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1.
Hum Genet ; 139(2): 227-245, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31919630

RESUMEN

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.


Asunto(s)
Ataxia/patología , Metilación de ADN , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/metabolismo , Síndrome del Cromosoma X Frágil/patología , Mitocondrias/patología , Proteínas Mitocondriales/metabolismo , Mutación , Proteoma/análisis , Temblor/patología , Ataxia/genética , Ataxia/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Fibroblastos/metabolismo , Fibroblastos/patología , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/metabolismo , Humanos , Masculino , Mitocondrias/metabolismo , Proteínas Mitocondriales/genética , ARN Interferente Pequeño/genética , Superóxido Dismutasa/antagonistas & inhibidores , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Temblor/genética , Temblor/metabolismo
2.
PLoS Genet ; 15(10): e1008356, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31593562

RESUMEN

Disrupted circadian rhythms is a prominent and early feature of neurodegenerative diseases including Huntington's disease (HD). In HD patients and animal models, striatal and hypothalamic neurons expressing molecular circadian clocks are targets of mutant Huntingtin (mHtt) pathogenicity. Yet how mHtt disrupts circadian rhythms remains unclear. In a genetic screen for modifiers of mHtt effects on circadian behavior in Drosophila, we discovered a role for the neurodegenerative disease gene Ataxin2 (Atx2). Genetic manipulations of Atx2 modify the impact of mHtt on circadian behavior as well as mHtt aggregation and demonstrate a role for Atx2 in promoting mHtt aggregation as well as mHtt-mediated neuronal dysfunction. RNAi knockdown of the Fragile X mental retardation gene, dfmr1, an Atx2 partner, also partially suppresses mHtt effects and Atx2 effects depend on dfmr1. Atx2 knockdown reduces the cAMP response binding protein A (CrebA) transcript at dawn. CrebA transcript level shows a prominent diurnal regulation in clock neurons. Loss of CrebA also partially suppresses mHtt effects on behavior and cell loss and restoration of CrebA can suppress Atx2 effects. Our results indicate a prominent role of Atx2 in mediating mHtt pathology, specifically via its regulation of CrebA, defining a novel molecular pathway in HD pathogenesis.


Asunto(s)
Ataxina-2/genética , Relojes Circadianos/genética , Proteína de Unión al Elemento de Respuesta al AMP Cíclico/genética , Proteínas de Drosophila/genética , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Animales , Ritmo Circadiano/genética , Modelos Animales de Enfermedad , Drosophila melanogaster/genética , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Humanos , Enfermedad de Huntington/patología , Proteínas Mutantes/genética , Neuronas/metabolismo , Transducción de Señal/genética
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(9): 866-869, 2019 Sep 10.
Artículo en Chino | MEDLINE | ID: mdl-31515777

RESUMEN

OBJECTIVE: To determine the CGG repeat number and methylation status of FMR1 gene for fetuses whose mothers have carried a FMR1 mutation. METHODS: For 30 pregnant women, the fetal CGG repeat number was determined with a GC-rich PCR system by using chorionic villus, amniotic fluid or umbilical blood samples. The methylation status of the FMR1 gene was confirmed with Southern blotting. RESULTS: In total 30 prenatal diagnoses were performed for 29 carriers of FMR1 gene mutations and 1 with FMR1 gene deletion mosaicism. Three fetuses were found to carry premutations, 9 were with full mutations and 1 with mosaicism of premutation and full mutations. Eighteen fetuses were normal. CONCLUSION: Considering the genetic complexity of Fragile X syndrome (FXS), single method may not suffice accurate determination of their genetic status. The pitfalls and technical limitations of protocols requires adoption of personalized strategy for its prenatal diagnosis.


Asunto(s)
Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/diagnóstico , Diagnóstico Prenatal , Femenino , Heterocigoto , Humanos , Mutación , Embarazo
4.
An Acad Bras Cienc ; 91(3): e20180882, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31553368

RESUMEN

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.


Asunto(s)
Trastorno del Espectro Autista/genética , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Mutación/genética , Adolescente , Alelos , Niño , Preescolar , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Masculino , Adulto Joven
5.
Int J Mol Sci ; 20(16)2019 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-31405222

RESUMEN

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.


Asunto(s)
Trastorno Autístico/genética , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , ARN Mensajero/genética , Alelos , Preescolar , Metilación de ADN , Humanos , Masculino , Mosaicismo , Mutación , Hermanos , Regulación hacia Arriba
6.
Pediatrics ; 144(3)2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31439621

RESUMEN

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.


Asunto(s)
Epilepsia Refractaria/genética , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Discapacidad Intelectual/genética , Mutación con Pérdida de Función , Adolescente , Adulto , Encefalopatías/genética , Niño , Preescolar , Femenino , Humanos , Estudios Retrospectivos
7.
Adv Exp Med Biol ; 1155: 155-162, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31468394

RESUMEN

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.


Asunto(s)
Quinasa 5 Dependiente de la Ciclina/metabolismo , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Taurina/farmacología , Testículo/fisiopatología , Animales , Suplementos Dietéticos , Modelos Animales de Enfermedad , Síndrome del Cromosoma X Frágil/fisiopatología , Masculino , Ratones , Ratones Noqueados , Expansión de Repetición de Trinucleótido
8.
Artículo en Ruso | MEDLINE | ID: mdl-31464297

RESUMEN

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.


Asunto(s)
Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil , Síndrome del Cromosoma X Frágil , Mutación , Insuficiencia Ovárica Primaria , Anciano , Ataxia , Niño , Femenino , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/diagnóstico , Síndrome del Cromosoma X Frágil/genética , Humanos , Insuficiencia Ovárica Primaria/diagnóstico , Insuficiencia Ovárica Primaria/genética , Factores de Riesgo , Temblor
9.
Artif Cells Nanomed Biotechnol ; 47(1): 3116-3122, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31352801

RESUMEN

Aim: Reports on the association of the CGG repeat length in the FMR1 gene with the severity of idiopathic POI are inconclusive. Therefore, a meta analysis was performed to investigate the relationship between the expansion of repeat CGG and idiopathic POI risk. Methods: Up to January 2019, 18 case-control or cohort studies involving 3394 idiopathic POI patients and 8461 controls were included for meta analysis. Results: Thirteen studies, including 2047 cases and 6912 controls, met our criteria for the assessment of the premutation and intermediate repeat length in patients with overt POI. Compared with controls, FMR1 gene premutation is significantly associated with overt POI (OR = 8.13; 95% CI: 4.35-15.19; p < .00001), whereas there was no significant correlation between intermediate repeat length and overt POI (OR = 0.86; 95% CI: 0.62-1.18; p = .34). Seven studies, representing 1347 patients and 1948 controls, were eligible for evaluation of the premutation and intermediate repeat length in occult POI. The association between premutation and occult POI was significant (p < .00001), with a pooled fixed effects OR of 11.32 (4.45-28.80), and no significant correlation of intermediate size to occult POI was found in the case-control comparison (OR = 1.00; 95% CI: 0.68-1.47; p = .98). Conclusion: There is a close association between premutation of the FMR1 gene and increased susceptibility to idiopathic POI of each stage and no correlation between intermediate repeat length of the FMR1 gene and the severity of idiopathic POI.


Asunto(s)
Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Insuficiencia Ovárica Primaria/genética , Secuencias Repetitivas de Ácidos Nucleicos/genética , Secuencia de Bases , Femenino , Humanos , Insuficiencia Ovárica Primaria/patología
10.
Nat Genet ; 51(8): 1222-1232, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31332380

RESUMEN

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.


Asunto(s)
Ataxia/genética , Encéfalo/patología , Síndrome del Cromosoma X Frágil/genética , Marcadores Genéticos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Distrofias Musculares/genética , Enfermedades Neurodegenerativas/genética , Temblor/genética , Expansión de Repetición de Trinucleótido/genética , Adulto , Ataxia/patología , Encéfalo/metabolismo , Estudios de Casos y Controles , Femenino , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/patología , Estudio de Asociación del Genoma Completo , Humanos , Cuerpos de Inclusión Intranucleares/genética , Cuerpos de Inclusión Intranucleares/patología , Desequilibrio de Ligamiento , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Masculino , Persona de Mediana Edad , Distrofias Musculares/patología , Mutación , Enfermedades Neurodegenerativas/patología , Neuroimagen/métodos , Linaje , Temblor/patología
11.
J Clin Neurosci ; 66: 269-270, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31178302

RESUMEN

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.


Asunto(s)
Ataxia/diagnóstico , Ataxia/genética , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/diagnóstico , Síndrome del Cromosoma X Frágil/genética , Temblor/diagnóstico , Temblor/genética , Anciano de 80 o más Años , Pruebas Genéticas/métodos , Humanos , Masculino
12.
Exp Brain Res ; 237(9): 2269-2278, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31161414

RESUMEN

Individuals with fragile X mental retardation 1 (FMR1) gene premutations are at increased risk for fragile X-associated tremor/ataxia syndrome (FXTAS) during aging. However, it is unknown whether older FMR1 premutation carriers, with or without FXTAS, exhibit functional motor control deficits compared with healthy individuals. The purpose of this study, therefore, was to determine whether older FMR1 premutation carriers exhibit impaired ability to perform functional motor tasks. Eight FMR1 premutation carriers (age: 58.88 ± 8.36 years) and eight age- and sex-matched healthy individuals (60.13 ± 9.25 years) performed (1) a steady isometric force control task with the index finger at 20% of their maximum voluntary contraction (MVC) and; (2) a single-step task. During the finger abduction task, firing rate of multiple motor units of the first dorsal interosseous (FDI) muscle was recorded. Compared with healthy controls, FMR1 premutation carriers exhibited (1) greater force variability (coefficient of variation of force) during isometric force (1.48 ± 1.02 vs. 0.63 ± 0.37%; P = 0.04); (2) reduced firing rate of multiple motor units during steady force, and; (3) reduced velocity of their weight transfer during stepping (156.62 ± 26.24 vs. 191.86 ± 18.83 cm/s; P = 0.01). These findings suggest that older FMR1 premutation carriers exhibit functional motor control deficits that reflect either subclinical issues associated with premutations independent of FXTAS, or prodromal markers of the development of FXTAS.


Asunto(s)
Ataxia/fisiopatología , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/fisiopatología , Actividad Motora/fisiología , Contracción Muscular/fisiología , Reclutamiento Neurofisiológico/fisiología , Temblor/fisiopatología , Anciano , Fenómenos Biomecánicos , Femenino , Dedos/fisiopatología , Pie/fisiopatología , Heterocigoto , Humanos , Contracción Isométrica/fisiología , Masculino , Persona de Mediana Edad
13.
PLoS Genet ; 15(5): e1008169, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31100062

RESUMEN

The Pol32 protein is one of the universal subunits of DNA polymerase δ (Pol δ), which is responsible for genome replication in eukaryotic cells. Although the role of Pol32 in DNA repair has been well-characterized, its exact function in genome replication remains obscure as studies in single cell systems have not established an essential role for Pol32 in the process. Here we characterize Pol32 in the context of Drosophila melanogaster development. In the rapidly dividing embryonic cells, loss of Pol32 halts genome replication as it specifically disrupts Pol δ localization to the nucleus. This function of Pol32 in facilitating the nuclear import of Pol δ would be similar to that of accessory subunits of DNA polymerases from mammalian Herpes viruses. In post-embryonic cells, loss of Pol32 reveals mitotic fragile sites in the Drosophila genome, a defect more consistent with Pol32's role as a polymerase processivity factor. Interestingly, these fragile sites do not favor repetitive sequences in heterochromatin, with the rDNA locus being a striking exception. Our study uncovers a possibly universal function for DNA polymerase ancillary factors and establishes a powerful system for the study of chromosomal fragile sites in a non-mammalian organism.


Asunto(s)
Sitios Frágiles del Cromosoma/fisiología , ADN Polimerasa III/genética , ADN Polimerasa III/metabolismo , Animales , Sitios Frágiles del Cromosoma/genética , Fragilidad Cromosómica/genética , Fragilidad Cromosómica/fisiología , Reparación del ADN , Replicación del ADN/genética , Replicación del ADN/fisiología , ADN Polimerasa Dirigida por ADN/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Mutagénesis , Señales de Localización Nuclear/metabolismo , Unión Proteica
14.
BMC Med Genet ; 20(1): 81, 2019 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-31096929

RESUMEN

BACKGROUND: The prevalence of CGG repeat expansion mutation in FMR1 gene varies among different populations. In this study, we investigated the prevalence of this mutation in women of reproductive age from northern China. METHODS: A total of 11,891 pre-conceptional or pregnant women, including 5037 pregnant women and 7357 women with the history of spontaneous abortion or induced abortion due to delayed growth of the embryos, were recruited. The number of CGG repeats in FMR1 was measured by the TRP-PCR method. We also offered genetic counseling and prenatal diagnosis to the women carrying pre-mutation or full mutation alleles. RESULTS: The prevalence of pre-mutation in reproductive women in northern China was 1/410, higher than that in southern China and Korea but lower than that in western countries. We also found that the prevalence of pre-mutation was relatively high (1/320) in women with abortion history. CONCLUSION: Screening for CGG repeat expansion mutation in FMR1 should be recommended to the women with the history of spontaneous abortion or induced abortion due to delayed growth of the embryos.


Asunto(s)
Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Mutación , Reproducción , Repeticiones de Trinucleótidos , Adolescente , China , Estudios de Cohortes , Femenino , Humanos , Embarazo , Resultado del Embarazo , Adulto Joven
16.
Mol Autism ; 10: 19, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31011411

RESUMEN

Background: Autism spectrum disorders (ASD) affect around 1.5% of people worldwide. Symptoms start around age 2, when children fail to maintain eye contact and to develop speech and other forms of communication. Disturbances in glutamatergic and GABAergic signaling that lead to synaptic changes and alter the balance between excitation and inhibition in the developing brain are consistently found in ASD. One of the hallmarks of these disorders is hypersensitivity to sensory stimuli; however, little is known about its underlying causes. Since the retina is the part of the CNS that converts light into a neuronal signal, we set out to study how it is affected in adolescent mice prenatally exposed to valproic acid (VPA), a useful tool to study ASD endophenotypes. Methods: Pregnant female mice received VPA (600 mg/kg, ip) or saline at gestational day 11. Their male adolescent pups (P29-35) were behaviorally tested for anxiety and social interaction. Proteins known to be related with ASD were quantified and visualized in their retinas by immunoassays, and retinal function was assessed by full-field scotopic electroretinograms (ERGs). Results: Early adolescent mice prenatally exposed to VPA displayed impaired social interest and increased anxiety-like behaviors consistent with an ASD phenotype. The expression of GABA, GAD, synapsin-1, and FMRP proteins were reduced in their retinas, while mGluR5 was increased. The a-wave amplitudes of VPA-exposed were smaller than those of CTR animals, whereas the b-wave and oscillatory potentials were normal. Conclusions: This study establishes that adolescent male mice of the VPA-induced ASD model have alterations in retinal function and protein expression compatible with those found in several brain areas of other autism models. These results support the view that synaptic disturbances with excitatory/inhibitory imbalance early in life are associated with ASD and point to the retina as a window to understand their subjacent mechanisms.


Asunto(s)
Trastorno del Espectro Autista/fisiopatología , Retina/metabolismo , Potenciales de Acción , Animales , Trastorno del Espectro Autista/etiología , Trastorno del Espectro Autista/metabolismo , Endofenotipos , Femenino , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Receptores de GABA/genética , Receptores de GABA/metabolismo , Receptores de Glutamato/genética , Receptores de Glutamato/metabolismo , Retina/fisiopatología , Conducta Social , Sinapsinas/genética , Sinapsinas/metabolismo , Ácido Valproico/toxicidad
17.
Res Dev Disabil ; 89: 76-82, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30959430

RESUMEN

BACKGROUND: Women who carry an FMR1 premutation (PM) allele and are mothers of children with fragile X syndrome (FXS) experience elevated maternal stress. In-person mindfulness sessions have been shown to be effective in alleviating maternal stress-related outcomes among mothers of children with intellectual and developmental disabilities. Our prior studies indicate women with a PM are at risk of social anxiety, a potential barrier to in-person mindfulness sessions. AIM: The main goals of this pilot study were to assess feasibility and adherence of an app-based mindfulness training program among mothers of children with FXS and to explore stress, social outcomes, and potential barriers to social support. METHODS: Participants (n = 18) completed questionnaires to assess stress and social anxiety, an app-based mindfulness program, and a semi-structured follow-up interview. RESULTS: Thirteen out of 18 (72%) participants completed the mindfulness program; of those, 10 (77%) found it helpful. Eight out of 18 (44%) participants met criteria for social anxiety and 11 (61%) reported having difficulties reaching out for help when needed. Women with social anxiety and those experiencing barriers to social support were more likely to find the program helpful. CONCLUSIONS: This study provides guidance for future mindfulness-based interventions to alleviate maternal stress in mothers of children with FXS.


Asunto(s)
Barreras de Comunicación , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/psicología , Atención Plena/métodos , Aplicaciones Móviles , Madres/psicología , Estrés Psicológico , Adulto , Ansiedad/etiología , Ansiedad/prevención & control , Niño , Estudios de Factibilidad , Femenino , Síndrome del Cromosoma X Frágil/diagnóstico , Síndrome del Cromosoma X Frágil/genética , Educación en Salud/métodos , Humanos , Masculino , Madres/educación , Proyectos Piloto , Apoyo Social , Estrés Psicológico/etiología , Estrés Psicológico/prevención & control , Estrés Psicológico/psicología
18.
Genes (Basel) ; 10(4)2019 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-30959842

RESUMEN

: This study describes monozygotic (MZ) male twins with fragile X syndrome (FXS), mosaic for normal size (NS: <44 CGGs), premutation (PM: 55­199 CGG) and full mutation (FM alleles ≥ 200) alleles, with autism. At 4 years of age chromosomal microarray confirmed monozygosity with both twins showing an XY sex complement. Normal size (30 CGG), PM (99 CGG) and FM (388­1632 CGGs) alleles were detected in Twin 1 (T1) by standard polymerase chain reaction (PCR) and Southern blot testing, while only PM (99 CGG) and FM (672­1025) alleles were identified in Twin 2 (T2). At ~5 years, T2 had greater intellectual impairments with a full scale IQ (FSIQ) of 55 and verbal IQ (VIQ) of 59, compared to FSIQ of 62 and VIQ of 78 for T1. This was consistent with the quantitative FMR1 methylation testing, revealing 10% higher methylation at 80% for T2; suggesting that less active unmethylated alleles were present in T2 as compared to T1. AmplideX methylation PCR also identified partial methylation, including an unmethylated NS allele in T2, undetected by standard testing. In conclusion, this report demonstrates significant differences in intellectual functioning between the MZ twins mosaic for NS, PM and FM alleles with partial FMR1 promoter methylation.


Asunto(s)
Trastorno Autístico/genética , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Discapacidad Intelectual/genética , Alelos , Trastorno Autístico/fisiopatología , Preescolar , Metilación de ADN/genética , Síndrome del Cromosoma X Frágil/fisiopatología , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Análisis por Micromatrices , Mosaicismo , Mutación/genética , Regiones Promotoras Genéticas , Expansión de Repetición de Trinucleótido , Gemelos Monocigóticos/genética
19.
Methods Mol Biol ; 1972: 199-210, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30847793

RESUMEN

Fragile X mental retardation 1 (FMR1) CGG repeat expansions cause fragile X syndrome-the leading monogenic form of intellectual disability-and increase the risk for fragile X-associated tremor ataxia syndrome and fragile X-associated primary ovarian insufficiency. Southern blot (SB) analysis is the current gold standard test for FMR1 molecular diagnosis. Several polymerase chain reaction (PCR)-based methods are now available for sizing FMR1 CGG repeat expansions. These methods offer higher diagnostic sensitivity and specificity compared to SB analysis, significantly reduce the turnaround time and increase throughput. In this chapter, we describe a triplet-repeat primed PCR protocol that employs capillary electrophoresis to resolve the derived amplicon products, enabling precise determination of the FMR1 genotypes in both males and females and characterization of the CGG repeat structure.


Asunto(s)
Cartilla de ADN/metabolismo , Electroforesis Capilar/métodos , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Reacción en Cadena de la Polimerasa/métodos , Expansión de Repetición de Trinucleótido/genética , Repeticiones de Trinucleótidos/genética , Humanos , Mutación/genética
20.
Methods Mol Biol ; 1942: 3-10, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30900171

RESUMEN

Fragile X syndrome (FXS) is one of the most common reasons for intellectual disability (ID). First described in the 1940s, it took many years to understand the disease. The awe-inspiring breakthroughs in both science and technology facilitated the recognition of the unique inheritance pattern and the genetic mechanism of fragile X. In this chapter we describe the history and evolution of our understanding of FXS as mirrored by advances in genetics.


Asunto(s)
Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/diagnóstico , Síndrome del Cromosoma X Frágil/historia , Pruebas Genéticas , Mutación , Síndrome del Cromosoma X Frágil/genética , Historia del Siglo XX , Humanos
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