Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss

DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability. DNA mismatch repair, cell cycle regulation in post-mitotic neurons and neurogenesis are influenced by DNA methylation. Here we show that mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy with dementia and hearing loss. Exome sequencing led to the identification of DNMT1 mutation c.1484A>G (p.Tyr495Cys) in two American kindreds and one Japanese kindred and a triple nucleotide change, c.1470-1472TCC>ATA (p.Asp490Glu-Pro491Tyr), in one European kindred. All mutations are within the targeting-sequence domain of DNMT1. These mutations cause premature degradation of mutant proteins, reduced methyltransferase activity and impaired heterochromatin binding during the G2 cell cycle phase leading to global hypomethylation and site-specific hypermethylation. Our study shows that DNMT1 mutations cause the aberrant methylation implicated in complex pathogenesis. The discovered DNMT1 mutations provide a new framework for the study of neurodegenerative diseases.     

Glutamate transporter EAAT2: regulation,function, and potential as a therapeutic target for neurological and psychiatric disease

Glutamate is the predominant excitatory neurotransmitter in the central nervous system. Excitatory amino acid transporter 2 (EAAT2) is primarily responsible for clearance of extracellular glutamate to prevent neuronal excitotoxicity and hyperexcitability. EAAT2 plays a critical role in regulation of synaptic activity and plasticity. In addition, EAAT2 has been implicated in the pathogenesis of many central nervous system disorders. In this review, we summarize current understanding of EAAT2, including structure, pharmacology, physiology, and functions, as well as disease relevancy, such as in stroke, Parkinson’s disease, epilepsy, amyotrophic lateral sclerosis, Alzheimer’s disease, major depressive disorder, and addiction. A large number of studies have demonstrated that up-regulation of EAAT2 protein provides significant beneficial effects in many disease models suggesting EAAT2 activation is a promising therapeutic approach. Several EAAT2 activators have been identified. Further understanding of EAAT2 regulatory mechanisms could improve development of drug-like compounds that spatiotemporally regulate EAAT2.     

Thrombin-stimulated cell division involves proteolysis of its cell surface receptor.

A cell-surface component of molecular weight 43,000 is cleaved by thrombin on cells that divide after thrombin treatment, but is not cleaved on cells that are unresponsive to its mitogenic action. Studies with a photoreactive derivative of thrombin showed that its cell surface receptor has a molecular weight of 43,000. This indicates that thrombin must cleave its receptor to stimulate cell division.     

Chronology of the early Solar System from chondrule-bearing calcium-aluminium-rich inclusions

Chondrules and Ca-Al-rich inclusions (CAIs) are high-temperature components of meteorites that formed during transient heating events in the early Solar System. A major unresolved issue is the relative timing of CAI and chondrule formation. From the presence of chondrule fragments in an igneous CAI, it was concluded that some chondrules formed before CAIs (ref. 5). This conclusion is contrary to the presence of relict CAIs inside chondrules, as well as to the higher abundance of 26Al in CAIs; both observations indicate that CAIs pre-date chondrules by 1-3 million years (Myr). Here we report that relict chondrule material in the Allende meteorite, composed of olivine and low-calcium pyroxene, occurs in the outer portions of two CAIs and is 16O-poor (Delta17O approximately -1 per thousand to -5 per thousand). Spinel and diopside in the CAI cores are 16O-rich (Delta17O up to -20 per thousand), whereas diopside in their outer zones, as well as melilite and anorthite, are 16O-depleted (Delta17O = -8 per thousand to 2 per thousand). Both chondrule-bearing CAIs are 26Al-poor with initial 26Al/27Al ratios of (4.7 +/- 1.4) x 10(-6) and <1.2 x 10(-6). We conclude that these CAIs had chondrule material added to them during a re-melting episode approximately 2 Myr after formation of CAIs with the canonical 26Al/27Al ratio of 5 x 10(-5).     

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Affiliated to Astrophysics Div., Space Science Department, European Space Agency.     

Submillimetre galaxies reside in dark matter haloes with masses greater than 3 × 10(11) solar masses

The extragalactic background light at far-infrared wavelengths comes from optically faint, dusty, star-forming galaxies in the Universe with star formation rates of a few hundred solar masses per year. These faint, submillimetre galaxies are challenging to study individually because of the relatively poor spatial resolution of far-infrared telescopes. Instead, their average properties can be studied using statistics such as the angular power spectrum of the background intensity variations. A previous attempt at measuring this power spectrum resulted in the suggestion that the clustering amplitude is below the level computed with a simple ansatz based on a halo model. Here we report excess clustering over the linear prediction at arcminute angular scales in the power spectrum of brightness fluctuations at 250, 350 and 500?μm. From this excess, we find that submillimetre galaxies are located in dark matter haloes with a minimum mass, M(min), such that log(10)[M(min)/M(⊙)] = 11.5(+0.7)(-0.2) at 350?μm, where M(⊙) is the solar mass. This minimum dark matter halo mass corresponds to the most efficient mass scale for star formation in the Universe, and is lower than that predicted by semi-analytical models for galaxy formation.     

Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function

Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.