The role of RAS mutations in MLL-rearranged leukaemia: A path to intervention?

Childhood acute lymphoblastic leukaemia (ALL) with MLL rearrangement (MLL-r) is an aggressive disease still associated with a high mortality rate. Recent investigations have identified co-operating mutations in the RAS pathway and although the functional consequences of these mutations are not yet fully understood, aberrant regulation of RAS pathway signalling at both transcriptional and protein levels is observed. Studies investigating the efficacy of specific inhibitors of this pathway, e.g. MEK-inhibitors, have also achieved encouraging results. In this context, this mini-review summarizes the available data surrounding MLL-r infant ALL with RAS mutation in relation to other well-known features of this intriguing disease

Gut-microbiota link in Parkinson’s disease: current perspectives

Parkinson’s disease(PD) is a metacentric neurodegenerative disorder results with accumulation and aggregation of alpha-synculein(α-Syn) (or alpha-synculeinopathy) in the substantia nigra in the central nervous system(CNS).Contributory factors include pesticide exposure, head injury and agriculture background. PD has been considered to be a non-genetic disorder, however around 15% individuals with PD have firstdegree relative who has the disease Mutations in genes including SNCA,LRRK2 and gluococerebrosidase (GBA) found to be risk factor for sporadic PD. Brain cells could be lost due to an abnormal accumulation of the protein alpha-synculein.This insoluble protein accumulates inside neurons forming inclusions called Lewy bodies. Other cell death mechanisms include proteasomal and lysosomal system dysfunction, but the mechanisms are not fully understood. Brain –gut axis(GBA) refers to central nervous system(CNS) control of the enteric nervous system(ENS) through vagus nerve intervention. PD is characterized by alphasynculeinopathy affecting all levels of the brain-gut axis.Both clinical and neuropathological evidences indicate the neurodegenerative changes in PD are accompanied by gastrointestinal symptoms that may precede or follow the central nervous systemimpairment. Frequent symptoms in PD include tremor, rigidity, slowness of movement and difficulty with walking. Treatment with L-DOPA(levodopa),with dopamine agonist, medications become less effective and produce complications. Research studies recommend new therapeutic approach in PD based on modification of the gut microbiota with probiotics, prebiotics, or even fecal microbiota transplantation

A negative screen for mutations in calstabin 1 and 2 genes in patients with dilated cardiomyopathy

<p>Abstract</p> <p>Background</p> <p>Calstabins 1 and 2 bind to Ryanodine receptors regulating muscle excitation-contraction coupling. Mutations in Ryanodine receptors affecting their interaction with calstabins lead to different cardiac pathologies. Animal studies suggest the involvement of calstabins with dilated cardiomyopathy.</p> <p>Results</p> <p>We tested the hypothesis that calstabins mutations may cause dilated cardiomyopathy in humans screening 186 patients with idiopathic dilated cardiomyopathy for genetic alterations in calstabins 1 and 2 genes (<it>FKBP12 </it>and <it>FKBP12.6)</it>. No missense variant was found. Five no-coding variations were found but not related to the disease.</p> <p>Conclusions</p> <p>These data corroborate other studies suggesting that mutations in <it>FKBP12 </it>and <it>FKBP12.6 </it>genes are not commonly related to cardiac diseases.</p

Irf4 is a positional and functional candidate gene for the control of serum IgM levels in the mouse

Natural IgM are involved in numerous immunological functions but the genetic factors that control the homeostasis of its secretion and upholding remain unknown. Prompted by the finding that C57BL/6 mice had significantly lower serum levels of IgM when compared with BALB/c mice, we performed a genome-wide screen and found that the level of serum IgM was controlled by a QTL on chromosome 13 reaching the highest level of association at marker D13Mit266 (LOD score¼3.54). This locus was named IgMSC1 and covered a region encompassing the interferon-regulatory factor 4 gene (Irf4). The number of splenic mature B cells in C57BL/6 did not differ from BALB/c mice but we found that low serum levels of IgM in C57BL/6 mice correlated with lower frequency of IgM-secreting cells in the spleen and in the peritoneal cavity. These results suggested that C57BL/6 mice have lower efficiency in late B-cell maturation, a process that is highly impaired in Irf4 knockout mice. In fact, we also found reduced Irf4 gene expression in B cells of C57BL/6 mice. Thus, we propose Irf4 as a candidate for the IgMSC1 locus, which controls IgM homeostatic levels at the level of B-cell terminal differentiation