FMR1 missense mutation associated with intellectual disability and seizures

Most patients inherit the syndrome through a maternal repeat expansion mutation that transcriptionally silences the FMR1 gene and results in loss of the gene product, FMRP. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation.

After sequencing 963 developmentally delayed males, we identified a patient with an R138Q missense mutation in the FMR1 gene.


The R138Q mutation does not impair FMRP’s postsynaptic function as a translation regulator, as evidenced by rescue of AMPA receptor trafficking, intact polyribosome association, and mRNA pull-down.  Expression of the mutant FMRP is unable to rescue structural defects at the neuro-muscular junction in fragile x mental retardation 1 deficient Drosophila.

We show that R138Q is a partial loss-of-function mutation that specifically impairs a presynaptic FMRP function while preserving the translation regulation capabilities of FMRP. Besides, the R138Q mutation also disrupts FMRP’s interaction with the large-conductance calcium-activated potassium (BK) channels that modulate AP width.

In summary, our study of the R138Q missense mutation in FMR1 provides a first step in opening the door of the domain-specific functions of FMRP in pre- and postsynaptic compartments, and their contribution to various elements of FXS pathophysiology.


World Cancer Day 2015: One in two British people will be diagnosed with the disease at some point in their lives

One in two people will develop a cancer at some point in their lives, experts now estimate. Previous calculations that indicated cancer will affect just over one in three people were underestimating the scale of the disease, according to a new analysis by Cancer Research UK. However, because of advances in treatment and early detection, more people are now surviving cancer.


Two-thirds of the increase in risk can be attributed to the fact we are now living longer, and cancer is a disease that becomes more likely the older we get. The additional third is down to changes in lifestyle, CRUK said. The study calculates the lifetime risk of cancer for men born in the UK in 1960 is 53.5 per cent and for women 47.55 per cent, averaging at 50.5 per cent. The risk is likely to increase for people born after 1960, and CRUK said it was confident in predicting that this meant at least half the population can now expect to get cancer.

Recent estimates suggest that half of people who get cancer now survive the disease for 10 years or more – so it is projected that despite more cases, the number of deaths attributable to cancer will remain stable at around one in four.

Changes in lifestyle that have contributed to the increase in cancer risk include an increase in obesity, which is linked to a number of cancers and is projected to continue rising. Higher consumption of red and processed meats is also linked to a rise in bowel cancer. Other factors include an increase in the culture of using sunbeds and sunbathing, which has increased incidence of skin cancer, while women having babies later and breastfeeding less is also raising their chance of developing breast cancer. As well as this, more cancers are being detected by screening programmes.

Many research associate gene with drug resistance in testicular cancer

Scientists at The Institute of Cancer Research, London, have uncovered several new genetic mutations that drive testicular cancer, and also identified a gene which may contribute to tumours becoming resistant to existing treatment. The finding, based on the whole-exome sequencing technology, published in the journal Nature Communications.

The research is the first to use state-of-the-art sequencing technology to look into the detail testicular germ cell tumours from 42 patients at the Royal Marsden NHS Foundation Trust, which make up the vast majority of testicular cancers and are the most common cancers in young men.

In the research, they uncovered a number of new chromosome duplications and other abnormalities that could result in the development of this cancer. For instance, they found defective copies of a DNA repair gene called XRCC2 in a patient who had become resistant to platinum-based chemotherapy, as well as verifying the link between XRCC2 and platinum resistance by sequencing an additional sample from another platinum-resistant tumour.

Although generally testicular cancer responds well to treatment, resistance to platinum-based chemotherapy is linked to a poor long-term survival rate. The research provides a clue to why around 3 percent of patients develop resistance to platinum chemotherapy, as well as new insights into testicular germ cell tumours generally.

A researcher, involved in this study, said ” we have identified new potential driver mutations for this type of cancer in the largest comprehensive sequencing study of testicular tumours published to date, and provided new evidence of a link between mutations in the gene XRCC2 and platinum treatment-resistant tumours. ”

He added, “we now need additional studies with a larger number of patients, focusing in particular on platinum-resistant tumours, to help our discoveries lead to new options for those unlucky men whose cancer progresses in spite of the best available treatments.

Another researcher said, ” survival rates for testicular cancer are generally very good, but a subset of men don’t respond to standard platinum chemotherapy, and the new research has identified a possible genetic cause for that drug resistance. Knowing which are the key genes driving a cancer’s development or helping it dodge the effects of chemotherapy is crucial to help us use current drugs more effectively and to design the next generation of drugs for personalized medicine.”

Nature medicine:BCL-2 inhibitor acute leukemia

Mutant isocitrate dehydrogenase (IDH) 1 and 2 proteins alter the epigenetic landscape in acute myeloid leukemia (AML) cells through production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). The study performed a large-scale RNA interference (RNAi) screen to identify genes that are synthetic lethal to the IDH1R132H mutation in AML and identified the anti-apoptotic gene BCL-2.IDH1- and IDH2-mutant primary human AML cells were more sensitive than IDH1/2 wild-type cells to ABT-199, a highly specific BCL-2 inhibitor that is currently in clinical trials for hematologic malignancies, both ex vivo and in xenotransplant models.


This sensitization effect was induced by (R)-2-HG-mediated inhibition of the activity of cytochrome c oxidase (COX) in the mitochondrial electron transport chain (ETC); suppression of COX activity lowered the mitochondrial threshold to trigger apoptosis upon BCL-2 inhibition. The research indicate that IDH1/2 mutation status may identify patients that are likely to respond to pharmacologic BCL-2 inhibition and form the rational basis for combining agents that disrupt ETC activity with ABT-199 in future clinical studies.


Steven M Chan, Daniel Thomas,et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia [J]. Nature medicine;2015.doi:10.1038/nm.3788.

Suppressing CHI3L1 Reduces Cancer Cell Metastasis

Researchers from University of Brown have found that by decreasing or blocking specific protein level, two different types of cancer cells could be suppressed to metastasize in mice. This protein is common in human and other animals. The imbalance of the protein contributes to cancer metastasis. This study was published in Cancer Research.


Chitinase 3-like-1(Chi3L1) is the prototypic mammalian CLP. It was originally discovered in mouse breast cancer cells. It is now known to be expressed by a variety of cells including macrophages, neutrophis, epithelial cells, smooth muscle cells and chondrocytes and is stimulated by a number of mediators including IL-12, IL-6, IL-1β, and IFNγ. The Chi3L1 is induced in cancers and portends a poor prognosis, but whether it contributes to cancer progression is unknown.

In this study, scientists hypothesized that host Chi3L1 plays an essential role in the pathogenesis of malignant melanoma and that interventions that alter the induction Chi3L1 decrease the metastatic spread of this tumor. To test this hypothesis they characterized the ability of B16-F10 melanoma cells to stimulate Chi3L1 in wild type mice and their ability to generate pulmonary metastasis in wild type(WT) mice and mice with null mutations of Chi3L1.

Their studies highlight a novel host pathway in which Sema7a stimulates the production of Chi3L1 by interacting with β1 integrin and inhibits Chi3L1 by interacting with Plexin C1. They also demonstrate that the host Sema7a- Chi3L1-IL-13Rα2 axis plays a critical role in the generation of a metastasis-permissive pulmonary microenvironment leading to melanoma lung metastasis.


Ma B, Herzog E L, Lee C G, et al. Role of Chitinase 3-like-1 and Semaphorin 7A in Pulmonary Melanoma Metastasis[J]. Cancer research, 2014: canres. 3339.2013.

Scientists Reveal the Molecular Mechanism of Skin Cancer’s Initiation, Propagation, and Deterioration.

Scientists from free University of Brussel have indicated that Twist1 could regulate the skin cancer‘s propagation and the function of cancer stem cells to suppress the deterioration process. They use transgenetic mice as the subjects, successfully identified the molecular of cancer’s initiation, propagation, and deterioration. This study was published in Cell Stem Cell.


The epithelial-to-mesenchymal transition(EMT) is a cellular process during which epithelial cells lose their adhesion properties and acquire mesenchymal features allowing their migration and invasion.Twist1, a basic-helix-loop-helix transcription factor, is one of the EMT-inducer prototypes. Twist1 deletion in mice leads to failure in neural tube closure associated with defects in the formation of the head mesenchyme and limb buds.

Mechanistically, Twist1 overexpression has been shown to rescue Myc-induced apoptosis through inhibition of p53. However, to what extent these different functions of Twist1 including its effect on EMT, stemness, proliferation, and apoptosis are functionally linked or whether these functions are independently regulated by Twist1 remians unknown.

In this study, using conditional deletion of Twist1 at different stages of skin tumorigenesis, researchers investigated the different functions of Twist1 and their interdependence during tumor initiation, maintenance, propagation, and malignant progression. They found that Twist1 is expressed at the earliest step of tumorigenesis and is essential for the initiation and maliganant progression of skin tumors in a gene-dosage-dependent manner. Conditional deletion of Twist1 in pre-existing tumors demonstrates the essential role of Twist1 in tumor maintenance. Twist1 inhibits oncogene-induced apoptosis in a p53-dependent manner, while the ability of Twist1 to promote tumor cell proliferation and propagation is regulated by a p53-in-dependent mechanism. Strikingly, these oncogenic functions of Twist are not dependent upon its ability to induce EMT.


Beck B, Lapouge G, Rorive S, et al. Different Levels of Twist1 Regulate Skin Tumor Initiation, Stemness, and Progression[J]. Cell stem cell, 2015, 16(1): 67-79.

Reduce the Spread of Cancer Growth by Inhibiting the CHI3L1

The latest studies establish a novel pathway through which Sem7a and its receptors regulate Chi3l1, revealing a host axis involving IL13Rα2 that plays a critical role in generating a pulmonary microenvironment that is critical to license metastasis.


The prototypic chitinase-like protein Chi3l1 is induced in cancers and portends a poor prognosis, but whether it contributes to cancer progression is unknown. To address this gap in knowledge, the scientists investigated the production of Chi3l1 in melanoma lung metastases. The study found that Chi3l1 was induced during pulmonary melanoma metastasis and that this induction was regulated by the semaphorin Sema7a, interacting in stimulatory or inhibitory ways with its β1 integrin or Plexin C1 receptors, respectively. In mouse strains with genetic deletions of Chi3l1 or Sema7a, there was a significant reduction in pulmonary metastasis. Notably, antiserum raised against Chi3l1 or Sema7a phenocopied the reduction produced by genetic deletions. Melanoma lung metastasis was also decreased in the absence of IL13Rα2, a recently identified receptor for Chi3l1, consistent with a key role for Chi3l1 in melanoma spread. The study confirmed roles for Sema7a and Chi3l1 in pulmonary metastasis of EMT6 breast cancer cells.

Taken together, the studies establish a novel pathway through which Sem7a and its receptors regulate Chi3l1, revealing a host axis involving IL13Rα2 that plays a critical role in generating a pulmonary microenvironment that is critical to license metastasis.


Bing Ma, Erica L. Herzog,et al.Role of Chitinase 3–like-1 and Semaphorin 7a in Pulmonary Melanoma Metastasis [J].Cancer Res; 75(3); 1–10.

Acetylation controls TDP-43 function and aggregation

TDP-43 is an RNA-binding protein and a biomarker of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration.  Here, we identify lysine acetylation as a novel post-translational modification controlling TDP-43 function and aggregation.

From a large scale identification of acetylation sites data (a global proteome contain 1,750 proteins), we found two acetylation sites (Lys-145 and Lys-192) on TDP-43. And then, confirmed the modification by pan-acetylation antibody and mass spectrum.


As TDP-43 binds to 6,000 genes and regulates target RNAs that are essential for proper neuronal development and synaptic function, given that the acetylated lysines are located within the RRM domains, we guess the acetylation may affect its RNA binding activity. The double mutant (TDP-K145Q or TDP-2KQ), showed a 50–65% decrease in RNA binding. TDP-43 acetylation mimics (K-Q) to the cytoplasm increased P-409/410 levels in insoluble fractions.

Co-expression of WT HDAC6, but not a catalytically inactive H803A mutant, together with CBP was sufficient to deacetylate cytoplasmic TDP-43 under normal cellular conditions.

We also show acetylated TDP-43 lesions are found in ALS patient spinal cord, indicating that aberrant TDP-43 acetylation and loss of RNA binding.

The identification of a reversible TDP-43 acetylation switch provides a novel framework to understand both physiological and pathological TDP-43 functions, which could lead to targeted therapies against ALS.

Scientists Demonstrate Metastasizing Mechanism of Lung Cancer

Scientists from University of Manchester have demonstrated that how proteins were cut in lung cancer cells, making metastasis possible. Their finding may be helpful in the development of cancer therapy to block metastasis in the future. This study was published in Cell Reports.


Metastasis, a multistep process beginning with local invasion and culminating in the colonization of distant organs by cancer cells, is responsible for more than 90% of all cancer deaths. Metastasis of arcinoma cells often commences with the disassembly of junctional complexes and downregulation of other epithelial traits coupled with the acquisition of migratory and invasive mesenchymal phenotype(epithelial-mesenchymal thransition[EMT]).

In this study, researchers show that in response to human grow factor(HGF), HUWE1(WWE domain-containing protein 1) ubiquitylates TIAM1(metastasis inducing protein 1) on lysine 595, triggering its proteasomal degradation predominantly at cell-cell adhesions, thereby enabling disassembly of cell junctions and induction of cell migration and invasion, including in lung carcinoma cells. They also show that TIAM1 and HUWE1 protein levels are negatively correlat3ed in early-stage lung cancer specimens, consistent with this regulatory mechanism operating in human tumors.


Vaughan L, Tan C T, Chapman A, et al. HUWE1 Ubiquitylates and Degrades the RAC Activator TIAM1 Promoting Cell-Cell Adhesion Disassembly, Migration, and Invasion[J]. Cell Reports, 2014.

New Cancer Therapy based on Gene Repair Mechanism Developed

Scientists from Case Western Reserve University have developed a new therapeutic method to weaken and kill cancer cells. This technique could enhance the level of cancer-inhibiting protein to kill tumors by directly targeting cancer cells. This study was published in PNAS.

Prompt response to double-strand break(DSB) caused by, for example, ionization radiation(IR), requires sequential and coordinated assembly of DNA damage response(DDR) proteins at damage sites. Recent research findings reveal key roles of the tumor suppressor p53-binding protein 1(53BP1) and BRCA1 in the decision making of DSB repair.


DSB repair sits at the core of genome stability maintenance. Abnormalities in the repair pathway often lead to the development of cancers and resistance to anti-cancer therapies. Tumor suppressor p53-binding protein 1(53BP1), a protein critical in regulating DSB repair, is reduced in advanced breast tumors. Furthermore, low levels of 53BP1 correlated with poor prognosis and resistance to chemotherapy. Thus, the protein level of 53BP1 is important for therapeutic response. However, mechanisms regulating 53BP1 protein levels are poorly understood.

In this study, researchers report a previously unidentified mechanism regulating the protein level of 53BP1, specifically, ubiquitin-conjugating enzyme H7(UbcH7)-dependent ubiquitination and proteasome-dependent degradation. They further propose an innovative hypothesis that increasing the protein level of 53BP1 enhances the effect of radiotherapy or chemotherapy through suppressing faithful DSB repair.


Han X, Zhang L, Chung J, et al. UbcH7 regulates 53BP1 stability and DSB repair[J]. Proceedings of the National Academy of Sciences, 2014, 111(49): 17456-17461.

Cancer related signaling pathway, e.g. Wnt signaling,stat3,NF-KB