Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome / Robert F. BERMAN in Journal of Neurodevelopmental Disorders, 6-1 (December 2014)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 6-1 (December 2014) . - p.25 Titre : Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome Type de document : texte imprimé Auteurs : Robert F. BERMAN, Auteur ; Ronald Am BUIJSEN, Auteur ; Karen USDIN, Auteur ; Elizabeth PINTADO, Auteur ; Frank KOOY, Auteur ; Dalyir PRETTO, Auteur ; Isaac N. PESSAH, Auteur ; Darling L. NELSON, Auteur ; Zachary ZALEWSKI, Auteur ; Nicholas CHARLET-BERGEURAND, Auteur ; Rob WILLEMSEN, Auteur ; Renate K. HUKEMA, Auteur Article en page(s) : p.25 Langues : Anglais (eng) Mots-clés : CGG trinucleotide repeat  Fmr1  Fmrp  Fxtas  Fragile X premutation  Intranuclear inclusions  Mouse models  RNA toxicity Index. décimale : PER Périodiques Résumé : Carriers of the fragile X premutation (FPM) have CGG trinucleotide repeat expansions of between 55 and 200 in the 5'-UTR of FMR1, compared to a CGG repeat length of between 5 and 54 for the general population. Carriers were once thought to be without symptoms, but it is now recognized that they can develop a variety of early neurological symptoms as well as being at risk for developing the late onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Several mouse models have contributed to our understanding of FPM and FXTAS, and findings from studies using these models are summarized here. This review also discusses how this information is improving our understanding of the molecular and cellular abnormalities that contribute to neurobehavioral features seen in some FPM carriers and in patients with FXTAS. Mouse models show much of the pathology seen in FPM carriers and in individuals with FXTAS, including the presence of elevated levels of Fmr1 mRNA, decreased levels of fragile X mental retardation protein, and ubiquitin-positive intranuclear inclusions. Abnormalities in dendritic spine morphology in several brain regions are associated with neurocognitive deficits in spatial and temporal memory processes, impaired motor performance, and altered anxiety. In vitro studies have identified altered dendritic and synaptic architecture associated with abnormal Ca(2+) dynamics and electrical network activity. FPM mice have been particularly useful in understanding the roles of Fmr1 mRNA, fragile X mental retardation protein, and translation of a potentially toxic polyglycine peptide in pathology. Finally, the potential for using these and emerging mouse models for preclinical development of therapies to improve neurological function in FXTAS is considered. En ligne : http://dx.doi.org/10.1186/1866-1955-6-25 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=346 [article] Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome [texte imprimé] / Robert F. BERMAN, Auteur ; Ronald Am BUIJSEN, Auteur ; Karen USDIN, Auteur ; Elizabeth PINTADO, Auteur ; Frank KOOY, Auteur ; Dalyir PRETTO, Auteur ; Isaac N. PESSAH, Auteur ; Darling L. NELSON, Auteur ; Zachary ZALEWSKI, Auteur ; Nicholas CHARLET-BERGEURAND, Auteur ; Rob WILLEMSEN, Auteur ; Renate K. HUKEMA, Auteur . - p.25. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 6-1 (December 2014) . - p.25 Mots-clés : CGG trinucleotide repeat  Fmr1  Fmrp  Fxtas  Fragile X premutation  Intranuclear inclusions  Mouse models  RNA toxicity Index. décimale : PER Périodiques Résumé : Carriers of the fragile X premutation (FPM) have CGG trinucleotide repeat expansions of between 55 and 200 in the 5'-UTR of FMR1, compared to a CGG repeat length of between 5 and 54 for the general population. Carriers were once thought to be without symptoms, but it is now recognized that they can develop a variety of early neurological symptoms as well as being at risk for developing the late onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Several mouse models have contributed to our understanding of FPM and FXTAS, and findings from studies using these models are summarized here. This review also discusses how this information is improving our understanding of the molecular and cellular abnormalities that contribute to neurobehavioral features seen in some FPM carriers and in patients with FXTAS. Mouse models show much of the pathology seen in FPM carriers and in individuals with FXTAS, including the presence of elevated levels of Fmr1 mRNA, decreased levels of fragile X mental retardation protein, and ubiquitin-positive intranuclear inclusions. Abnormalities in dendritic spine morphology in several brain regions are associated with neurocognitive deficits in spatial and temporal memory processes, impaired motor performance, and altered anxiety. In vitro studies have identified altered dendritic and synaptic architecture associated with abnormal Ca(2+) dynamics and electrical network activity. FPM mice have been particularly useful in understanding the roles of Fmr1 mRNA, fragile X mental retardation protein, and translation of a potentially toxic polyglycine peptide in pathology. Finally, the potential for using these and emerging mouse models for preclinical development of therapies to improve neurological function in FXTAS is considered. En ligne : http://dx.doi.org/10.1186/1866-1955-6-25 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=346

Synaptic vesicle dynamic changes in a model of fragile X / Jantine A.C. BROEK in Molecular Autism, 7 (2016)  

Public ISBD [article]  inMolecular Autism > 7 (2016) . - 17p. Titre : Synaptic vesicle dynamic changes in a model of fragile X Type de document : texte imprimé Auteurs : Jantine A.C. BROEK, Auteur ; Zhanmin LIN, Auteur ; H. Martijn DE GRUITER, Auteur ; Heleen VAN 'T SPIJKER, Auteur ; Elize D. HAASDIJK, Auteur ; David J. COX, Auteur ; Sureyya OZCAN, Auteur ; Gert W.A. VAN CAPPELLEN, Auteur ; Adriaan B. HOUTSMULLER, Auteur ; Rob WILLEMSEN, Auteur ; Chris I. DE ZEEUW, Auteur ; Sabine BAHN, Auteur Article en page(s) : 17p. Langues : Anglais (eng) Mots-clés : Animals  Animals, Congenic  Cells, Cultured  Cerebellum/pathology/physiopathology  Fluorescent Dyes  Fragile X Mental Retardation Protein/genetics/physiology  Fragile X Syndrome/genetics/metabolism/physiopathology  Hippocampus/pathology/physiopathology  Intravital Microscopy  Male  Mass Spectrometry/methods  Mice  Mice, Inbred C57BL  Mice, Knockout  Mice, Neurologic Mutants  Microscopy, Electron  Models, Animal  Nerve Tissue Proteins/analysis  Presynaptic Terminals/secretion  Proteome  Purkinje Cells/physiology/ultrastructure  Pyridinium Compounds  Quaternary Ammonium Compounds  Signal Transduction  Synaptic Transmission  Synaptic Vesicles/metabolism  Synaptosomes/metabolism  Electron microscopy  Fragile X syndrome (FXS)  Mass spectrometry (MS)  Quantitative live-cell imaging Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS) is a single-gene disorder that is the most common heritable cause of intellectual disability and the most frequent monogenic cause of autism spectrum disorders (ASD). FXS is caused by an expansion of trinucleotide repeats in the promoter region of the fragile X mental retardation gene (Fmr1). This leads to a lack of fragile X mental retardation protein (FMRP), which regulates translation of a wide range of messenger RNAs (mRNAs). The extent of expression level alterations of synaptic proteins affected by FMRP loss and their consequences on synaptic dynamics in FXS has not been fully investigated. METHODS: Here, we used an Fmr1 knockout (KO) mouse model to investigate the molecular mechanisms underlying FXS by monitoring protein expression changes using shotgun label-free liquid-chromatography mass spectrometry (LC-MS(E)) in brain tissue and synaptosome fractions. FXS-associated candidate proteins were validated using selected reaction monitoring (SRM) in synaptosome fractions for targeted protein quantification. Furthermore, functional alterations in synaptic release and dynamics were evaluated using live-cell imaging, and interpretation of synaptic dynamics differences was investigated using electron microscopy. RESULTS: Key findings relate to altered levels of proteins involved in GABA-signalling, especially in the cerebellum. Further exploration using microscopy studies found reduced synaptic vesicle unloading of hippocampal neurons and increased vesicle unloading in cerebellar neurons, which suggests a general decrease of synaptic transmission. CONCLUSIONS: Our findings suggest that FMRP is a regulator of synaptic vesicle dynamics, which supports the role of FMRP in presynaptic functions. Taken together, these studies provide novel insights into the molecular changes associated with FXS. En ligne : http://dx.doi.org/10.1186/s13229-016-0080-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328 [article] Synaptic vesicle dynamic changes in a model of fragile X [texte imprimé] / Jantine A.C. BROEK, Auteur ; Zhanmin LIN, Auteur ; H. Martijn DE GRUITER, Auteur ; Heleen VAN 'T SPIJKER, Auteur ; Elize D. HAASDIJK, Auteur ; David J. COX, Auteur ; Sureyya OZCAN, Auteur ; Gert W.A. VAN CAPPELLEN, Auteur ; Adriaan B. HOUTSMULLER, Auteur ; Rob WILLEMSEN, Auteur ; Chris I. DE ZEEUW, Auteur ; Sabine BAHN, Auteur . - 17p. Langues : Anglais (eng) in Molecular Autism > 7 (2016) . - 17p. Mots-clés : Animals  Animals, Congenic  Cells, Cultured  Cerebellum/pathology/physiopathology  Fluorescent Dyes  Fragile X Mental Retardation Protein/genetics/physiology  Fragile X Syndrome/genetics/metabolism/physiopathology  Hippocampus/pathology/physiopathology  Intravital Microscopy  Male  Mass Spectrometry/methods  Mice  Mice, Inbred C57BL  Mice, Knockout  Mice, Neurologic Mutants  Microscopy, Electron  Models, Animal  Nerve Tissue Proteins/analysis  Presynaptic Terminals/secretion  Proteome  Purkinje Cells/physiology/ultrastructure  Pyridinium Compounds  Quaternary Ammonium Compounds  Signal Transduction  Synaptic Transmission  Synaptic Vesicles/metabolism  Synaptosomes/metabolism  Electron microscopy  Fragile X syndrome (FXS)  Mass spectrometry (MS)  Quantitative live-cell imaging Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS) is a single-gene disorder that is the most common heritable cause of intellectual disability and the most frequent monogenic cause of autism spectrum disorders (ASD). FXS is caused by an expansion of trinucleotide repeats in the promoter region of the fragile X mental retardation gene (Fmr1). This leads to a lack of fragile X mental retardation protein (FMRP), which regulates translation of a wide range of messenger RNAs (mRNAs). The extent of expression level alterations of synaptic proteins affected by FMRP loss and their consequences on synaptic dynamics in FXS has not been fully investigated. METHODS: Here, we used an Fmr1 knockout (KO) mouse model to investigate the molecular mechanisms underlying FXS by monitoring protein expression changes using shotgun label-free liquid-chromatography mass spectrometry (LC-MS(E)) in brain tissue and synaptosome fractions. FXS-associated candidate proteins were validated using selected reaction monitoring (SRM) in synaptosome fractions for targeted protein quantification. Furthermore, functional alterations in synaptic release and dynamics were evaluated using live-cell imaging, and interpretation of synaptic dynamics differences was investigated using electron microscopy. RESULTS: Key findings relate to altered levels of proteins involved in GABA-signalling, especially in the cerebellum. Further exploration using microscopy studies found reduced synaptic vesicle unloading of hippocampal neurons and increased vesicle unloading in cerebellar neurons, which suggests a general decrease of synaptic transmission. CONCLUSIONS: Our findings suggest that FMRP is a regulator of synaptic vesicle dynamics, which supports the role of FMRP in presynaptic functions. Taken together, these studies provide novel insights into the molecular changes associated with FXS. En ligne : http://dx.doi.org/10.1186/s13229-016-0080-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328

Transcriptomic profiling of unmethylated full mutation carriers implicates TET3 in FMR1 CGG repeat expansion methylation dynamics in fragile X syndrome / Grace FARMILOE in Journal of Neurodevelopmental Disorders, 17 (2025)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 17 (2025) Titre : Transcriptomic profiling of unmethylated full mutation carriers implicates TET3 in FMR1 CGG repeat expansion methylation dynamics in fragile X syndrome Type de document : texte imprimé Auteurs : Grace FARMILOE, Auteur ; Veronika BEJCZY, Auteur ; Elisabetta TABOLACCI, Auteur ; Rob WILLEMSEN, Auteur ; Frank JACOBS, Auteur Langues : Anglais (eng) Mots-clés : Fragile X Mental Retardation Protein/genetics  Fragile X Syndrome/genetics/metabolism  Humans  DNA Methylation/genetics  Trinucleotide Repeat Expansion/genetics  Male  Gene Expression Profiling  Fibroblasts/metabolism  Female  Heterozygote  Mutation  Promoter Regions, Genetic  Adult Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the expansion of a CGG repeat in the 5'UTR of the FMR1 (fragile X messenger ribonucleoprotein 1) gene. Healthy individuals possess a repeat 30-55 CGG units in length. Once the CGG repeat exceeds 200 copies it triggers methylation at the locus. This methylation covers the FMR1 promoter region and silences expression of the gene and the production of FMRP (fragile X messenger ribonucleoprotein). The loss of FMRP is responsible for a number of pathologies including neurodevelopmental delay and autism spectrum disorder. Methylation of the expanded repeat in the FMR1 locus is the causal factor for FXS, however it is not known why the expanded repeat triggers this epigenetic change or how exactly DNA methylation is established. Intriguingly, genetic engineering of expanded CGG repeats of over 300 copies in the FMR1 locus in mice remains unmethylated. Also in humans, in very rare cases, individuals can have an FMR1 CGG expansion > 200 copies but the locus remains unmethylated. These unmethylated full mutation (UFM) individuals give us a rare opportunity to investigate the mechanism of FMR1 promoter methylation. METHODS: Fibroblasts were obtained from a healthy control, an FXS patient and two unmethylated full expansion carriers. RNA was extracted and comparative transcriptomic analysis was performed on all samples. Whole genome sequencing was carried out on DNA from the two UFM carriers and the results analysed to investigate DNA variants that could explain the observed differences in gene expression. RESULTS: Our analyses focused on genes involved in epigenetic modification. We show that Tet methylcytosine dioxygenase 3 (TET3), a gene involved in DNA methylation, is significantly downregulated in UFM carriers compared to healthy controls or FXS patient derived cells. Genomic analyses reveal a number of rare variants present in the TET3 locus in UFM carriers when compared to the reference genome. However, no clear modifying TET3 variants were identified. CONCLUSION: Our results suggest that TET3 is a candidate factor responsible for the lack of methylation of the expanded FMR1 locus. Further analyses are needed to further elucidate this relationship, however given its potential to directly interact with CGG repeats and its ambiguous role in 5-hydroxy-methylation of CG containing sequences, TET3 is a strong candidate for further exploration. En ligne : https://dx.doi.org/10.1186/s11689-025-09609-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] Transcriptomic profiling of unmethylated full mutation carriers implicates TET3 in FMR1 CGG repeat expansion methylation dynamics in fragile X syndrome [texte imprimé] / Grace FARMILOE, Auteur ; Veronika BEJCZY, Auteur ; Elisabetta TABOLACCI, Auteur ; Rob WILLEMSEN, Auteur ; Frank JACOBS, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 17 (2025) Mots-clés : Fragile X Mental Retardation Protein/genetics  Fragile X Syndrome/genetics/metabolism  Humans  DNA Methylation/genetics  Trinucleotide Repeat Expansion/genetics  Male  Gene Expression Profiling  Fibroblasts/metabolism  Female  Heterozygote  Mutation  Promoter Regions, Genetic  Adult Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the expansion of a CGG repeat in the 5'UTR of the FMR1 (fragile X messenger ribonucleoprotein 1) gene. Healthy individuals possess a repeat 30-55 CGG units in length. Once the CGG repeat exceeds 200 copies it triggers methylation at the locus. This methylation covers the FMR1 promoter region and silences expression of the gene and the production of FMRP (fragile X messenger ribonucleoprotein). The loss of FMRP is responsible for a number of pathologies including neurodevelopmental delay and autism spectrum disorder. Methylation of the expanded repeat in the FMR1 locus is the causal factor for FXS, however it is not known why the expanded repeat triggers this epigenetic change or how exactly DNA methylation is established. Intriguingly, genetic engineering of expanded CGG repeats of over 300 copies in the FMR1 locus in mice remains unmethylated. Also in humans, in very rare cases, individuals can have an FMR1 CGG expansion > 200 copies but the locus remains unmethylated. These unmethylated full mutation (UFM) individuals give us a rare opportunity to investigate the mechanism of FMR1 promoter methylation. METHODS: Fibroblasts were obtained from a healthy control, an FXS patient and two unmethylated full expansion carriers. RNA was extracted and comparative transcriptomic analysis was performed on all samples. Whole genome sequencing was carried out on DNA from the two UFM carriers and the results analysed to investigate DNA variants that could explain the observed differences in gene expression. RESULTS: Our analyses focused on genes involved in epigenetic modification. We show that Tet methylcytosine dioxygenase 3 (TET3), a gene involved in DNA methylation, is significantly downregulated in UFM carriers compared to healthy controls or FXS patient derived cells. Genomic analyses reveal a number of rare variants present in the TET3 locus in UFM carriers when compared to the reference genome. However, no clear modifying TET3 variants were identified. CONCLUSION: Our results suggest that TET3 is a candidate factor responsible for the lack of methylation of the expanded FMR1 locus. Further analyses are needed to further elucidate this relationship, however given its potential to directly interact with CGG repeats and its ambiguous role in 5-hydroxy-methylation of CG containing sequences, TET3 is a strong candidate for further exploration. En ligne : https://dx.doi.org/10.1186/s11689-025-09609-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI) / Stephanie L. SHERMAN in Journal of Neurodevelopmental Disorders, 6-1 (December 2014)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 6-1 (December 2014) . - p.26 Titre : Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI) Type de document : texte imprimé Auteurs : Stephanie L. SHERMAN, Auteur ; Eliza C. CURNOW, Auteur ; Charles A. EASLEY, Auteur ; Peng JIN, Auteur ; Renate K. HUKEMA, Auteur ; Maria Isabel TEJADA, Auteur ; Rob WILLEMSEN, Auteur ; Karen USDIN, Auteur Article en page(s) : p.26 Langues : Anglais (eng) Mots-clés : CGG repeat  Fertility  Fragile X syndrome  Premature ovarian failure  Primary ovarian insufficiency  Repeat expansion disorder Index. décimale : PER Périodiques Résumé : Fragile X-associated primary ovarian insufficiency (FXPOI) is among the family of disorders caused by the expansion of a CGG repeat sequence in the 5' untranslated region of the X-linked gene FMR1. About 20% of women who carry the premutation allele (55 to 200 unmethylated CGG repeats) develop hypergonadotropic hypogonadism and cease menstruating before age 40. Some proportion of those who are still cycling show hormonal profiles indicative of ovarian dysfunction. FXPOI leads to subfertility and an increased risk of medical conditions associated with early estrogen deficiency. Little progress has been made in understanding the etiology of this clinically significant disorder. Understanding the molecular mechanisms of FXPOI requires a detailed knowledge of ovarian FMR1 mRNA and FMRP's function. In humans, non-invasive methods to discriminate the mechanisms of the premutation on ovarian function are not available, thus necessitating the development of model systems. Vertebrate (mouse and rat) and invertebrate (Drosophila melanogaster) animal studies for the FMR1 premutation and ovarian function exist and have been instrumental in advancing our understanding of the disease phenotype. For example, rodent models have shown that FMRP is highly expressed in oocytes where it is important for folliculogenesis. The two premutation mouse models studied to date show evidence of ovarian dysfunction and, together, suggest that the long repeat in the transcript itself may have some pathological effect quite apart from any effect of the toxic protein. Further, ovarian morphology in young animals appears normal and the primordial follicle pool size does not differ from that of wild-type animals. However, there is a progressive premature decline in the levels of most follicle classes. Observations also include granulosa cell abnormalities and altered gene expression patterns. Further comparisons of these models are now needed to gain insight into the etiology of the ovarian dysfunction. Premutation model systems in non-human primates and those based on induced pluripotent stem cells show particular promise and will complement current models. Here, we review the characterization of the current models and describe the development and potential of the new models. Finally, we will discuss some of the molecular mechanisms that might be responsible for FXPOI. En ligne : http://dx.doi.org/10.1186/1866-1955-6-26 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=346 [article] Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI) [texte imprimé] / Stephanie L. SHERMAN, Auteur ; Eliza C. CURNOW, Auteur ; Charles A. EASLEY, Auteur ; Peng JIN, Auteur ; Renate K. HUKEMA, Auteur ; Maria Isabel TEJADA, Auteur ; Rob WILLEMSEN, Auteur ; Karen USDIN, Auteur . - p.26. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 6-1 (December 2014) . - p.26 Mots-clés : CGG repeat  Fertility  Fragile X syndrome  Premature ovarian failure  Primary ovarian insufficiency  Repeat expansion disorder Index. décimale : PER Périodiques Résumé : Fragile X-associated primary ovarian insufficiency (FXPOI) is among the family of disorders caused by the expansion of a CGG repeat sequence in the 5' untranslated region of the X-linked gene FMR1. About 20% of women who carry the premutation allele (55 to 200 unmethylated CGG repeats) develop hypergonadotropic hypogonadism and cease menstruating before age 40. Some proportion of those who are still cycling show hormonal profiles indicative of ovarian dysfunction. FXPOI leads to subfertility and an increased risk of medical conditions associated with early estrogen deficiency. Little progress has been made in understanding the etiology of this clinically significant disorder. Understanding the molecular mechanisms of FXPOI requires a detailed knowledge of ovarian FMR1 mRNA and FMRP's function. In humans, non-invasive methods to discriminate the mechanisms of the premutation on ovarian function are not available, thus necessitating the development of model systems. Vertebrate (mouse and rat) and invertebrate (Drosophila melanogaster) animal studies for the FMR1 premutation and ovarian function exist and have been instrumental in advancing our understanding of the disease phenotype. For example, rodent models have shown that FMRP is highly expressed in oocytes where it is important for folliculogenesis. The two premutation mouse models studied to date show evidence of ovarian dysfunction and, together, suggest that the long repeat in the transcript itself may have some pathological effect quite apart from any effect of the toxic protein. Further, ovarian morphology in young animals appears normal and the primordial follicle pool size does not differ from that of wild-type animals. However, there is a progressive premature decline in the levels of most follicle classes. Observations also include granulosa cell abnormalities and altered gene expression patterns. Further comparisons of these models are now needed to gain insight into the etiology of the ovarian dysfunction. Premutation model systems in non-human primates and those based on induced pluripotent stem cells show particular promise and will complement current models. Here, we review the characterization of the current models and describe the development and potential of the new models. Finally, we will discuss some of the molecular mechanisms that might be responsible for FXPOI. En ligne : http://dx.doi.org/10.1186/1866-1955-6-26 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=346

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