the normal allele. Five affected patients were detected (detection rate 2.56%). AGG interspersion pattern analysis showed stability of transmission to the next generation for 12 intermediate alleles. The found detection rate of FXS in our survey among MR patients was similar to the detection rate reported in literature. Taking into account the number of confirmed FXS cases we suggest that FXS is still clinically unrecognized in paediatrician practice.

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

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.

scholarly journals Experiences of the Molecular Diagnosis of Fragile X Syndrome in Ecuador

2021 ◽  
Vol 12 ◽  
Author(s):  
Juan Pozo-Palacios ◽  
Arianne Llamos-Paneque ◽  
Christian Rivas ◽  
Emily Onofre ◽  
Andrea López-Cáceres ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Molecular Diagnosis ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Geographical Area ◽  
Cgg Repeat ◽  
Common Cause ◽  
Fragile X Mental Retardation

Fragile X syndrome (FXS) is the most common cause of hereditary intellectual disability and the second most common cause of intellectual disability of genetic etiology. This complex neurodevelopmental disorder is caused by an alteration in the CGG trinucleotide expansion in fragile X mental retardation gene 1 (FMR1) leading to gene silencing and the subsequent loss of its product: fragile X mental retardation protein 1 (FMRP). Molecular diagnosis is based on polymerase chain reaction (PCR) screening followed by Southern blotting (SB) or Triplet primer-PCR (TP-PCR) to determine the number of CGG repeats in the FMR1 gene. We performed, for the first time, screening in 247 Ecuadorian male individuals with clinical criteria to discard FXS. Analysis was carried out by the Genetics Service of the Hospital de Especialidades No. 1 de las Fuerzas Armadas (HE-1), Ecuador. The analysis was performed using endpoint PCR for CGG fragment expansion analysis of the FMR1 gene. Twenty-two affected males were identified as potentially carrying the full mutation in FMR1 and thus diagnosed with FXS that is 8.1% of the sample studied. The average age at diagnosis of the positive cases was 13 years of age, with most cases from the geographical area of Pichincha (63.63%). We confirmed the familial nature of the disease in four cases. The range of CGG variation in the population was 12–43 and followed a modal distribution of 27 repeats. Our results were similar to those reported in the literature; however, since it was not possible to differentiate between premutation and mutation cases, we can only establish a molecular screening approach to identify an expanded CGG repeat, which makes it necessary to generate national strategies to optimize molecular tests and establish proper protocols for the diagnosis, management, and follow-up of patients, families, and communities at risk of presenting FXS.

scholarly journals Fragile X syndrome in Calcutta, India

2001 ◽  
Vol 38 (3) ◽  
pp. 264-271 ◽  
Author(s):  
Sharmila Saha ◽  
Parimal Karmakar ◽  
Chandrahas Chatterjee ◽  
Dalia Banerjee ◽  
Shyamal Das ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Clinical Features ◽  
Untranslated Region ◽  
Fragile X ◽  
Eastern Region ◽  
Ethnic Variation ◽  
Cgg Repeat ◽  
Repeat Size ◽  
Cgg Repeats

Fragile-X-linked mental retardation usually results from amplification of the CGG repeat in the 5' untranslated region of the FMR1 gene. To assess the extent of variation of the CGG repeat in the population from the eastern region of India we studied 98 mentally retarded individuals living in and around Calcutta and identified 21 distinct alleles ranging in size from 8 to 44 CGG repeats. A repeat size of 28 was the most frequent; this value is different from the most frequent repeat size found in other studies, indicating a racial or ethnic variation. Patients with the clinical features of the syndrome have been found to carry expanded CGG repeats. Thus, it can be inferred that the expansion of CGG repeats may be a frequent cause of the syndrome in our population.

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