Κυριακή 27 Νοεμβρίου 2016
Bi-allelic IARS Mutations in a Child with Intra-Uterine Growth Retardation, Neonatal Cholestasis, and Mild Developmental Delay
Abstract
Recently, bi-allelic mutations in cytosolic isoleucyl-tRNA synthetase (IARS) have been described in three individuals with growth delay, hepatic dysfunction, and neurodevelopmental disabilities. Here we report an additional subject with this condition identified by whole-exome sequencing. Our findings support the association between this disorder and neonatal cholestasis with distinct liver pathology. Furthermore, we provide functional data on two novel missense substitutions and expand the phenotype to include mild developmental delay, skin hyper-elasticity, and hypervitaminosis D.
Graphical Abstract
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Novel mutations in KARS cause hypertrophic cardiomyopathy and combined mitochondrial respiratory chain defect
Abstract
Mutations in KARS, which encodes for both mitochondrial and cytoplasmic lysyl-tRNA synthethase, have been so far associated with three different phenotypes: the recessive form of Charcot Mary-Tooth polyneuropathy, the autosomal recessive non-syndromic hearing loss and the last recently described condition related to congenital visual impairment and progressive microcephaly. Here we report the case of a 14-years-old-girl with severe cardiomyopathy associated to mild psychomotor delay and mild myopathy; moreover, a diffuse reduction of cytochrome C oxidase (COX, complex IV) and a combined enzymatic defect of complex I (CI) and IV (CIV) was evident in muscle biopsy. Using the TruSight One sequencing panel we identified two novel mutations in KARS. Both mutations, never reported previously, occur in a highly conserved region of the catalytic domain and had a dramatic effect on KARS stability. Structural analysis confirmed the pathogenic role of the identified variants. Our findings confirm and emphasize that mt-ARSs enzymes are related to a broad clinical spectrum due to their multiple and still unknown functions.
Graphical Abstract
mutations in KARS impact on the mitochondrial function causing combined mitochondrial CI and CIV deficiencies and a hypertrophic cardiomyopathy.
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Role of TRPM7 in Cerebral Ischaemia and Hypoxia
Abstract
Transient receptor potential melastatin 7 (TRPM7) channel, a calcium-permeable non-selective divalent cation channel, is broadly expressed in various cells and tissues, including the brain. TRPM7 is thought to be coupled to the metabolic state and regulate calcium homeostasis in the cell. TRPM7 takes part in a wide range of cell biology processes that affect cell growth and proliferation, as well as in embryonic development and skeleton formation. TRPM7 plays a significant role in ischaemic and hypoxic brain injury and neuronal cell death. TRPM7, as a key non-glutamate mechanism of cerebral ischaemia, also triggers an intracellular ionic imbalance and neuronal cell death in ischaemia and hypoxia. We have reported that TRPM7 is expressed in neurons of the hippocampus and cortex and activation of TRPM7 induced ischaemic neuronal cell death; suppression of TRPM7 with virally mediated gene silencing using siRNA reduced ischaemic neuronal cell death and improved neurobehavioural outcomes in vivo. Recently, we also demonstrated that inhibition of TRPM7 using pharmacological means promoted neuronal outgrowth in vitro and provided neuroprotection against brain injury to hypoxia in vivo. Thus, we have shown the contributions of TRPM7 in many physiological and pathophysiological processes, including hypoxia and ischaemia.
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NC first responders receive pink ambulance
The idea behind a pink ambulance sporting breast cancer awareness ribbons is that it will strike up conversations and spread a pro-mammogram message to the community.
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Intestinal stem cell transplantation
Abstract
Organoid technologies to expand intestinal epithelial cells are gaining increasing attention as a useful tool to investigate many aspects of intestinal epithelial biology and pathology. One important application of organoid systems would be to use intestinal epithelial cells expanded in culture for following transplantation experiments. In this article, we present a brief overview of the studies that have succeeded in generating new epithelial tissues in the surface of native intestines in mice by organoid transplantation. We also discuss possible applications of this experimental approach in basic research on the intestinal epithelium as well as in regenerative medicine for various types of intestinal diseases in humans.
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