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1.
Hum Genet ; 139(2): 227-245, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31919630

RESUMO

Fragile X-related disorders are due to a dynamic mutation of the CGG repeat at the 5' UTR of the FMR1 gene, coding for the RNA-binding protein FMRP. As the CGG sequence expands from premutation (PM, 56-200 CGGs) to full mutation (> 200 CGGs), FMRP synthesis decreases until it is practically abolished in fragile X syndrome (FXS) patients, mainly due to FMR1 methylation. Cells from rare individuals with no intellectual disability and carriers of an unmethylated full mutation (UFM) produce slightly elevated levels of FMR1-mRNA and relatively low levels of FMRP, like in PM carriers. With the aim of clarifying how UFM cells differ from CTRL and FXS cells, a comparative proteomic approach was undertaken, from which emerged an overexpression of SOD2 in UFM cells, also confirmed in PM but not in FXS. The SOD2-mRNA bound to FMRP in UFM more than in the other cell types. The high SOD2 levels in UFM and PM cells correlated with lower levels of superoxide and reactive oxygen species (ROS), and with morphological anomalies and depolarization of the mitochondrial membrane detected through confocal microscopy. The same effect was observed in CTRL and FXS after treatment with MC2791, causing SOD2 overexpression. These mitochondrial phenotypes reverted after knock-down with siRNA against SOD2-mRNA and FMR1-mRNA in UFM and PM. Overall, these data suggest that in PM and UFM carriers, which have high levels of FMR1 transcription and may develop FXTAS, SOD2 overexpression helps to maintain low levels of both superoxide and ROS with signs of mitochondrial degradation.


Assuntos
Ataxia/patologia , Metilação de DNA , Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/patologia , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Mutação , Proteoma/análise , Tremor/patologia , Ataxia/genética , Ataxia/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Fibroblastos/metabolismo , Fibroblastos/patologia , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Humanos , Masculino , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , RNA Interferente Pequeno/genética , Superóxido Dismutase/antagonistas & inibidores , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Tremor/genética , Tremor/metabolismo
2.
Hum Genet ; 139(4): 499-512, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31980904

RESUMO

CHD8, which encodes Chromodomain helicase DNA-binding protein 8, is one of a few well-established Autism Spectrum Disorder (ASD) genes. Over 60 mutations have been reported in subjects with variable phenotypes, but little is known concerning genotype-phenotype correlations. We have identified four novel de novo mutations in Chinese subjects: two nonsense variants (c.3562C>T/p.Arg1188X, c.2065C>A/p.Glu689X), a splice site variant (c.4818-1G>A) and a missense variant (c.3502T>A/p.Tyr1168Asn). Three of these were identified from a 445-member ASD cohort by ASD gene panel sequencing of the 96 subjects who remained negative after molecular testing for copy number variation, Rett syndrome, FragileX and tuberous sclerosis complex (TSC). The fourth (p.Glu689X) was detected separately by diagnostic trio exome sequencing. We used diagnostic instruments and a comprehensive review of phenotypes, including prenatal and postnatal growth parameters, developmental milestones, and dysmorphic features to compare these four subjects. In addition to autism, they also presented with prenatal onset macrocephaly, intellectual disability, overgrowth during puberty, sleep disorder, and dysmorphic features, including broad forehead with prominent supraorbital ridges, flat nasal bridge, telecanthus and large ears. For further comparison, we compiled a comprehensive list of CHD8 variants from the literature and databases, which revealed constitutive and somatic truncating variants in the HELIC (Helicase-C) domain in ASD and in cancer patients, respectively, but not in the general population. Furthermore, HELIC domain mutations were associated with a severe phenotype defined by a greater number of clinical features, lower verbal IQ, and a prominent, consistent pattern of overgrowth as measured by weight, height and head circumference. Overall, this study adds to the ASD-associated loss-of-function mutations in CHD8 and highlights the clinical importance of the HELIC domain of CHD8.


Assuntos
Transtorno do Espectro Autista/genética , Códon sem Sentido , Proteínas de Ligação a DNA/genética , Síndrome do Cromossomo X Frágil/genética , Transtornos do Desenvolvimento da Linguagem/genética , Mutação de Sentido Incorreto , Fenótipo , Síndrome de Rett/genética , Fatores de Transcrição/genética , Esclerose Tuberosa/genética , Transtorno do Espectro Autista/enzimologia , Criança , Feminino , Síndrome do Cromossomo X Frágil/enzimologia , Humanos , Transtornos do Desenvolvimento da Linguagem/enzimologia , Masculino , Domínios Proteicos , Síndrome de Rett/enzimologia , Esclerose Tuberosa/enzimologia
3.
Gene ; 731: 144359, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31935509

RESUMO

FMRP is an RNA-binding protein, loss of which causes fragile X syndrome (FXS). FMRP has several isoforms resulted from alternative splicing (AS) of fragile X mental retardation 1 (FMR1) gene, but their biological functions are still poorly understood. In the analysis of alternatively spliced FMR1 transcripts in the blood cells from a patient with FXS-like phenotypes (normal CGG repeats and no mutation in coding sequence of FMR1), we identified three novel FMR1 transcripts that include a previously unidentified microexon (46 bp), terming the exon 9a. This microexon exists widely in unaffected individuals, inclusion of which introduces an in-frame termination codon. To address whether these exon 9a-containing transcripts could produce protein by evading nonsense-mediated decay (NMD), Western blot was used to analysis blood cell lysate from unaffected individuals and a 34 kDa protein that consistent in size with the molecular weight of the predicted truncated protein produced from mRNA with this microexon was found. Meanwhile, treatment of peripheral blood mononuclear cells with an inhibitor of NMD (Cycloheximide) did not result in significant increase in exon 9a-containing transcripts. Using confocal immunofluorescence, we found the truncated protein displayed both nuclear and cytoplasmic localization in HEK293T and HeLa cells due to lacking C-terminal domains including KH2, NES, and RGG, while the full-length FMRP protein mainly localized in the cytoplasm. Therefore, we hypothesize that the inclusion of this microexon to generate exon 9a-containing transcripts may regulate the normal functionality of FMRP, and the dysregulation of normal FMRP due to increased exon 9a-containing alternatively spliced transcripts in that patient may be associated with the manifestation of FXS phenotype.


Assuntos
Proteína do X Frágil de Retardo Mental/genética , Proteína do X Frágil de Retardo Mental/metabolismo , Processamento de RNA/fisiologia , Adulto , Processamento Alternativo/fisiologia , Estudos de Casos e Controles , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Éxons/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Síndrome do Cromossomo X Frágil/patologia , Células HEK293 , Células HeLa , Humanos , Masculino , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Distribuição Tecidual
4.
Nat Commun ; 10(1): 4814, 2019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645553

RESUMO

Sensory hypersensitivity is a common and debilitating feature of neurodevelopmental disorders such as Fragile X Syndrome (FXS). How developmental changes in neuronal function culminate in network dysfunction that underlies sensory hypersensitivities is unknown. By systematically studying cellular and synaptic properties of layer 4 neurons combined with cellular and network simulations, we explored how the array of phenotypes in Fmr1-knockout (KO) mice produce circuit pathology during development. We show that many of the cellular and synaptic pathologies in Fmr1-KO mice are antagonistic, mitigating circuit dysfunction, and hence may be compensatory to the primary pathology. Overall, the layer 4 network in the Fmr1-KO exhibits significant alterations in spike output in response to thalamocortical input and distorted sensory encoding. This developmental loss of layer 4 sensory encoding precision would contribute to subsequent developmental alterations in layer 4-to-layer 2/3 connectivity and plasticity observed in Fmr1-KO mice, and circuit dysfunction underlying sensory hypersensitivity.


Assuntos
Síndrome do Cromossomo X Frágil/metabolismo , Neurônios/metabolismo , Córtex Somatossensorial/metabolismo , Sinapses/metabolismo , Potenciais de Ação , Animais , Simulação por Computador , Modelos Animais de Doenças , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Knockout , Técnicas de Patch-Clamp , Fenótipo , Córtex Somatossensorial/citologia
5.
Nat Commun ; 10(1): 4813, 2019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645626

RESUMO

Cellular and circuit hyperexcitability are core features of fragile X syndrome and related autism spectrum disorder models. However, the cellular and synaptic bases of this hyperexcitability have proved elusive. We report in a mouse model of fragile X syndrome, glutamate uncaging onto individual dendritic spines yields stronger single-spine excitation than wild-type, with more silent spines. Furthermore, fewer spines are required to trigger an action potential with near-simultaneous uncaging at multiple spines. This is, in part, from increased dendritic gain due to increased intrinsic excitability, resulting from reduced hyperpolarization-activated currents, and increased NMDA receptor signaling. Using super-resolution microscopy we detect no change in dendritic spine morphology, indicating no structure-function relationship at this age. However, ultrastructural analysis shows a 3-fold increase in multiply-innervated spines, accounting for the increased single-spine glutamate currents. Thus, loss of FMRP causes abnormal synaptogenesis, leading to large numbers of poly-synaptic spines despite normal spine morphology, thus explaining the synaptic perturbations underlying circuit hyperexcitability.


Assuntos
Potenciais de Ação/fisiologia , Espinhas Dendríticas/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Ácido Glutâmico/metabolismo , Sinapses/metabolismo , Animais , Espinhas Dendríticas/ultraestrutura , Modelos Animais de Doenças , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/patologia , Masculino , Camundongos , Camundongos Knockout , Neurogênese , Neurônios/metabolismo , Neurônios/ultraestrutura , Técnicas de Patch-Clamp , Córtex Somatossensorial/citologia , Sinapses/ultraestrutura
6.
An Acad Bras Cienc ; 91(3): e20180882, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31553368

RESUMO

Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by dynamic mutations of a CGG repetition segment in an X chromosome's single gene. It is considered the leading hereditary cause of both Autism Spectrum Disorders and Intellectual Disability. Some authors suggest that all individuals diagnosed with some of these latter conditions to be clinically and molecularly trialled for FXS due to the high levels of comorbidity between both conditions and also due to the variable expressiveness of this syndrome. This study has focused on verifying the presence of FMR1 expanded alleles since there is a lack of information about this kind of mutation in autism patients from the northern region of Brazil. The presence of large alleles for this gene could offer new therapeutic or pharmacological methods for the treatment of these patients. Both the presence and the frequency of CGG expansions were verified in 90 autism males by molecular analysis. Four of them had intermediate alleles and four others presented premutated alleles. Premutation carriers are on the propensity of developing the late onset Fragile X-associated tremor/ataxia syndrome. No full mutation alleles were found. Further studies are necessary to obtain more accurate statistical data about this kind of dynamic mutation.


Assuntos
Transtorno do Espectro Autista/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Mutação/genética , Adolescente , Alelos , Criança , Pré-Escolar , Predisposição Genética para Doença , Testes Genéticos , Humanos , Masculino , Adulto Jovem
7.
Int J Mol Sci ; 20(16)2019 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-31405222

RESUMO

Although fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with ≥200 cytosine-guanine-guanine (CGG) repeats, and a decrease in FMR1 mRNA and its protein (FMRP), incomplete silencing has been associated with more severe autism features in FXS males. This study reports on brothers (B1 and B2), aged 5 and 2 years, with autistic features and language delay, but a higher non-verbal IQ in comparison to typical FXS. CGG sizing using AmplideX PCR only identified premutation (PM: 55-199 CGGs) alleles in blood. Similarly, follow-up in B1 only revealed PM alleles in saliva and skin fibroblasts; whereas, an FM expansion was detected in both saliva and buccal DNA of B2. While Southern blot analysis of blood detected an unmethylated FM, methylation analysis with a more sensitive methodology showed that B1 had partially methylated PM alleles in blood and fibroblasts, which were completely unmethylated in buccal and saliva cells. In contrast, B2 was partially methylated in all tested tissues. Moreover, both brothers had FMR1 mRNA ~5 fold higher values than those of controls, FXS and PM cohorts. In conclusion, the presence of unmethylated FM and/or PM in both brothers may lead to an overexpression of toxic expanded mRNA in some cells, which may contribute to neurodevelopmental problems, including elevated autism features.


Assuntos
Transtorno Autístico/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , RNA Mensageiro/genética , Alelos , Pré-Escolar , Metilação de DNA , Humanos , Masculino , Mosaicismo , Mutação , Irmãos , Regulação para Cima
8.
Artigo em Russo | MEDLINE | ID: mdl-31464297

RESUMO

The objective of this study is to provide a detailed description of clinical characteristics of disorders associated with FMR1 gene, which is located on the long arm of chromosome X. The most frequent FMR1 mutations are related to CGG-repeat expansion in the promoter region: premutation (from 55 to 199), full mutation (more than 200 repeats). The first section of the article is devoted to the fragile X mental retardation syndrome (FX syndrome) caused by FMR1 full mutation. The clinical characteristics of FX syndrome are presented. The second section provides information about specific phenotypes associated with FMR1 premutation that can be observed in maternal relatives (grandmother, mother's siblings, grandfather) of the child. The most frequent symptoms that observed in permutation carriers are mild cognitive impairment, ASD, ADHD in children, fragile X-associated tremor/ataxia syndrome (FXTAS) in older carries, fragile X-associated primary ovarian insufficiency (FXPOI) in women. The last section provides information about screening diagnostic instruments that help to identify the risk of fragile X syndrome. It also presents the key questions to be asked to family members in order to identify the risk of the permutation.


Assuntos
Proteína do X Frágil de Retardo Mental , Síndrome do Cromossomo X Frágil , Mutação , Insuficiência Ovariana Primária , Idoso , Ataxia , Criança , Feminino , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/genética , Humanos , Insuficiência Ovariana Primária/diagnóstico , Insuficiência Ovariana Primária/genética , Fatores de Risco , Tremor
10.
Adv Exp Med Biol ; 1155: 155-162, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468394

RESUMO

Fragile X syndrome is an X-linked dominant disorder and the most common cause of inherited mental retardation. It is caused by trinucleotide repeat expansion in the fragile X mental retardation 1 gene (FMR1) at the Xq27.3. The expansion blocks expression of the gene product, Fragile X Mental Retardation Protein (FMRP). The syndrome includes mild to moderate mental retardation and behavioral manifestations such as tactile defensiveness, gaze avoidance, repetitive motor mannerisms, perseverative (repetitive) speech, hyperarousal and it frequently includes seizures. This behavioral phenotype overlaps significantly with autism spectrum disorder. The knockout mice lack normal Fmr1 protein and show macro-orchidism, learning deficits, and hyperactivity. Consequently, this knockout mouse may serve as a valuable tool in the elucidation of the physiological role of FMR1 and the mechanisms involved in macroorchidism, abnormal behavior, abnormalities comparable to those of human fragile X patients. In this study we evaluated the effects of taurine on the testicular physiology to better understand the cellular mechanisms underlying macro-orchidism. We found that there was a significant decrease in the number of Leydig cells in the testis of fragile X mouse. Furthermore, the expression of somatostatin was drastically decreased and differential expression pattern of CDK5 in fragile X mouse testis. In the control testis, CDK is expressed in primary and secondary spermatids whereas in the Fmr1 ko mice CDK 5 is expressed mainly in spermatogonia. Taurine supplementation led to an increase in CDK5 expression in both controls and Ko mice. CDKs (Cyclin-dependent kinases) are a group of serine/threonine protein kinases activated by binding to a regulatory subunit cyclin. Over 20 functionally diverse proteins involved in cytoskeleton dynamics, cell adhesion, transport, and membrane trafficking act as CDK5 substrates elucidating the molecular mechanisms of CDK5 function. CDK5 phosphorylates a diverse list of substrates, implicating it in the regulation of a range of cellular processes. CDK5 is expressed in Leydig cells, Sertoli cells, spermatogonia and peritubular cells indicating a role in spermatogenesis. In this study we examined the expression levels of CDK5 and how it is affected by taurine supplementation in the testes and found that taurine plays an important role in testicular physiology and corrected some of the pathophysiology observed in the fragile x mouse testis.


Assuntos
Quinase 5 Dependente de Ciclina/metabolismo , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Taurina/farmacologia , Testículo/fisiopatologia , Animais , Suplementos Nutricionais , Modelos Animais de Doenças , Síndrome do Cromossomo X Frágil/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Expansão das Repetições de Trinucleotídeos
11.
Pediatrics ; 144(3)2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31439621

RESUMO

Girls with pathogenic variants in FMR1, the gene responsible for Fragile X syndrome, have received relatively little attention in the literature. The reports of girls with trinucleotide expansions or deletions affecting FMR1 describe variable phenotypes; having normal intelligence and no severe neurologic sequelae is not uncommon. We reviewed epilepsy genetics research databases for girls with FMR1 pathogenic variants and seizures to characterize the spectrum of epilepsy phenotypes. We identified 4 patients, 3 of whom had drug-resistant focal epilepsy. Two had severe developmental and epileptic encephalopathy with late-onset epileptic spasms. Our findings demonstrate that FMR1 loss-of-function variants can result in severe neurologic phenotypes in girls. Similar cases may be missed because clinicians may not always perform Fragile X testing in girls, particularly those with severe neurodevelopmental impairment or late-onset spasms.


Assuntos
Epilepsia Resistente a Medicamentos/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Deficiência Intelectual/genética , Mutação com Perda de Função , Adolescente , Adulto , Encefalopatias/genética , Criança , Pré-Escolar , Feminino , Humanos , Estudos Retrospectivos
12.
J Med Syst ; 43(8): 261, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31267258

RESUMO

There are frequent studies undergoing related to the Fragile X syndrome caused due to the triplet CGG replicates on the X chromosome of Fragile X Mental Retardation 1 (FMR1) gene. Mutations of this chromosome can lead to Fragile X syndrome, rational disability, and other cognitive discrepancies. A novel approach based on Rajan Transform is proposed to analyze the spectral density of codons. The traditional transform like Fourier transform provides imaginary values whereas the Rajan Transform exhibits only the real values. The mutations there in the DNA are successfully distinguished by using the Rajan Transform which is suitable tool for the spectral analysis of DNA sequences. The utilization of the Rajan Transform urges larger profits in terms of minimal false alarm rate and thereby leading to an increase in the accuracy of the spectral analysis.


Assuntos
Códon/genética , Síndrome do Cromossomo X Frágil/genética , Análise de Sequência de DNA , Análise Espectral/métodos , Síndrome de Donohue , Análise de Fourier
13.
PLoS One ; 14(7): e0219924, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31348790

RESUMO

The FMR1 premutation (PM) is relatively common in the general population. Evidence suggests that PM carriers may exhibit subtle differences in specific cognitive and language abilities. This study examined potential mechanisms underlying such differences through the study of gaze and language coordination during a language processing task (rapid automatized naming; RAN) among female carriers of the FMR1 PM. RAN taps a complex set of underlying neuropsychological mechanisms, with breakdowns implicating processing disruptions in fundamental skills that support higher order language and executive functions, making RAN (and analysis of gaze/language coordination during RAN) a potentially powerful paradigm for revealing the phenotypic expression of the FMR1 PM. Forty-eight PM carriers and 56 controls completed RAN on an eye tracker, where they serially named arrays of numbers, letters, colors, and objects. Findings revealed a pattern of inefficient language processing in the PM group, including a greater number of eye fixations (namely, visual regressions) and reduced eye-voice span (i.e., the eyes' lead over the voice) relative to controls. Differences were driven by performance in the latter half of the RAN arrays, when working memory and processing load are the greatest, implicating executive skills. RAN deficits were associated with broader social-communicative difficulties among PM carriers, and with FMR1-related molecular genetic variation (higher CGG repeat length, lower activation ratio, and increased levels of the fragile X mental retardation protein; FMRP). Findings contribute to an understanding of the neurocognitive profile of PM carriers and indicate specific gene-behavior associations that implicate the role of the FMR1 gene in language-related processes.


Assuntos
Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Mutação , Fala , Adulto , Estudos de Casos e Controles , Função Executiva , Movimentos Oculares , Feminino , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/psicologia , Heterozigoto , Humanos , Testes de Linguagem , Pessoa de Meia-Idade , Desempenho Psicomotor , Autorrelato , Expansão das Repetições de Trinucleotídeos
14.
Nat Genet ; 51(8): 1222-1232, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31332380

RESUMO

Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.


Assuntos
Ataxia/genética , Encéfalo/patologia , Síndrome do Cromossomo X Frágil/genética , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Distrofias Musculares/genética , Doenças Neurodegenerativas/genética , Tremor/genética , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Ataxia/patologia , Encéfalo/metabolismo , Estudos de Casos e Controles , Feminino , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/patologia , Estudo de Associação Genômica Ampla , Humanos , Corpos de Inclusão Intranuclear/genética , Corpos de Inclusão Intranuclear/patologia , Desequilíbrio de Ligação , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Masculino , Pessoa de Meia-Idade , Distrofias Musculares/patologia , Mutação , Doenças Neurodegenerativas/patologia , Neuroimagem/métodos , Linhagem , Tremor/patologia
15.
J Clin Neurosci ; 66: 269-270, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31178302

RESUMO

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder associated with dysfunction of movement, memory, and the peripheral nervous system. We report an 82 years old male who presented with tremors and difficulty with balance that started at 65 years of age. His motor examination revealed decreased strength in left lower extremity. Tremors were seen in both the upper limbs at rest that worsened with movement. Bilateral lower extremities showed absent vibration and proprioception sensations, absent reflexes and upgoing toes. Electrodiagnostic studies revealed sensory predominant axonal sensory-motor peripheral polyneuropathy. Brain MRI revealed microvascular ischemic changes. The cervical and lumbar MRI showed diffuse degenerative changes. Genetic test for heritable causes of ataxia revealed a premutation in Fragile X gene (84 CGG repeats), confirming the diagnosis of FXTAS. On further genetic testing three out of his four daughters also tested positive for the FMR1 premutation. In appropriate clinical setting, Fragile X-associated tremor/ataxia syndrome (FXTAS) should be considered in every middle aged/elderly patient who presented with slowly progressive ataxia, tremor and peripheral polyneuropathy without any history of cognitive or neurological disabilities in childhood.


Assuntos
Ataxia/diagnóstico , Ataxia/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/genética , Tremor/diagnóstico , Tremor/genética , Idoso de 80 Anos ou mais , Testes Genéticos/métodos , Humanos , Masculino
16.
PLoS One ; 14(5): e0217275, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31112584

RESUMO

Fragile X syndrome, the most common inherited form of intellectual disability, is caused by the CGG trinucleotide expansion in the 5'-untranslated region of the Fmr1 gene on the X chromosome, which silences the expression of the fragile X mental retardation protein (FMRP). FMRP has been shown to bind to a G-rich region within the PSD-95 mRNA, which encodes for the postsynaptic density protein 95, and together with microRNA-125a to mediate the reversible inhibition of the PSD-95 mRNA translation in neurons. The miR-125a binding site within the PSD-95 mRNA 3'-untranslated region (UTR) is embedded in a G-rich region bound by FMRP, which we have previously demonstrated folds into two parallel G-quadruplex structures. The FMRP regulation of PSD-95 mRNA translation is complex, being mediated by its phosphorylation. While the requirement for FMRP in the regulation of PSD-95 mRNA translation is clearly established, the exact mechanism by which this is achieved is not known. In this study, we have shown that both unphosphorylated FMRP and its phosphomimic FMRP S500D bind to the PSD-95 mRNA G-quadruplexes with high affinity, whereas only FMRP S500D binds to miR-125a. These results point towards a mechanism by which, depending on its phosphorylation status, FMRP acts as a switch that potentially controls the stability of the complex formed by the miR-125a-guided RNA induced silencing complex (RISC) and PSD-95 mRNA.


Assuntos
Proteína 4 Homóloga a Disks-Large/biossíntese , Proteína do X Frágil de Retardo Mental/metabolismo , MicroRNAs/metabolismo , RNA Mensageiro/metabolismo , Substituição de Aminoácidos , Sequência de Bases , Sítios de Ligação/genética , Proteína 4 Homóloga a Disks-Large/genética , Proteína do X Frágil de Retardo Mental/química , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Quadruplex G , Humanos , MicroRNAs/química , MicroRNAs/genética , Modelos Moleculares , Fosforilação , Ligação Proteica , Biossíntese de Proteínas , RNA Mensageiro/química , RNA Mensageiro/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
18.
Mol Biol Rep ; 46(4): 4185-4193, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31098807

RESUMO

Studies of X-linked pedigrees were the first to identify genes implicated in intellectual disability (ID) and autism spectrum disorder (ASD). However, some pedigrees present a huge clinical variability between the affected members. This intrafamilial heterogeneity may be due to cooccurrence of two disorders. In the present study, we describe a multiplex X-linked pedigree in which three siblings have ID, ASD and dysmorphic features but with variable severity. Through Fragile X syndrome test, we identified the full FMR1 mutation in only two males. Whole exome sequencing allowed us to identify a novel hemizygous variant (p.Gln2080_Gln2083del) in MED12 gene in two males. So, the first patient has FXS, the second has both FMR1 and MED12 mutations while the third has only the MED12 variant. MED12 mutations are implicated in several forms of X-linked ID. Family segregation and genotype-phenotype-correlation were in favor of a cooccurrence of two forms of X-linked ID. Our work provides further evidence of the involvement of MED12 in XLID. Moreover, through these results, it is noteworthy to raise awareness that intrafamilial heterogeneity in FXS multiplex families could result from the cooccurrence of multiple clinical entities involving at least two separate genetic loci. This should be taken into consideration for genetic testing and counselling in patients/families with atypical disease symptoms.


Assuntos
Síndrome do Cromossomo X Frágil/genética , Complexo Mediador/genética , Adolescente , Transtorno Autístico/genética , Família , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/metabolismo , Genes Ligados ao Cromossomo X , Estudos de Associação Genética , Variação Genética/genética , Humanos , Deficiência Intelectual/genética , Masculino , Complexo Mediador/metabolismo , Mutação , Linhagem , Fenótipo , Irmãos , Sequenciamento Completo do Exoma
19.
Neurotherapeutics ; 16(2): 248-262, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31098852

RESUMO

Nucleotide repeat disorders encompass more than 30 diseases, most of which show dominant inheritance, such as Huntington's disease, spinocerebellar ataxias, and myotonic dystrophies. Yet others, including Friedreich's ataxia, are recessively inherited. A common feature is the presence of a DNA tandem repeat in the disease-associated gene and the propensity of the repeats to expand in germ and in somatic cells, with ensuing neurological and frequently also neuromuscular defects. Repeat expansion is the most frequent event in these diseases; however, sequence contractions, deletions, and mutations have also been reported. Nucleotide repeat sequences are predisposed to adopt non-B-DNA conformations, such as hairpins, cruciform, and intramolecular triple-helix structures (triplexes), also known as H-DNA. For gain-of-function disorders, oligonucleotides can be used to target either transcripts or duplex DNA and in diseases with recessive inheritance oligonucleotides may be used to alter repressive DNA or RNA conformations. Most current treatment strategies are aimed at altering transcript levels, but therapies directed against DNA are also emerging, and novel strategies targeting DNA, instead of RNA, are described. Different mechanisms using modified oligonucleotides are discussed along with the structural aspects of repeat sequences, which can influence binding modes and efficiencies.


Assuntos
Reparo do DNA , Doenças Neurodegenerativas/tratamento farmacológico , Oligonucleotídeos/uso terapêutico , Sequências de Repetição em Tandem , Atrofia Bulboespinal Ligada ao X/tratamento farmacológico , Atrofia Bulboespinal Ligada ao X/genética , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/genética , Humanos , Doença de Huntington/tratamento farmacológico , Doença de Huntington/genética , Doenças Neurodegenerativas/genética , Conformação de Ácido Nucleico
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