Gene Summary

Gene:FMR1; fragile X mental retardation 1
Summary:The protein encoded by this gene binds RNA and is associated with polysomes. The encoded protein may be involved in mRNA trafficking from the nucleus to the cytoplasm. A trinucleotide repeat (CGG) in the 5' UTR is normally found at 6-53 copies, but an expansion to 55-230 repeats is the cause of fragile X syndrome. Expansion of the trinucleotide repeat may also cause one form of premature ovarian failure (POF1). Multiple alternatively spliced transcript variants that encode different protein isoforms and which are located in different cellular locations have been described for this gene. [provided by RefSeq, May 2010]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:synaptic functional regulator FMR1
Source:NCBIAccessed: 13 March, 2017


What does this gene/protein do?
Show (11)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 13 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Brain Tumours
  • Brain Tumours
  • Ubiquitin-Protein Ligases
  • p53 Protein
  • DNA-Binding Proteins
  • Acute Lymphocytic Leukaemia
  • Case-Control Studies
  • Molecular Sequence Data
  • Oligonucleotide Array Sequence Analysis
  • Cloning, Molecular
  • Nerve Tissue Proteins
  • Polymerase Chain Reaction
  • Mutation
  • Teratoma
  • Tuberous Sclerosis
  • Transfection
  • BRCA2 Protein
  • Neoplasm Proteins
  • RNA-Binding Proteins
  • TOR Serine-Threonine Kinases
  • Breast Cancer
  • X Chromosome
  • Gene Silencing
  • Genetic Predisposition
  • Genotype
  • DNA Methylation
  • Messenger RNA
  • Cell Differentiation
  • Tremor
  • FISH
  • Base Sequence
  • Alleles
  • Translocation
  • Fragile X Mental Retardation Protein
  • Testis
  • Ovarian Cancer
  • Fragile X Syndrome
  • Pregnancy
  • Reproduction
  • Trinucleotide Repeats
  • Cancer Gene Expression Regulation
Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: FMR1 (cancer-related)

Scopim-Ribeiro R, Machado-Neto JA, de Melo Campos P, et al.
Low Ten-eleven-translocation 2 (TET2) transcript level is independent of TET2 mutation in patients with myeloid neoplasms.
Diagn Pathol. 2016; 11:28 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: New sequencing technologies have enabled the identification of mutations in Ten-eleven-translocation 2 (TET2), an enzyme that catalyzes the conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5-hmC) in myeloid neoplasms. We have recently identified reduced TET2 mRNA expression in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), which is associated with a poor overall survival in MDS. We herein aimed to investigate TET2 mutations and their impact on TET2 expression in a cohort of patients with myeloid neoplasms, including MDS and AML patients.
FINDINGS: TET2 mutations were observed in 8 out of 19 patients (42 %) with myeloid neoplasms. The TET2 expression profile was similar between in wild type and in TET2 mutated patients.
CONCLUSION: Our results suggest that TET2 expression is reduced in MDS/AML patients, independently of mutational status.

Goldberg Y, Halpern N, Hubert A, et al.
Mutated MCM9 is associated with predisposition to hereditary mixed polyposis and colorectal cancer in addition to primary ovarian failure.
Cancer Genet. 2015; 208(12):621-4 [PubMed] Related Publications
Mutations in MCM9, which encodes DNA helicase, were recently shown to cause a clinical phenotype of primary ovarian failure and chromosomal instability. MCM9 plays an essential role in homologous recombination-mediated double-strand break repair. We describe a multiplex family with early colorectal carcinoma and mixed polyposis associated with primary hypergonadotropic hypogonadism. A combination of whole genome homozygosity mapping as well as exome sequencing and targeted gene sequencing identified a homozygous c.672_673delGGinsC mutation that predicts a truncated protein, p.Glu225Lysfs*4. Our data expand the phenotypic spectrum of MCM9 mutations and suggest a link between MCM9 and inherited predisposition to mixed polyposis and early-onset colorectal cancer.

Palma Cde S, Grassi ML, Thomé CH, et al.
Proteomic Analysis of Epithelial to Mesenchymal Transition (EMT) Reveals Cross-talk between SNAIL and HDAC1 Proteins in Breast Cancer Cells.
Mol Cell Proteomics. 2016; 15(3):906-17 [PubMed] Free Access to Full Article Related Publications
Epithelial to mesenchymal transition (EMT)(1) occurs naturally during embryogenesis, tissue repair, cancer progression, and metastasis. EMT induces cellular and microenvironmental changes resulting in loss of epithelial and acquisition of mesenchymal phenotypes, which promotes cellular invasive and migratory capabilities. EMT can be triggered by extracellular factors, including TGF-β, HGF, and EGF. Overexpression of transcription factors, such as SNAIL, SLUG, ZEB1/2, and TWIST1, also induces EMT and is correlated to cancer aggressiveness. Here, the breast adenocarcinoma cell line MCF7 was transduced with SNAIL to identify specific mechanisms controlled by this transcription factor during EMT. Overexpression of SNAIL led to EMT, which was thoroughly validated by molecular, morphological, and functional experiments. Subcellular proteome enrichment followed by GEL-LC-MS/MS was performed to provide extensive protein fractionation and in-depth proteomic analysis. Quantitative analysis relied on a SILAC strategy, using the invasive breast cancer cell line MDA-MB-231 as a reference for quantitation. Subsets of proteins enriched in each subcellular compartment led to a complementary list of 4289 proteins identified with high confidence. A subset of differentially expressed proteins was validated by Western blot, including regulation in specific cellular compartments, potentially caused by protein translocation. Protein network analysis highlighted complexes involved in cell cycle control and epigenetic regulation. Flow cytometry analysis indicated that SNAIL overexpression led to cell cycle arrest in G0/G1 phases. Furthermore, down-regulation of HDAC1 was observed, supporting the involvement of epigenetic processes in SNAIL-induced EMT. When HDAC1 activity was inhibited, MCF7 not only apparently initiated EMT but also up-regulated SNAIL, indicating the cross-talk between these two proteins. Both HDAC1 inhibition and SNAIL overexpression activated the AKT pathway. These molecular mechanisms appear to be essential to EMT and therefore for cancer metastasis. Specific control of such epigenetic processes might then represent effective approaches for clinical management of metastatic cancer.

Espósito DL, Bollela VR, Feitosa AL, da Fonseca BA
Expression Profiles of Cytokine mRNAs in the Pleural Fluid Reveal Differences Among Tuberculosis, Malignancies, and Pneumonia-Exudative Pleural Effusions.
Lung. 2015; 193(6):1001-7 [PubMed] Related Publications
INTRODUCTION: Tuberculosis (TB) and malignant diseases are the most common causes of lymphocytic pleural effusion in adults. Serum and pleural fluid cytokine levels have been analyzed to help in the differential diagnosis, but with limited results.
PURPOSE: This study investigates transcription levels of selected cytokine genes in pleural effusion of patients under investigation for TB.
METHODS: This was a prospective study that included adult patients under investigation for pleural effusion in Brazil. The expression of 19 cytokine genes was analyzed by RT-qPCR.
RESULTS: The majority of cytokine-related genes expressed in pleural fluid of TB patients were similar in non-TB patients, except for RORA and RORC genes, which showed a statistically higher level in TB. All cytokines in the Th17 pattern were induced in TB patients' pleural fluid. Patients with malignant pleural effusion expressed higher levels of IFN-α1, IFN-β1, TNF-α, IL-4 and IL-6, and suppression of TGFβ-1.
CONCLUSION: There is still a lot to understand about the cytokine roles in the pro- and anti-inflammatory environment of exudative pleural effusions. The data presented here showed an increased expression of Th17 pattern cytokines genes in TB patients that could be used as markers to differentiate tuberculous pleuritis from other common causes of exudative pleural effusion.

Benevides L, da Fonseca DM, Donate PB, et al.
IL17 Promotes Mammary Tumor Progression by Changing the Behavior of Tumor Cells and Eliciting Tumorigenic Neutrophils Recruitment.
Cancer Res. 2015; 75(18):3788-99 [PubMed] Related Publications
The aggressiveness of invasive ductal carcinoma (IDC) of the breast is associated with increased IL17 levels. Studying the role of IL17 in invasive breast tumor pathogenesis, we found that metastatic primary tumor-infiltrating T lymphocytes produced elevated levels of IL17, whereas IL17 neutralization inhibited tumor growth and prevented the migration of neutrophils and tumor cells to secondary disease sites. Tumorigenic neutrophils promote disease progression, producing CXCL1, MMP9, VEGF, and TNFα, and their depletion suppressed tumor growth. IL17A also induced IL6 and CCL20 production in metastatic tumor cells, favoring the recruitment and differentiation of Th17. In addition, IL17A changed the gene-expression profile and the behavior of nonmetastatic tumor cells, causing tumor growth in vivo, confirming the protumor role of IL17. Furthermore, high IL17 expression was associated with lower disease-free survival and worse prognosis in IDC patients. Thus, IL17 blockade represents an attractive approach for the control of invasive breast tumors.

Assis PA, De Figueiredo-Pontes LL, Lima AS, et al.
Halofuginone inhibits phosphorylation of SMAD-2 reducing angiogenesis and leukemia burden in an acute promyelocytic leukemia mouse model.
J Exp Clin Cancer Res. 2015; 34:65 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Halofuginone (HF) is a low-molecular-weight alkaloid that has been demonstrated to interfere with Metalloproteinase-2 (MMP-2) and Tumor Growth Factor-β (TGF-β) function and, to present antiangiogenic, antiproliferative and proapoptotic properties in several solid tumor models. Based on the fact that high levels of Vascular Endothelial Growth Factor (VEGF) and increased angiogenesis have been described in acute myeloid leukemia and associated with disease progression, we studied the in vivo effects of HF using an Acute Promyelocytic Leukemia (APL) mouse model.
METHODS: NOD/SCID mice were transplanted with leukemic cells from hCG-PML/RARA transgenic mice (TM) and treated with HF 150 μg/kg/day for 21 days. The leukemic infiltration and the percentage of VEGF+ cells were evaluated by morphology and flow cytometry. The effect of HF on the gene expression of several pro- and antiangiogenic factors, phosphorylation of SMAD2 and VEGF secretion was assessed in vitro using NB4 and HUVEC cells.
RESULTS: HF treatment resulted in hematological remission with decreased accumulation of immature cell and lower amounts of VEGF in BM of leukemic mice. In vitro, HF modulated gene expression of several pro- and antiangiogenic factors, reduced VEGF secretion and phosphorylation of SMAD2, blocking TGF-β-signaling.
CONCLUSION: Taken together, our results demonstrate that HF inhibits SMAD2 signaling and reduces leukemia growth and angiogenesis.

Collins DT, Mannina EM, Mendonca M
Total body irradiation in a patient with fragile X syndrome for acute lymphoblastic leukemia in preparation for stem cell transplantation: A case report and literature review.
Am J Med Genet A. 2015; 167A(10):2444-6 [PubMed] Related Publications
Fragile X syndrome (FXS) is a congenital disorder caused by expansion of CGG trinucleotide repeat at the 5' end of the fragile X mental retardation gene 1 (FMR1) on the X chromosome that leads to chromosomal instability and diminished serum levels of fragile X mental retardation protein (FMRP). Afflicted individuals often have elongated features, marfanoid habitus, macroorchidism and intellectual impairment. Evolving literature suggests the condition may actually protect from malignancy while chromosomal instability would presumably elevate the risk. Increased sensitivity to ionizing radiation should also be predicted by unstable sites within the DNA. Interestingly, in this report, we detail a patient with FXS diagnosed with acute lymphoblastic leukemia treated with induction followed by subsequent cycles of hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) with a complete response who then was recommended to undergo peripheral stem cell transplantation. The patient underwent total body irradiation (TBI) as a component of his conditioning regimen and despite the concern of his clinicians, developed minimal acute toxicity and successful engraftment. The pertinent literature regarding irradiation of patients with FXS is also reviewed.

Sicchieri RD, da Silveira WA, Mandarano LR, et al.
ABCG2 is a potential marker of tumor-initiating cells in breast cancer.
Tumour Biol. 2015; 36(12):9233-43 [PubMed] Related Publications
The existence of tumor-initiating cells (TICs) within solid tumors has been hypothesized to explain tumor heterogeneity and resistance to cancer therapy. In breast cancer, the expression of CD44 and CD24 and the activity of aldehyde dehydrogenase 1 (ALDH1) can be used to selectively isolate a cell population enriched in TICs. However, the ideal marker to identify TICs has not been established. The aim of this study was to evaluate the expression of novel potential markers for TIC in breast carcinoma. We prospectively analyzed the expression of CD44, CD24, ABCG2, and CXCR4, and the activity of ALDH1 by using flow cytometry in 48 invasive ductal carcinomas from locally advanced and metastatic breast cancer patients who were administered primary chemotherapy. A mammosphere assay was employed in 30 samples. The relationship among flow cytometric analyses, ABCG2 gene expression, and clinical and pathological responses to therapy was analyzed. The GSE32646 database was analyzed in silico to identify genes associated with tumors with low and high ABCG2 expression. We observed that the presence of ABCG2(+) cells within the primary tumor was the only marker to predict the formation of mammospheres in vitro (R (2) = 0.15, p = 0.029). Quantitative polymerase chain reaction (qPCR) revealed a positive correlation between ABCG2 expression and the presence of ABCG2(+) cells within the primary tumor. The expression of ABCG2 was predictive of the response to neoadjuvant chemotherapy in our experiments and in the GSE32646 dataset (p = 0.04 and p = 0.002, respectively). The in silico analysis demonstrated that ABCG2(Up) breast cancer samples have a slower cell cycle and a higher expression of membrane proteins but a greater potential for chromosomal instability, metastasis, immune evasion, and resistance to hypoxia. Such genetic characteristics are compatible with highly aggressive and resistant tumors. Our results support the hypothesis that the presence of ABCG2(+) cells in breast carcinomas is a marker of resistance to chemotherapy, and based on in vitro assays and the genetic profile, we show, for the first time, that ABCG2 protein can be used as an independent marker for TIC identification in breast cancer.

Becker AP, Scapulatempo-Neto C, Carloni AC, et al.
KIAA1549: BRAF Gene Fusion and FGFR1 Hotspot Mutations Are Prognostic Factors in Pilocytic Astrocytomas.
J Neuropathol Exp Neurol. 2015; 74(7):743-54 [PubMed] Free Access to Full Article Related Publications
Up to 20% of patients with pilocytic astrocytoma (PA) experience a poor outcome. BRAF alterations and Fibroblast growth factor receptor 1 (FGFR1) point mutations are key molecular alterations in Pas, but their clinical implications are not established. We aimed to determine the frequency and prognostic role of these alterations in a cohort of 69 patients with PAs. We assessed KIAA1549:BRAF fusion by fluorescence in situ hybridization and BRAF (exon 15) mutations by capillary sequencing. In addition, FGFR1 expression was analyzed using immunohistochemistry, and this was compared with gene amplification and hotspot mutations (exons 12 and 14) assessed by fluorescence in situ hybridization and capillary sequencing. KIAA1549:BRAF fusion was identified in almost 60% of cases. Two tumors harbored mutated BRAF. Despite high FGFR1 expression overall, no cases had FGFR1 amplifications. Three cases harbored a FGFR1 p.K656E point mutation. No correlation was observed between BRAF and FGFR1 alterations. The cases were predominantly pediatric (87%), and no statistical differences were observed in molecular alterations-related patient ages. In summary, we confirmed the high frequency of KIAA1549:BRAF fusion in PAs and its association with a better outcome. Oncogenic mutations of FGFR1, although rare, occurred in a subset of patients with worse outcome. These molecular alterations may constitute alternative targets for novel clinical approaches, when radical surgical resection is unachievable.

Leszczynska KB, Foskolou IP, Abraham AG, et al.
Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT.
J Clin Invest. 2015; 125(6):2385-98 [PubMed] Free Access to Full Article Related Publications
Restoration of hypoxia-induced apoptosis in tumors harboring p53 mutations has been proposed as a potential therapeutic strategy; however, the transcriptional targets that mediate hypoxia-induced p53-dependent apoptosis remain elusive. Here, we demonstrated that hypoxia-induced p53-dependent apoptosis is reliant on the DNA-binding and transactivation domains of p53 but not on the acetylation sites K120 and K164, which, in contrast, are essential for DNA damage-induced, p53-dependent apoptosis. Evaluation of hypoxia-induced transcripts in multiple cell lines identified a group of genes that are hypoxia-inducible proapoptotic targets of p53, including inositol polyphosphate-5-phosphatase (INPP5D), pleckstrin domain-containing A3 (PHLDA3), sulfatase 2 (SULF2), B cell translocation gene 2 (BTG2), cytoplasmic FMR1-interacting protein 2 (CYFIP2), and KN motif and ankyrin repeat domains 3 (KANK3). These targets were also regulated by p53 in human cancers, including breast, brain, colorectal, kidney, bladder, and melanoma cancers. Downregulation of these hypoxia-inducible targets associated with poor prognosis, suggesting that hypoxia-induced apoptosis contributes to p53-mediated tumor suppression and treatment response. Induction of p53 targets, PHLDA3, and a specific INPP5D transcript mediated apoptosis in response to hypoxia through AKT inhibition. Moreover, pharmacological inhibition of AKT led to apoptosis in the hypoxic regions of p53-deficient tumors and consequently increased radiosensitivity. Together, these results identify mediators of hypoxia-induced p53-dependent apoptosis and suggest AKT inhibition may improve radiotherapy response in p53-deficient tumors.

Martins CS, Santana-Lemos BA, Saggioro FP, et al.
Telomere length and telomerase expression in pituitary tumors.
J Endocrinol Invest. 2015; 38(11):1243-6 [PubMed] Related Publications
PURPOSE: Telomere dysfunction and telomerase activation underlie cancer transformation. This study aims to investigate the contribution of telomere biology to pituitary tumor behavior.
SUBJECTS AND METHODS: Samples from 50 patients with pituitary tumors (11 ACTH-secreting, 18 GH-secreting, and 21 non-secreting tumors) and 7 subjects without pituitary lesions were collected. The expressions of telomerase essential components TERT and TERC and tumor telomere content were measured by quantitative PCR techniques.
RESULTS: Telomerase (TERT) expression was detected in 36% of tumors. No correlation was observed between TERT and TERC expression level and tumor size in any tumor type. There was no association between gene expression and clinical findings. Telomere content (T/S ratio) was similar between pituitary adenomas (0.39 ± 0.16) and normal pituitaries (0.47 ± 0.12; p = 0.24) and also was between the different adenoma types: ACTH-secreting (0.43 ± 0.08), GH-secreting (0.31 ± 0.12), and non-secreting (0.42 ± 0.20; p = 0.10) tumors.
CONCLUSIONS: The telomere content and expression of telomerase components are comparable between normal pituitary glands and tumor tissues, suggesting that telomere biology does not play an important role in pituitary tumor development.

Hua J, Xu B, Yang Y, et al.
Follicle Online: an integrated database of follicle assembly, development and ovulation.
Database (Oxford). 2015; 2015:bav036 [PubMed] Free Access to Full Article Related Publications
Folliculogenesis is an important part of ovarian function as it provides the oocytes for female reproductive life. Characterizing genes/proteins involved in folliculogenesis is fundamental for understanding the mechanisms associated with this biological function and to cure the diseases associated with folliculogenesis. A large number of genes/proteins associated with folliculogenesis have been identified from different species. However, no dedicated public resource is currently available for folliculogenesis-related genes/proteins that are validated by experiments. Here, we are reporting a database 'Follicle Online' that provides the experimentally validated gene/protein map of the folliculogenesis in a number of species. Follicle Online is a web-based database system for storing and retrieving folliculogenesis-related experimental data. It provides detailed information for 580 genes/proteins (from 23 model organisms, including Homo sapiens, Mus musculus, Rattus norvegicus, Mesocricetus auratus, Bos Taurus, Drosophila and Xenopus laevis) that have been reported to be involved in folliculogenesis, POF (premature ovarian failure) and PCOS (polycystic ovary syndrome). The literature was manually curated from more than 43,000 published articles (till 1 March 2014). The Follicle Online database is implemented in PHP + MySQL + JavaScript and this user-friendly web application provides access to the stored data. In summary, we have developed a centralized database that provides users with comprehensive information about genes/proteins involved in folliculogenesis. This database can be accessed freely and all the stored data can be viewed without any registration. Database URL:

Ebrahimi-Fakhari D, Sahin M
Autism and the synapse: emerging mechanisms and mechanism-based therapies.
Curr Opin Neurol. 2015; 28(2):91-102 [PubMed] Related Publications
PURPOSE OF REVIEW: Recent studies have implicated hundreds of genetic variants in the cause of autism spectrum disorder (ASD). Genes involved in 'monogenic' forms of syndromic ASD converge on common pathways that are involved in synaptic development, plasticity and signaling. In this review, we discuss how these 'developmental synaptopathies' inform our understanding of the molecular disease in ASD and highlight promising approaches that have bridged the gap between the bench and the clinic.
RECENT FINDINGS: Accumulating evidence suggests that synaptic deficits in syndromic and nonsyndromic ASD can be mapped to gene mutations in pathways that control synaptic protein synthesis and degradation, postsynaptic scaffold architecture and neurotransmitter receptors. This is recapitulated in models of Fragile X syndrome (FXS), Tuberous Sclerosis Complex (TSC), Angelman syndrome and Phelan-McDermid syndrome (PMS), all of which cause syndromic ASD. Important recent advances include the development of mouse models and patient-derived induced pluripotent stem cell (iPSC) lines that enable a detailed investigation of synaptic deficits and the identification of potential targets for therapy. Examples of the latter include mGluR5 antagonists in FXS, mTOR inhibitors in TSC and insulin-like growth factor 1 (IGF-1) in PMS.
SUMMARY: Identifying converging pathways in syndromic forms of ASD will uncover novel therapeutic targets for non-syndromic ASD. Insights into developmental synaptopathies will lead to rational development of mechanism-based therapies and clinical trials that may provide a blueprint for other common pathways implicated in the molecular neuropathology of ASD.

Machado-Neto JA, Lazarini M, Favaro P, et al.
ANKHD1 silencing inhibits Stathmin 1 activity, cell proliferation and migration of leukemia cells.
Biochim Biophys Acta. 2015; 1853(3):583-93 [PubMed] Related Publications
ANKHD1 is highly expressed in human acute leukemia cells and potentially regulates multiple cellular functions through its ankyrin-repeat domains. In order to identify interaction partners of the ANKHD1 protein and its role in leukemia cells, we performed a yeast two-hybrid system screen and identified SIVA, a cellular protein known to be involved in proapoptotic signaling pathways. The interaction between ANKHD1 and SIVA was confirmed by co-imunoprecipitation assays. Using human leukemia cell models and lentivirus-mediated shRNA approaches, we showed that ANKHD1 and SIVA proteins have opposing effects. While it is known that SIVA silencing promotes Stathmin 1 activation, increased cell migration and xenograft tumor growth, we showed that ANKHD1 silencing leads to Stathmin 1 inactivation, reduced cell migration and xenograft tumor growth, likely through the inhibition of SIVA/Stathmin 1 association. In addition, we observed that ANKHD1 knockdown decreases cell proliferation, without modulating apoptosis of leukemia cells, while SIVA has a proapoptotic function in U937 cells, but does not modulate proliferation in vitro. Results indicate that ANKHD1 binds to SIVA and has an important role in inducing leukemia cell proliferation and migration via the Stathmin 1 pathway. ANKHD1 may be an oncogene and participate in the leukemia cell phenotype.

El Hachem H, Atallah D, Grynberg M
Fertility preservation in breast cancer patients.
Future Oncol. 2014; 10(10):1767-77 [PubMed] Related Publications
Breast cancer is the most common malignant tumor in women of reproductive age, and is characterized by a high survival rate owing to improved antineoplastic treatments. Young survivors face the prospect of a diminished fertility as a consequence of the gonadotoxic chemotherapy, and many are seeking ways to preserve their fertility. Embryo and/or oocyte cryopreservation following controlled ovarian stimulation is currently the fertility preservation method of choice, but breast cancer patients may have contraindications to exogenous gonadotropin administration and may not have enough time to undergo ovarian stimulation prior to chemotherapy. Fortunately, many other options are available for these women, such as the letrozole-follicle-stimulating hormone ovarian stimulation protocol, in vitro maturation of oocytes and ovarian tissue cryopreservation. In this review, we discuss the benefits and disadvantages of the different fertility preservation techniques that can be offered to breast cancer patients.

Campos-Melo D, Droppelmann CA, Volkening K, Strong MJ
RNA-binding proteins as molecular links between cancer and neurodegeneration.
Biogerontology. 2014; 15(6):587-610 [PubMed] Related Publications
For many years, epidemiological studies have suggested an association between cancer and neurodegenerative disorders-two disease processes that seemingly have little in common. Although these two disease processes share disruptions in a wide range of cellular pathways, including cell survival, cell death and the cell cycle, the end result is very divergent: uncontrolled cell survival and proliferation in cancer and progressive neuronal cell death in neurodegeneration. Despite the clinical data connecting these two disease processes, little is known about the molecular links between them. Among the mechanisms affected in cancer and neurodegenerative diseases, alterations in RNA metabolism are obtaining significant attention given the critical role for RNA transcription, maturation, transport, stability, degradation and translation in normal cellular function. RNA-binding proteins (RBPs) are integral to each stage of RNA metabolism through their participation in the formation of ribonucleoprotein complexes (RNPs). RBPs have a broad range of functions including posttranscriptional regulation of mRNA stability, splicing, editing and translation, mRNA export and localization, mRNA polyadenylation and miRNA biogenesis, ultimately impacting the expression of every single gene in the cell. In this review, we examine the evidence for RBPs as being key a molecular linkages between cancer and neurodegeneration.

Gleicher N, McAlpine JN, Gilks CB, et al.
Absence of BRCA/FMR1 correlations in women with ovarian cancers.
PLoS One. 2014; 9(7):e102370 [PubMed] Free Access to Full Article Related Publications
Previously reported findings in Austrian BRCA1/2 mutation carriers suggested a possible dependency of embryos with BRCA1/2 mutations on so-called low alleles of the fragile X mental retardation 1 (FMR1) gene, characterized by less than 26 CGG repeats (CGG(n<26)). The hypothesis arose from a study reporting highly statistically significant enrichment of low FMR1 alleles, significantly exceeding low allele prevalence in a general population, suggesting embryo lethality of BRCA1/2 mutations, "rescued" by presence of low FMR1 alleles. Such a dependency would also offer an explanation for the so-called "BRCA-paradox," characterized by BRCA1/2 deficient embryonic tissues being anti-proliferative (thereby potentially causing embryo-lethality) but proliferative in malignant tumors, including breast and ovarian cancers. Follow up investigations by other investigators, however, at most demonstrated trends towards enrichment but, mostly, no enrichment at all, raising questions about the original observation and hypothesis. We in this study, therefore, investigated CGGn of the FMR1 gene of 86 anonymized DNA samples from women with various forms of ovarian cancer, and were unable to demonstrate differences in prevalence of low FMR1 alleles either between positive and negative ovarian cancer patients for BRCA1/2 or between ovarian cancer patients and reported rates in non-cancer populations. This raises further questions about a suggested dependency between BRCA1/2 and FMR1, but also raises the possibility that investigated Austrian BRCA1/2 carrier populations differ from those in other countries. Either only selected BRCA1/2 mutations, therefore, interact with low FMR1 alleles or the Austrian data reflect only coincidental observations.

Persani L, Rossetti R, Di Pasquale E, et al.
The fundamental role of bone morphogenetic protein 15 in ovarian function and its involvement in female fertility disorders.
Hum Reprod Update. 2014 Nov-Dec; 20(6):869-83 [PubMed] Related Publications
BACKGROUND: A large number of studies have contributed to understanding the general mechanisms driving ovarian folliculogenesis in humans and show a complex endocrine dialog between the central nervous system, the pituitary and the ovary, integrated by various intraovarian paracrine messages. The role of intraovarian paracrine regulation has acquired more relevance in the recent years owing to the discovery of previously unknown factors, such as the oocyte-derived bone morphogenetic protein (BMP)15.
METHODS: A thorough literature search was carried out in order to summarize what has been reported so far on the role of BMP15, and the BMP15 paralog, growth and differentiation factor 9 (GDF9), in ovarian function and female fertility. Research articles published in English until March 2014 were included.
RESULTS: The biological actions of BMP15 include: (i) the promotion of follicle growth and maturation starting from the primary gonadotrophin-independent phases of folliculogenesis; (ii) the regulation of follicular granulosa cell (GC) sensitivity to FSH action and the determination of ovulation quota; (iii) the prevention of GC apoptosis and (iv) the promotion of oocyte developmental competence. The existence of biologically active heterodimers with GDF9, and/or the synergistic co-operation of BMP15 and GDF9 homodimers are indeed relevant in this context. Experimental disruption of the bmp15 gene in mice resulted in a mild fertility defect limited to females, whereas natural missense mutations in ewes cause variable phenotypes (ranging from hyperprolificacy to complete sterility) depending on a fine gene dosage mechanism also involving GDF9. Strong evidence supports the concept that such a mechanism plays an important role in the regulation of ovulation rate across mammalian and non-mammalian species. Following the discovery of sheep fecundity genes, several research groups have focused on alterations in human BMP15 associated with primary ovarian insufficiency (POI) or polycystic ovary syndrome. Several variants of BMP15 are significantly associated with POI supporting their pathogenic role, but the underlying biological mechanism is still under investigation and of great interest in medicine. BMP15 maps to the Xp locus involved in the determination of the ovarian defect in Turner syndrome and significantly contributes to the determination of ovarian reserve. Pioneering studies in women undergoing controlled ovarian stimulation indicate that BMP15 may represent a marker of ovarian response or oocyte quality.
CONCLUSIONS: BMP15, an oocyte-derived growth and differentiation factor, is a critical regulator of folliculogenesis and GC activities. Variations in BMP15 gene dosage have a relevant influence on ovarian function and can account for several defects of female fertility. The modulation of BMP15 action may have interesting pharmacological perspectives and the analysis of BMP15 may become a useful marker in IVF procedures. Recent outcomes indicate that the close interactions of BMP15/GDF9 have a critical biological impact that should be taken into account in future studies.

Lawrenson K, Lee N, Torres HA, et al.
Src as a novel therapeutic target for endometriosis.
Gynecol Oncol. 2014; 135(1):100-7 [PubMed] Related Publications
BACKGROUND: Endometriosis is a common condition that is associated with an increased risk of developing ovarian carcinoma. Improved in vitro models of this disease are needed to better understand how endometriosis, a benign disease, can undergo neoplastic transformation, and for the development of novel treatment strategies to prevent this progression.
METHODS: We describe the generation and in vitro characterization of novel TERT immortalized ovarian endometriosis epithelial cell lines (EEC16-TERT).
RESULTS: Expression of TERT alone was sufficient to immortalize endometriosis epithelial cells. TERT immortalization induces an epithelial-to-mesenchymal transition and perturbation in the expression of genes involved in the development of ovarian cancer. EEC16-TERT was non-tumorigenic when xenografted into immunocompromised mice but grew in anchorage-independent growth assays in an epidermal growth factor and hydrocortisone dependent manner. Colony formation in agar was abolished by inhibition of Src, and the Src pathway was found to be activated in human endometriosis lesions.
CONCLUSIONS: This new in vitro model system mimics endometriosis and the early stages of neoplastic transformation in the development of endometriosis associated ovarian cancer. We demonstrate the potential clinical relevance of this model by identifying Src activation as a novel pathway in endometriosis that could be targeted therapeutically, perhaps as a novel strategy to manage endometriosis clinically, or to prevent the development of endometriosis-associated ovarian cancer.

Casarini L, Simoni M
Gene polymorphisms in female reproduction.
Methods Mol Biol. 2014; 1154:75-90 [PubMed] Related Publications
This chapter presents an overview of the gene polymorphisms underlying the functions of ovarian receptors and their clinical implications in the female fecundity. A selection of genetic studies revealing significant associations between receptor polymorphisms, gene mutations, and some pathological conditions (i.e., female infertility, premature ovarian failure, polycystic ovary syndrome, endometriosis) are reviewed.

Machado-Neto JA, Lazarini M, Favaro P, et al.
ANKHD1, a novel component of the Hippo signaling pathway, promotes YAP1 activation and cell cycle progression in prostate cancer cells.
Exp Cell Res. 2014; 324(2):137-45 [PubMed] Related Publications
ANKHD1 is a multiple ankyrin repeat containing protein, recently identified as a novel member of the Hippo signaling pathway. The present study aimed to investigate the role of ANKHD1 in DU145 and LNCaP prostate cancer cells. ANKHD1 and YAP1 were found to be highly expressed in prostate cancer cells, and ANKHD1 silencing decreased cell growth, delayed cell cycle progression at the S phase, and reduced tumor xenograft growth. Moreover, ANKHD1 knockdown downregulated YAP1 expression and activation, and reduced the expression of CCNA2, a YAP1 target gene. These findings indicate that ANKHD1 is a positive regulator of YAP1 and promotes cell growth and cell cycle progression through Cyclin A upregulation.

He H, Teng H, Zhou T, et al.
Unravelling the proteome of adult rhesus monkey ovaries.
Mol Biosyst. 2014; 10(3):653-62 [PubMed] Related Publications
Ovarian physiology and pathology are important areas of scientific research. Efforts have been made to identify the ovary-related transcriptomes in different species. However, the proteomic studies are limited. The rhesus monkey is very similar to humans, and it is widely used in the study of reproductive biology and medicine. In this study, using an optimized proteomics platform, we successfully identified 5723 rhesus ovarian proteins, of which 4325 proteins were consistently identified in all three replicates and with at least 2 unique peptides. The 4325 proteins were chosen for further analysis. Through gene ontology and pathway analyses, we obtained a preliminary understanding of the function of these proteins. A random immunohistochemistry analysis was used to determine the expression of proteins in various cell types. By comparing the genes identified in this study with genes that were reported to have relatively high levels of expression in human oocytes, we obtained genes that were predicted to play roles in maintenance of normal ovarian physiology. Searching the identified genes from this study against the MGI database gave us a list of proteins those exist in the rhesus monkey ovary and are important for female mouse reproduction as well. The overlap of genes in this study and the genes whose abnormal expression or dysfunction were reported to be associated with human polycystic ovary syndrome (PCOS) and premature ovarian failure (POF) prompted us to use the rhesus monkey to study these two common causes of female infertility. This study may provide a basis for future studies of human reproductive disorders using the rhesus monkey as a model.

Mateu-Huertas E, Rodriguez-Revenga L, Alvarez-Mora MI, et al.
Blood expression profiles of fragile X premutation carriers identify candidate genes involved in neurodegenerative and infertility phenotypes.
Neurobiol Dis. 2014; 65:43-54 [PubMed] Related Publications
Male premutation carriers presenting between 55 and 200 CGG repeats in the Fragile-X-associated (FMR1) gene are at risk of developing Fragile X Tremor/Ataxia Syndrome (FXTAS), and females undergo Premature Ovarian Failure (POF1). Here, we have evaluated gene expression profiles from blood in male FMR1 premutation carriers and detected a strong deregulation of genes enriched in FXTAS relevant biological pathways, including inflammation, neuronal homeostasis and viability. Gene expression profiling distinguished between control individuals, carriers with FXTAS and carriers without FXTAS, with levels of expanded FMR1 mRNA being increased in FXTAS patients. In vitro studies in a neuronal cell model indicate that expression levels of expanded FMR1 5'-UTR are relevant in modulating the transcriptome. Thus, perturbations of the transcriptome may be an interplay between the CGG expansion size and FMR1 expression levels. Several deregulated genes (DFFA, BCL2L11, BCL2L1, APP, SOD1, RNF10, HDAC5, KCNC3, ATXN7, ATXN3 and EAP1) were validated in brain samples of a FXTAS mouse model. Downregulation of EAP1, a gene involved in the female reproductive system physiology, was confirmed in female carriers. Decreased levels were detected in female carriers with POF1 compared to those without POF1, suggesting that EAP1 levels contribute to ovarian insufficiency. In summary, gene expression profiling in blood has uncovered mechanisms that may underlie different pathological aspects of the premutation. A better understanding of the transcriptome dynamics in relation with expanded FMR1 mRNA expression levels and CGG expansion size may provide mechanistic insights into the disease process and a more accurate FXTAS diagnosis to the myriad of phenotypes associated with the premutation.

Rosti RO, Sadek AA, Vaux KK, Gleeson JG
The genetic landscape of autism spectrum disorders.
Dev Med Child Neurol. 2014; 56(1):12-8 [PubMed] Related Publications
Autism spectrum disorders (ASDs) are a group of heterogeneous neurodevelopmental disorders that show impaired communication and socialization, restricted interests, and stereotypical behavioral patterns. Recent advances in molecular medicine and high throughput screenings, such as array comparative genomic hybridization (CGH) and exome and whole genome sequencing, have revealed both novel insights and new questions about the nature of this spectrum of disorders. What has emerged is a better understanding about the genetic architecture of various genetic subtypes of ASD and correlations of genetic mutations with specific autism subtypes. Based on this new information, we outline a strategy for advancing diagnosis, prognosis, and counseling for patients and families.

Ricci MT, Pennese L, Gismondi V, et al.
The FMR1 CGG repeat test is not a candidate prescreening tool for identifying women with a high probability of being carriers of BRCA mutations.
Eur J Hum Genet. 2014; 22(2):280-2 [PubMed] Free Access to Full Article Related Publications
The identification of women with a high probability of being carriers of pathogenic BRCA mutation is not straightforward and a major improvement would be the availability of markers of mutations that could be directly evaluated in individuals asking for genetic testing. The FMR1 gene testing was recently proposed as a candidate prescreening tool because an association between BRCA pathogenic mutations and FMR1 genotypes with 'low alleles' (CGG repeat number <26) was observed. To confirm this hypothesis, we evaluated the distribution of FMR1 alleles and genotypes between BRCA mutation carriers and non-carriers in a cohort of 147 Italian women, free of cancer or affected by breast and/or ovarian cancer, who were tested for the presence of BRCA mutation in a clinical setting. The distribution of FMR1 CGG repeat numbers in the two groups was similar (lower allele median/mean were 30/27.4 and 30/27.9, respectively; Mann-Whitney test P=0.997) and no difference in the FMR1 genotype distribution was present (χ(2)=0.503, d.f.=2, P=0.78). This result is in contrast with literature data and suggests that FMR1 genetic testing is not a candidate BRCA prescreening tool.

Georges A, Auguste A, Bessière L, et al.
FOXL2: a central transcription factor of the ovary.
J Mol Endocrinol. 2014; 52(1):R17-33 [PubMed] Related Publications
Forkhead box L2 (FOXL2) is a gene encoding a forkhead transcription factor preferentially expressed in the ovary, the eyelids and the pituitary gland. Its germline mutations are responsible for the blepharophimosis ptosis epicanthus inversus syndrome, which includes eyelid and mild craniofacial defects associated with primary ovarian insufficiency. Recent studies have shown the involvement of FOXL2 in virtually all stages of ovarian development and function, as well as in granulosa cell (GC)-related pathologies. A central role of FOXL2 is the lifetime maintenance of GC identity through the repression of testis-specific genes. Recently, a highly recurrent somatic FOXL2 mutation leading to the p.C134W subtitution has been linked to the development of GC tumours in the adult, which account for up to 5% of ovarian malignancies. In this review, we summarise data on FOXL2 modulators, targets, partners and post-translational modifications. Despite the progresses made thus far, a better understanding of the impact of FOXL2 mutations and of the molecular aspects of its function is required to rationalise its implication in various pathophysiological processes.

Godoy PR, Mello SS, Magalhães DA, et al.
Ionizing radiation-induced gene expression changes in TP53 proficient and deficient glioblastoma cell lines.
Mutat Res. 2013; 756(1-2):46-55 [PubMed] Related Publications
The genetic heterogeneity presented by different cell lines derived from glioblastoma (GBM) seems to influence their responses to antitumoral agents. Although GBM tumors present several genomic alterations, it has been assumed that TP53, frequently mutated in GBM, may to some extent be responsible for differences in cellular responses to antitumor agents, but this is not clear yet. To directly determine the impact of TP53 on GBM response to ionizing radiation, we compared the transcription profiles of four GBM cell lines (two with wild-type (WT) TP53 and two with mutant (MT) TP53) after 8Gy of gamma-rays. Transcript profiles of cells analyzed 30 min and 6h after irradiation showed that WT TP53 cells presented a higher number of modulated genes than MT TP53 cells. Our findings also indicate that there are several pathways (apoptosis, DNA repair/stress response, cytoskeleton organization and macromolecule metabolic process) in radiation responses of GBM cell lines that were modulated only in WT TP53 cells (30 min and 6h). Interestingly, the majority of differentially expressed genes did not present the TP53 binding site, suggesting secondary effects of TP53 on transcription. We conclude that radiation-induced changes in transcription profiles of irradiated GBM cell lines mainly depend on the functional status of TP53.

Hagerman P
Fragile X-associated tremor/ataxia syndrome (FXTAS): pathology and mechanisms.
Acta Neuropathol. 2013; 126(1):1-19 [PubMed] Free Access to Full Article Related Publications
Since its discovery in 2001, our understanding of fragile X-associated tremor/ataxia syndrome (FXTAS) has undergone a remarkable transformation. Initially characterized rather narrowly as an adult-onset movement disorder, the definition of FXTAS is broadening; moreover, the disorder is now recognized as only one facet of a much broader clinical pleiotropy among children and adults who carry premutation alleles of the FMR1 gene. Furthermore, the intranuclear inclusions of FXTAS, once thought to be a CNS-specific marker of the disorder, are now known to be widely distributed in multiple non-CNS tissues; this observation fundamentally changes our concept of the disease, and may provide the basis for understanding the diverse medical problems associated with the premutation. Recent work on the pathogenic mechanisms underlying FXTAS indicates that the origins of the late-onset neurodegenerative disorder actually lie in early development, raising the likelihood that all forms of clinical involvement among premutation carriers have a common underlying mechanistic basis. There has also been great progress in our understanding of the triggering event(s) in FXTAS pathogenesis, which is now thought to involve sequestration of one or more nuclear proteins involved with microRNA biogenesis. Moreover, there is mounting evidence that mitochondrial dysregulation contributes to the decreased cell function and loss of viability, evident in mice even during the neonatal period. Taken together, these recent findings offer hope for early interventions for FXTAS, well before the onset of overt disease, and for the treatment of other forms of clinical involvement among premutation carriers.

Zhao H, Chen ZJ
Genetic association studies in female reproduction: from candidate-gene approaches to genome-wide mapping.
Mol Hum Reprod. 2013; 19(10):644-54 [PubMed] Related Publications
Many genetic association studies have been performed to investigate disorders of female reproduction, such as polycystic ovary syndrome, premature ovarian failure and endometriosis. These disorders typically manifest heterogeneously, and their pathogeneses are influenced by polygenic and environmental factors. Researchers evaluating these genetic associations have chosen candidate genes related to hormone action, steroid biosynthesis, inflammatory cytokines and autoimmune factors. Several of these genes have yielded statistically significant associations with female reproductive disorders; however, few associations have been robust and reproducible. Whole-genome association studies generate more reliable and unbiased results and represent a breakthrough in genetic studies of female reproduction. Nevertheless, to date only a very small fraction of the overall heritability has been identified and so further studies are needed.

Gabitzsch EK, Hashmi SS, Koenig MK, et al.
Self-reported reproductive health in women with tuberous sclerosis complex.
Genet Med. 2013; 15(12):966-71 [PubMed] Related Publications
PURPOSE: Little is known about sex-specific manifestations of tuberous sclerosis complex. Inactivating mutations in the TSC1 and TSC2 genes cause tuberous sclerosis complex, and recent evidence points to a crucial role for these genes in maintaining appropriate ovarian function. The main objective of this study was to estimate reproductive dysfunction in a sample of women with tuberous sclerosis complex.
METHODS: We designed a three-part questionnaire that included demographic information, reproductive history, and tuberous sclerosis complex history, and developed strict criteria to assess patterns in menstrual cyclicity; we analyzed 182 responses from female adult members of the Tuberous Sclerosis Alliance.
RESULTS: More than one-third of women in our sample displayed some degree of menstrual irregularity, and their reported miscarriage rate was 41%. More than 4% of women had reproductive histories suggestive of premature ovarian insufficiency, higher than the general population estimate of 1%.
CONCLUSION: Our data reveal an underappreciated aspect of tuberous sclerosis complex in affected women, suggesting that a further exploration of the role the tuberous sclerosis complex genes play in reproductive function is warranted.

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