Molecular Biomarkers in Fragile X Syndrome

Zafarullah, Marwa; Tassone, Flora

doi:10.3390/brainsci9050096

Cited by 24 publications

(24 citation statements)

References 184 publications

(223 reference statements)

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“…Namely, integration of diagnostic genomic data with complementary FMR1 assays and more accurate FMRP profiles is necessary [ 36 ]. The integration of these data can clarify the relationships between genotype and protein expression and the neurobehavioral phenotype [ 37 ]. Such links may improve disease prognostics and characterization of response to pharmacological and other therapeutic interventions [ 11 , 36 ], as well as help stratify patients with FXS in clinical trials [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

A Genotype-Phenotype Study of High-Resolution FMR1 Nucleic Acid and Protein Analyses in Fragile X Patients with Neurobehavioral Assessments

et al. 2020

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Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene, which encodes a protein with a critical role in synaptic plasticity. The molecular abnormality underlying FMR1 silencing, CGG repeat expansion, is well characterized; however, delineation of the pathway from DNA to RNA to protein using biosamples from well characterized patients with FXS is limited. Since FXS is a common and prototypical genetic disorder associated with intellectual disability (ID) and autism spectrum disorder (ASD), a comprehensive assessment of the FMR1 DNA-RNA-protein pathway and its correlations with the neurobehavioral phenotype is a priority. We applied nine sensitive and quantitative assays evaluating FMR1 DNA, RNA, and FMRP parameters to a reference set of cell lines representing the range of FMR1 expansions. We then used the most informative of these assays on blood and buccal specimens from cohorts of patients with different FMR1 expansions, with emphasis on those with FXS (N = 42 total, N = 31 with FMRP measurements). The group with FMRP data was also evaluated comprehensively in terms of its neurobehavioral profile, which allowed molecular–neurobehavioral correlations. FMR1 CGG repeat expansions, methylation levels, and FMRP levels, in both cell lines and blood samples, were consistent with findings of previous FMR1 genomic and protein studies. They also demonstrated a high level of agreement between blood and buccal specimens. These assays further corroborated previous reports of the relatively high prevalence of methylation mosaicism (slightly over 50% of the samples). Molecular-neurobehavioral correlations confirmed the inverse relationship between overall severity of the FXS phenotype and decrease in FMRP levels (N = 26 males, mean 4.2 ± 3.3 pg FMRP/ng genomic DNA). Other intriguing findings included a significant relationship between the diagnosis of FXS with ASD and two-fold lower levels of FMRP (mean 2.8 ± 1.3 pg FMRP/ng genomic DNA, p = 0.04), in particular observed in younger age- and IQ-adjusted males (mean age 6.9 ± 0.9 years with mean 3.2 ± 1.2 pg FMRP/ng genomic DNA, 57% with severe ASD), compared to FXS without ASD. Those with severe ID had even lower FMRP levels independent of ASD status in the male-only subset. The results underscore the link between FMR1 expansion, gene methylation, and FMRP deficit. The association between FMRP deficiency and overall severity of the neurobehavioral phenotype invites follow up studies in larger patient cohorts. They would be valuable to confirm and potentially extend our initial findings of the relationship between ASD and other neurobehavioral features and the magnitude of FMRP deficit. Molecular profiling of individuals with FXS may have important implications in research and clinical practice.

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Section: Introductionmentioning

confidence: 99%

A Genotype-Phenotype Study of High-Resolution FMR1 Nucleic Acid and Protein Analyses in Fragile X Patients with Neurobehavioral Assessments

et al. 2020

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“…Namely, integration of diagnostic genomic data with complementary FMR1 assays and more accurate FMRP pro les is necessary [36]. The data integration enables to clarify relationships between genotype and protein expression and the neurobehavioral phenotype [37]. Such links may improve disease prognostics and characterization of response to pharmacological and other therapeutic interventions [11,36], as well as help stratify patients with FXS in clinical trials [38].…”

Section: Introductionmentioning

confidence: 99%

A Genotype-Phenotype Study of High-Resolution FMR1 Nucleic Acid and Protein Analyses in Fragile X Patients With Neurobehavioral Assessments

Budimirović

Schlageter

Sadic-Filipovic

et al. 2020

Preprint

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Background. Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene, which encodes a protein with a critical role in synaptic plasticity. The molecular abnormality underlying FMR1 silencing, CGG repeat expansion, is well characterized; however, delineation of the pathway from DNA to RNA to protein using biosamples from well characterized patients with FXS is limited. Since FXS is a common and prototypical genetic disorder associated with intellectual disability (ID) and autism spectrum disorder (ASD), a comprehensive assessment of the FMR1 DNA-RNA-protein pathway and its correlations with the neurobehavioral phenotype is a priority.Methods. We applied nine sensitive and quantitative assays evaluating FMR1 DNA, RNA, and FMRP parameters to a reference set of cell lines representing the range of FMR1 expansions. We then used the most informative of these assays on blood and buccal specimens from cohorts of patients with different FMR1 expansions, with emphasis on those with FXS (N = 42 total, N = 31 with FMRP measurements). The group with FMRP data was also evaluated comprehensively in terms of its neurobehavioral profile, which allowed molecular-neurobehavioral correlations. Results. FMR1 CGG repeat expansions, methylation levels, and FMRP levels, in both cell lines and blood samples, were consistent with previous FMR1 genomic and protein studies. They also demonstrated a high level of agreement between blood and buccal specimens. These assays further corroborated previous reports of the relatively high prevalence of methylation mosaicism. Molecular-neurobehavioral correlations confirmed the inverse relationship between overall severity of the FXS phenotype and decrease in FMRP levels. Other intriguing findings included a potential relationship between diagnosis of FXS with ASD and very low levels of FMRP, compared to FXS without ASD. Conclusions. The results underscore the link between FMR1 expansion, gene methylation, and FMRP deficit. The association between FMRP deficiency and overall severity of the neurobehavioral phenotype invites follow up studies in larger patient cohorts. They would be valuable to confirm and potentially extend our initial findings of a relationship between ASD and other neurobehavioral features and the magnitude of FMRP deficit. Molecular profiling of individuals with FXS may have important implications in research and clinical practice.

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“…These pro-inflammatory cytokines can modulate responses in the central nervous system and can alter neurodevelopment. An aberrant immune response during neurodevelopment could lead to changes in early brain development and produce a neurological dysfunction related to ASD [ 24 , 25 , 26 , 27 , 28 ]. Some previous studies reported elevated levels of pro-inflammatory cytokines such as TNFα and IL-1β in children with ASD compared to typically developing children [ 21 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the levels of Eotaxin, MCP-1, and RANTES were significantly different for FXS + ASD compared to FXS. There was a significantly distinct profile of the cytokines: Eotaxin, RANTES, and MPC-1 in FXS + ASD compared to the controls [ 28 ]. It is unknown whether the cytokine changes are determinants in the development of FXS and if they occur throughout the lifetime of FXS [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…There was a significantly distinct profile of the cytokines: Eotaxin, RANTES, and MPC-1 in FXS + ASD compared to the controls [ 28 ]. It is unknown whether the cytokine changes are determinants in the development of FXS and if they occur throughout the lifetime of FXS [ 28 ]. Usually the cytokines belonging to the same either pro-inflammatory or anti-inflammatory groups showed similar results [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

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Salivary Cytokine Profile as a Possible Predictor of Autism Spectrum Disorder

Samborska-Mazur

Kostiukow

Miechowicz

et al. 2020

JCM

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Autism spectrum disorder (ASD) is characterized by neurodevelopmental disorders and alterations in immune function and cytokine levels. The aim of this study is to determine the salivary levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1), Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES), and Eotaxin in children with ASD and in healthy controlsto assess their predictive potential. We explored correlations between the cytokine levels and the neurodevelopmental disorders related to ASD. The study comprised 19 children with ASD and 19 typically developing (TD) ones. We analyzed salivary levels of IL-1β, IL-6, IL-8, TNFα, MCP-1, RANTES, and eotaxin on Luminex with custom-designed 7-plex kits. The level of RANTES in ASD children was significantly lower than those of TD. In TDs, the salivary levels of IL-1β, MCP-1, and TNFα correlated positively with age. In ASD, the cytokine levels did not correlate with age. There were statistically significant differences between the RANTES level and aggression and gait disturbances, between IL-8 level and fixations/stimulations, and between IL-1β level and no active speech. The levels of the cytokine detected can manifest both systemic and local changes related to ASD. The cytokine pattern cannot be used as a sole ASD predictor, but the salivary levels may be helpful in categorizing the ASD subtype.

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Molecular Biomarkers in Fragile X Syndrome

Cited by 24 publications

References 184 publications

A Genotype-Phenotype Study of High-Resolution FMR1 Nucleic Acid and Protein Analyses in Fragile X Patients with Neurobehavioral Assessments

A Genotype-Phenotype Study of High-Resolution FMR1 Nucleic Acid and Protein Analyses in Fragile X Patients with Neurobehavioral Assessments

A Genotype-Phenotype Study of High-Resolution FMR1 Nucleic Acid and Protein Analyses in Fragile X Patients With Neurobehavioral Assessments

Salivary Cytokine Profile as a Possible Predictor of Autism Spectrum Disorder

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