LAMB1 gene analysis should be considered for intellectually disabled patients with cerebellar cysts, white matter signal change, and cortical malformation. Muscular involvement is absent, in contrast ...to the α‐dystroglycanopathy types of congenital muscular dystrophies.
Context. The Bulge is the least understood major stellar population of the Milky Way. Most of what we know about the formation and evolution of the Bulge comes from bright giant stars. The underlying ...assumption that giants represent all the stars, and accurately trace the chemical evolution of a stellar population, is under debate. In particular, recent observations of a few microlensed dwarf stars give a very different picture of the evolution of the Bulge from that given by the giant stars. Aims. We aim to resolve the apparent discrepancy between Bulge metallicity distributions derived from microlensed dwarf stars and giant stars. Additionally, we aim to put observational constraints on the elemental abundance trends and chemical evolution of the Bulge. Methods. We perform a detailed elemental abundance analysis of dwarf stars in the Galactic bulge, based on high-resolution spectra that were obtained while the stars were optically magnified during gravitational microlensing events. The analysis method is the same as for a large sample of F and G dwarf stars in the Solar neighbourhood, enabling a fully differential comparison between the Bulge and the local stellar populations in the Galactic disc. Results. We present detailed elemental abundances and stellar ages for six new dwarf stars in the Galactic bulge. Combining these with previous events, here re-analysed with the same methods, we study a homogeneous sample of 15 stars, which constitute the largest sample to date of microlensed dwarf stars in the Galactic bulge. We find that the stars span the full range of metallicities from Fe/H = -0.72 to + 0.54, and an average metallicity of <Fe/H> = -0.08 +/- 0.47, close to the average metallicity based on giant stars in the Bulge. Furthermore, the stars follow well-defined abundance trends, that for Fe/H<0 are very similar to those of the local Galactic thick disc. This suggests that the Bulge and the thick disc have had, at least partially, comparable chemical histories. At sub-solar metallicities we find the Bulge dwarf stars to have consistently old ages, while at super-solar metallicities we find a wide range of ages. Using the new age and abundance results from the microlensed dwarf stars we investigate possible formation scenarios for the Bulge.
The chimeric fusion protein AML1-ETO, created by the t(8;21) translocation, recruits histone deacetylase (HDAC) to AML1-dependent promoters, resulting in transcriptional repression of the target ...genes. We analyzed the transcriptional changes in t(8;21) Kasumi-1 AML cells in response to the HDAC inhibitors, depsipeptide (FK228) and suberoylanilide hydroxamic acid (SAHA), which induced marked growth inhibition and apoptosis. Using cDNA array, annexin A1 (ANXA1) was identified as one of the FK228-induced genes. Induction of ANXA1 mRNA was associated with histone acetylation in ANXA1 promoter and reversal of the HDAC-dependent suppression of C/EBPalpha by AML1-ETO with direct recruitment of C/EBPalpha to ANXA1 promoter. This led to increase in the N-terminal cleaved isoform of ANXA1 protein and accumulation of ANXA1 on cell membrane. Neutralization with anti-ANXA1 antibody or gene silencing with ANXA1 siRNA inhibited FK228-induced apoptosis, suggesting that the upregulation of endogenous ANXA1 promotes cell death. FK228-induced ANXA1 expression was associated with massive increase in cell attachment and engulfment of Kasumi-1 cells by human THP-1-derived macrophages, which was completely abrogated with ANXA1 knockdown via siRNA transfection or ANXA1 neutralization. These findings identify a novel mechanism of action of HDAC inhibitors, which induce the expression and externalization of ANXA1 in leukemic cells, which in turn mediates the phagocytic clearance of apoptotic cells by macrophages.
We report the detection of sub-Saturn-mass planet MOA-2008-BLG-310Lb and argue that it is the strongest candidate yet for a bulge planet. Deviations from the single-lens fit are smoothed out by ...finite-source effects and therefore are not immediately apparent from the light curve. Nevertheless, we find that a model in which the primary has a planetary companion is favored over the single-lens model by DELTAchi{sup 2} {approx} 880 for an additional 3 degrees of freedom. Detailed analysis yields a planet/star mass ratio q = (3.3 +- 0.3) x 10{sup -4} and an angular separation between the planet and star within 10% of the angular Einstein radius. The small angular Einstein radius, theta{sub E} = 0.155 +- 0.011 mas, constrains the distance to the lens to be D{sub L} >6.0 kpc if it is a star (M{sub L} >0.08 M{sub sun}). This is the only microlensing exoplanet host discovered so far that must be in the bulge if it is a star. By analyzing VLT NACO adaptive optics images taken near the baseline of the event, we detect additional blended light that is aligned to within 130 mas of the lensed source. This light is plausibly from the lens, but could also be due to a companion to the lens or source, or possibly an unassociated star. If the blended light is indeed due to the lens, we can estimate the mass of the lens, M{sub L} = 0.67 +- 0.14 M{sub sun}, planet mass m = 74 +- 17 M{sub +}, and projected separation between the planet and host, 1.25 +- 0.10 AU, putting it right on the 'snow line'. If not, then the planet has lower mass, is closer to its host and is colder. To distinguish among these possibilities on reasonable timescales would require obtaining Hubble Space Telescope images almost immediately, before the source-lens relative motion of mu= 5 mas yr{sup -1} causes them to separate substantially.
Saitsu H, Hoshino H, Kato M, Nishiyama K, Okada I, Yoneda Y, Tsurusaki Y, Doi H, Miyake N, Kubota M, Hayasaka K, Matsumoto N. Paternal mosaicism of an STXBP1 mutation in OS.
Ohtahara syndrome (OS) is ...one of the most severe and earliest forms of epilepsy. We have recently identified that the de novo mutations of STXBP1 are important causes for OS. Here we report a paternal somatic mosaicism of an STXBP1 mutation. The affected daughter had onset of spasms at 1 month of age, and interictal electroencephalogram showed suppression‐burst pattern, leading to the diagnosis of OS. She had a heterozygous c.902+5G>A mutation of STXBP1, which affects donor splicing of exon 10, resulting in 138‐bp insertion of intron 10 sequences in the transcript. The mutant transcript had a premature stop codon, and was degraded by nonsense‐mediated mRNA decay in lymphoblastoid cells derived from the patient. High‐resolution melting analysis of clinically unaffected parental DNAs suggested that the father was somatic mosaic for the mutation, which was also suggested by sequencing. Cloning of PCR products amplified with the paternal DNA samples extracted from blood, saliva, buccal cells, and nails suggested that 5.3%, 8.7%, 11.9%, and 16.9% of alleles harbored the mutation, respectively. This is a first report of somatic mosaicism of an STXBP1 mutation, which has implications in genetic counseling of OS.
Conventional PCR-based direct sequencing of candidate genes for a family with X-linked leucoencephalopathy with unknown aetiology failed to identify any causative mutations.
To carry out exome ...sequencing of entire transcripts of the whole X chromosome to investigate a family with X linked leucoencephalopathy.
Next-generation sequencing of all the transcripts of the X chromosome, after liquid-based genome partitioning, was performed on one of the two affected male subjects (the proband) and an unaffected male subject (his brother). A nonsense mutation in MCT8 (c.1102A→T (p.R368X)) was identified in the proband. Subsequent PCR-based direct sequencing of other family members confirmed the presence of this mutation, hemizygous in the other affected brother and heterozygous in the proband's mother and maternal grandmother. MCT8 mutations usually cause abnormal thyroid function in addition to neurological abnormalities, but this proband had normal thyroid function.
Single-lane exome next-generation sequencing is sufficient to fully analyse all the transcripts of the X chromosome. This method is particularly suitable for mutation screening of X-linked recessive disorders and can avoid biases in candidate gene choice.
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