Mechanisms of Genome Instability in the Fragile X-Related Disorders

The Fragile X-related disorders (FXDs), which include the intellectual disability fragile X syndrome (FXS), are disorders caused by expansion of a CGG-repeat tract in the 5′ UTR of the X-linked FMR1 gene. These disorders are named for FRAXA, the folate-sensitive fragile site that localizes with the CGG-repeat in individuals with FXS. Two pathological FMR1 allele size classes are distinguished. Premutation (PM) alleles have 54–200 repeats and confer the risk of fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). PM alleles are prone to both somatic and germline expansion, with female PM carriers being at risk of having a child with >200+ repeats. Inheritance of such full mutation (FM) alleles causes FXS. Contractions of PM and FM alleles can also occur. As a result, many carriers are mosaic for different sized alleles, with the clinical presentation depending on the proportions of these alleles in affected tissues. Furthermore, it has become apparent that the chromosomal fragility of FXS individuals reflects an underlying problem that can lead to chromosomal numerical and structural abnormalities. Thus, large numbers of CGG-repeats in the FMR1 gene predisposes individuals to multiple forms of genome instability. This review will discuss our current understanding of these processes.

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Analysis of unstable DNA sequence in FMR1 gene in Polish families with fragile X syndrome.

Acta Biochimica Polonica ◽

10.18388/abp.1996_4508 ◽

1996 ◽

Vol 43 (2) ◽

pp. 383-388

Author(s):

M Milewski ◽

M Zygulska ◽

J Bal ◽

W H Deelen ◽

E Obersztyn ◽

...

Keyword(s):

Fragile X Syndrome ◽

Dna Sequence ◽

Clinical Features ◽

Fragile Site ◽

Fragile X ◽

Fmr1 Gene ◽

Repeat Number ◽

Full Mutation ◽

Cgg Repeats ◽

Large Expansion

The unstable DNA sequence in the FMR1 gene was analyzed in 85 individuals from Polish families with fragile X syndrome in order to characterize mutations responsible for the disease in Poland. In all affected individuals classified on the basis of clinical features and expression of the fragile site at X(q27.3) a large expansion of the unstable sequence (full mutation) was detected. About 5% (2 of 43) of individuals with full mutation did not express the fragile site. Among normal alleles, ranging in size from 20 to 41 CGG repeats, allele with 29 repeats was the most frequent (37%). Transmission of premutated and fully mutated alleles to the offspring was always associated with size increase. No change in repeat number was found when normal alleles were transmitted.

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Early Onset of Fragile X Associated Tremor and Ataxia Syndrome: A Case Report from Iran

Caspian Journal of Neurological Sciences ◽

10.32598/cjns.7.25.8 ◽

2021 ◽

Vol 7 (3) ◽

pp. 180-183

Author(s):

Shahin Koohmanaee ◽

◽

Fatemeh Kharaee ◽

Reza Bayat ◽

Maryam Shahrokhi ◽

...

Keyword(s):

Early Onset ◽

Fragile X ◽

Fmr1 Gene ◽

Case Presentation ◽

Old Adults ◽

Cgg Repeats ◽

Clinical Presentations ◽

Ataxia Syndrome ◽

Magnetic Resonance Imaging Mri ◽

First Time

Background: Different alleles of Fragile X Mental Retardation1 (FMR1) gene with separate molecular etiologies cause Fragile X Syndrome (FXS) and Fragile X-associated Tremor and Ataxia Syndrome (FXTAS). Premutation alleles with 55 to 200 repeats in the FMR1 gene lead to FXTAS. It is carried by 1 in 209 women and 1 in 430 men. FXTAS commonly appears in 50- to 70-year-old adults. Case Presentation: An 11 months old boy was referred to the hospital due to clinical presentations of productive cough seizure, mental disability, and ataxia. Magnetic Resonance Imaging (MRI), Electroencephalography (EEG), hematology, biochemistry, hormone, and genetic tests were done. Triplet repeat PCR (TP PCR) showed 99 CGG repeats as permutation alleles. Conclusion: In this study, the authors reported the early onset of FXTAS in an 11 months old boy for the first time.

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

BioMed Research International ◽

10.1155/2021/4359308 ◽

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.

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Abundancy of polymorphic CGG repeats in the human genome suggest a broad involvement in neurological disease

Scientific Reports ◽

10.1038/s41598-021-82050-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Dale J. Annear ◽

Geert Vandeweyer ◽

Ellen Elinck ◽

Alba Sanchis-Juan ◽

Courtney E. French ◽

...

Keyword(s):

Human Disease ◽

Fragile X ◽

Disease Genes ◽

Cgg Repeat ◽

Neurodevelopmental Disease ◽

Repeat Units ◽

Cgg Repeats ◽

Repeat Expansions ◽

Ataxia Syndrome ◽

Strong Candidate

AbstractExpanded CGG-repeats have been linked to neurodevelopmental and neurodegenerative disorders, including the fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). We hypothesized that as of yet uncharacterised CGG-repeat expansions within the genome contribute to human disease. To catalogue the CGG-repeats, 544 human whole genomes were analyzed. In total, 6101 unique CGG-repeats were detected of which more than 93% were highly variable in repeat length. Repeats with a median size of 12 repeat units or more were always polymorphic but shorter repeats were often polymorphic, suggesting a potential intergenerational instability of the CGG region even for repeats units with a median length of four or less. 410 of the CGG repeats were associated with known neurodevelopmental disease genes or with strong candidate genes. Based on their frequency and genomic location, CGG repeats may thus be a currently overlooked cause of human disease.

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Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome

Biochemical Journal ◽

10.1042/bj20091960 ◽

2010 ◽

Vol 429 (3) ◽

pp. 545-552 ◽

Cited By ~ 104

Author(s):

Catherine Ross-Inta ◽

Alicja Omanska-Klusek ◽

Sarah Wong ◽

Cedrick Barrow ◽

Dolores Garcia-Arocena ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Fragile X ◽

Mitochondrial Protein ◽

Additional Treatment ◽

Cgg Repeat ◽

Cgg Repeats ◽

Nitrative Stress ◽

Ataxia Syndrome

FXTAS (fragile X-associated tremor/ataxia syndrome) is a late-onset neurodegenerative disorder that affects individuals who are carriers of premutation expansions (55–200 CGG repeats) in the 5′ untranslated region of the FMR1 (fragile X mental retardation 1) gene. The role of MD (mitochondrial dysfunction) in FXTAS was evaluated in fibroblasts and brain samples from premutation carriers with and without FXTAS symptoms, with a range of CGG repeats. This study resulted in several important conclusions: (i) decreased NAD- and FAD-linked oxygen uptake rates and uncoupling between electron transport and synthesis of ATP were observed in fibroblasts from premutation carriers; (ii) a lower expression of mitochondrial proteins preceded both in age and in CGG repeats the appearance of overt clinical involvement; (iii) the CGG repeat size required for altered mitochondrial protein expression was also smaller than that required to produce brain intranuclear inclusions from individuals with the premutation who died, suggesting that MD is an incipient pathological process occurring in individuals who do not display overt features of FXTAS; and (iv) on the basis of the CGG repeats, MD preceded the increase in oxidative/nitrative stress damage, indicating that the latter is a late event. MD in carriers of small CGG repeats, even when the allele size is not sufficient to produce FXTAS, may predispose them to other disorders (e.g. Parkinson's disease) that are likely to involve MD, and to environmental stressors, which may trigger the development of FXTAS symptoms. Detection of MD is of critical importance to the management of FXTAS, since it opens up additional treatment options for this disorder.

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Abnormal GABA-mediated and cerebellar inhibition in women with the fragile X premutation

Journal of Neurophysiology ◽

10.1152/jn.00730.2012 ◽

2013 ◽

Vol 109 (5) ◽

pp. 1315-1322 ◽

Cited By ~ 17

Author(s):

Virginia Conde ◽

Francisco J. Palomar ◽

María José Lama ◽

Raquel Martínez ◽

Fátima Carrillo ◽

...

Keyword(s):

Primary Motor Cortex ◽

Fragile X ◽

Intracortical Inhibition ◽

Noninvasive Brain Stimulation ◽

Cgg Repeat ◽

Afferent Inhibition ◽

Fragile X Premutation ◽

Cgg Repeats ◽

Structural Abnormalities ◽

Cerebellar Inhibition

The fragile X syndrome is a mutation-driven developmental disorder caused by a repetition over 200 times of the CGG trinucleotide situated in the 5′-untranslated region of the fragile X mental retardation 1 gene ( FMR1). The interval between 55 and 199 CGG repeats, which is over the normal range but below full mutation, is named fragile X premutation. Recent studies have focused on the asymptomatic state of fragile X premutation carriers and their potentially relevant preclinical features. However, the underlying neurological mechanisms leading to altered functions in fragile X premutation carriers are still poorly understood. In this study, we wanted to test the hypothesis that asymptomatic women who carry the fragile X premutation present GABAergic and cerebellar abnormalities compared with healthy women without the premutation. We performed noninvasive brain stimulation protocols on both asymptomatic fragile X premutation carriers and controls comprising of measures of GABAA- and GABAB-mediated intracortical inhibition, afferent inhibition, and cerebello-motor functional interactions. Premutation carriers presented an absence of cerebellar inhibition over primary motor cortex as well as a reduced GABAA-mediated intracortical and afferent inhibition compared with healthy nonpremutated controls. These alterations are most probably dependent on a dysfunctional GABAergic mechanism associated with the fragile X premutation condition as previously found in CGG-repeat animal models. Furthermore, the lack of cerebello-motor inhibition could be related to the cerebellar structural abnormalities previously found in carriers of the premutation.

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Neuroimaging Insight Into Fragile X-Associated Neuropsychiatric Disorders: Literature Review

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.728952 ◽

2021 ◽

Vol 12 ◽

Author(s):

Andrea Elias-Mas ◽

Maria Isabel Alvarez-Mora ◽

Conxita Caro-Benito ◽

Laia Rodriguez-Revenga

Keyword(s):

Brain Function ◽

Psychiatric Symptoms ◽

Fragile X ◽

Clinical Manifestations ◽

Neuropsychiatric Disorders ◽

Psychiatric Symptomatology ◽

Cgg Repeat ◽

Cgg Repeats ◽

Ataxia Syndrome ◽

Insight Into

FMR1 premutation is defined by 55–200 CGG repeats in the Fragile X Mental Retardation 1 (FMR1) gene. FMR1 premutation carriers are at risk of developing a neurodegenerative disease called fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI) in adulthood. In the last years an increasingly board spectrum of clinical manifestations including psychiatric disorders have been described as occurring at a greater frequency among FMR1 premutation carriers. Herein, we reviewed the neuroimaging findings reported in relation with psychiatric symptomatology in adult FMR1 premutation carriers. A structured electronic literature search was conducted on FMR1 premutation and neuroimaging yielding a total of 3,229 articles examined. Of these, 7 articles were analyzed and are included in this review. The results showed that the main radiological findings among adult FMR1 premutation carriers presenting neuropsychiatric disorders were found on the amygdala and hippocampus, being the functional abnormalities more consistent and the volumetric changes more inconsistent among studies. From a molecular perspective, CGG repeat size, FMR1 mRNA and FMRP levels have been investigated in relation with the neuroimaging findings. Based on the published results, FMRP might play a key role in the pathophysiology of the psychiatric symptoms described among FMR1 premutation carriers. However, additional studies including further probes of brain function and a broader scope of psychiatric symptom measurement are required in order to obtain a comprehensive landscape of the neuropsychiatric phenotype associated with the FMR1 premutation.

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Faculty Opinions recommendation of CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718009175.793482222 ◽

2013 ◽

Author(s):

Richard J Maraia ◽

Nathan Blewett

Keyword(s):

Fragile X ◽

Cgg Repeat ◽

Ataxia Syndrome

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Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

International Journal of Molecular Sciences ◽

10.3390/ijms22168368 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8368

Author(s):

Luis M. Valor ◽

Jorge C. Morales ◽

Irati Hervás-Corpión ◽

Rosario Marín

Keyword(s):

Neurodegenerative Disorder ◽

Late Onset ◽

Fragile X ◽

Endocrine System ◽

Molecular Pathogenesis ◽

Adult Women ◽

Adult Men ◽

Cgg Repeats ◽

Reproductive Impairment ◽

Ataxia Syndrome

Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, lifespan. In particular, the expansions of the CGG-repeats stretch at the 5’-UTR of the Fragile X Mental Retardation 1 (FMR1) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). In this review, we will describe the pathological mechanisms of the adult “gain-of-function” syndromes that are mainly caused by the toxic actions of CGG RNA and FMRpolyG peptide. There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. Mitochondrial dysfunction, altered miRNA expression, endocrine system failure, and impairment of the GABAergic transmission are some of the affectations that are susceptible to be tracked using peripheral blood for monitoring of the motor, cognitive, psychiatric and reproductive impairment of the CGG-expansion carriers. We provided some illustrative examples from our own cohort. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers.

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