82 research outputs found
Clinical and molecular characterization of a cohort of patients with novel nucleotide alterations of the Dystrophin gene detected by direct sequencing
<p>Abstract</p> <p>Background</p> <p>Duchenne and Becker Muscular dystrophies (DMD/BMD) are allelic disorders caused by mutations in the dystrophin gene, which encodes a sarcolemmal protein responsible for muscle integrity. Deletions and duplications account for approximately 75% of mutations in DMD and 85% in BMD. The implementation of techniques allowing complete gene sequencing has focused attention on small point mutations and other mechanisms underlying complex rearrangements.</p> <p>Methods</p> <p>We selected 47 patients (41 families; 35 DMD, 6 BMD) without deletions and duplications in <it>DMD </it>gene (excluded by multiplex ligation-dependent probe amplification and multiplex polymerase chain reaction analysis). This cohort was investigated by systematic direct sequence analysis to study sequence variation. We focused our attention on rare mutational events which were further studied through transcript analysis.</p> <p>Results</p> <p>We identified 40 different nucleotide alterations in DMD gene and their clinical correlates; altogether, 16 mutations were novel. DMD probands carried 9 microinsertions/microdeletions, 19 nonsense mutations, and 7 splice-site mutations. BMD patients carried 2 nonsense mutations, 2 splice-site mutations, 1 missense substitution, and 1 single base insertion. The most frequent stop codon was TGA (n = 10 patients), followed by TAG (n = 7) and TAA (n = 4). We also analyzed the molecular mechanisms of five rare mutational events. They are two frame-shifting mutations in the <it>DMD </it>gene 3'end in BMD and three novel splicing defects: IVS42: c.6118-3C>A, which causes a leaky splice-site; c.9560A>G, which determines a cryptic splice-site activation and c.9564-426 T>G, which creates pseudoexon retention within IVS65.</p> <p>Conclusion</p> <p>The analysis of our patients' sample, carrying point mutations or complex rearrangements in <it>DMD </it>gene, contributes to the knowledge on phenotypic correlations in dystrophinopatic patients and can provide a better understanding of pre-mRNA maturation defects and dystrophin functional domains. These data can have a prognostic relevance and can be useful in directing new therapeutic approaches, which rely on a precise definition of the genetic defects as well as their molecular consequences.</p
Duchenne muscular dystrophy caused by a frame-shift mutation in the acceptor splice site of intron 26
Antisense PMO cocktails effectively skip dystrophin exons 45-55 in myotubes transdifferentiated from DMD patient fibroblasts
Antisense-mediated exon skipping has made significant progress as a therapeutic platform in recent years, especially in the case of Duchenne muscular dystrophy (DMD). Despite FDA approval of eteplirsen-the first-ever antisense drug clinically marketed for DMD-exon skipping therapy still faces the significant hurdles of limited applicability and unknown truncated protein function. In-frame exon skipping of dystrophin exons 45-55 represents a significant approach to treating DMD, as a large proportion of patients harbor mutations within this "hotspot" region. Additionally, patients harboring dystrophin exons 45-55 deletion mutations are reported to have exceptionally mild to asymptomatic phenotypes. Here, we demonstrate that a cocktail of phosphorodiamidate morpholino oligomers can effectively skip dystrophin exons 45-55 in vitro in myotubes transdifferentiated from DMD patient fibroblast cells. This is the first report of substantive exons 45-55 skipping in DMD patient cells. These findings help validate the use of transdifferentiated patient fibroblast cells as a suitable cell model for dystrophin exon skipping assays and further emphasize the feasibility of dystrophin exons 45-55 skipping in patients
Observation and study of baryonic B decays: B -> D(*) p pbar, D(*) p pbar pi, and D(*) p pbar pi pi
We present a study of ten B-meson decays to a D(*), a proton-antiproton pair,
and a system of up to two pions using BaBar's data set of 455x10^6 BBbar pairs.
Four of the modes (B0bar -> D0 p anti-p, B0bar -> D*0 p anti-p, B0bar -> D+ p
anti-p pi-, B0bar -> D*+ p anti-p pi-) are studied with improved statistics
compared to previous measurements; six of the modes (B- -> D0 p anti-p pi-, B-
-> D*0 p anti-p pi-, B0bar -> D0 p anti-p pi- pi+, B0bar -> D*0 p anti-p pi-
pi+, B- -> D+ p anti-p pi- pi-, B- -> D*+ p anti-p pi- pi-) are first
observations. The branching fractions for 3- and 5-body decays are suppressed
compared to 4-body decays. Kinematic distributions for 3-body decays show
non-overlapping threshold enhancements in m(p anti-p) and m(D(*)0 p) in the
Dalitz plots. For 4-body decays, m(p pi-) mass projections show a narrow peak
with mass and full width of (1497.4 +- 3.0 +- 0.9) MeV/c2, and (47 +- 12 +- 4)
MeV/c2, respectively, where the first (second) errors are statistical
(systematic). For 5-body decays, mass projections are similar to phase space
expectations. All results are preliminary.Comment: 28 pages, 90 postscript figures, submitted to LP0
Midwives' knowledge, attitudes and practice about alcohol exposure and the risk of fetal alcohol spectrum disorder
All-sky search for gravitational-wave bursts in the second joint LIGO-Virgo run
We present results from a search for gravitational-wave bursts in the data
collected by the LIGO and Virgo detectors between July 7, 2009 and October 20,
2010: data are analyzed when at least two of the three LIGO-Virgo detectors are
in coincident operation, with a total observation time of 207 days. The
analysis searches for transients of duration < 1 s over the frequency band
64-5000 Hz, without other assumptions on the signal waveform, polarization,
direction or occurrence time. All identified events are consistent with the
expected accidental background. We set frequentist upper limits on the rate of
gravitational-wave bursts by combining this search with the previous LIGO-Virgo
search on the data collected between November 2005 and October 2007. The upper
limit on the rate of strong gravitational-wave bursts at the Earth is 1.3
events per year at 90% confidence. We also present upper limits on source rate
density per year and Mpc^3 for sample populations of standard-candle sources.
As in the previous joint run, typical sensitivities of the search in terms of
the root-sum-squared strain amplitude for these waveforms lie in the range 5
10^-22 Hz^-1/2 to 1 10^-20 Hz^-1/2. The combination of the two joint runs
entails the most sensitive all-sky search for generic gravitational-wave bursts
and synthesizes the results achieved by the initial generation of
interferometric detectors.Comment: 15 pages, 7 figures: data for plots and archived public version at
https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=70814&version=19, see
also the public announcement at
http://www.ligo.org/science/Publication-S6BurstAllSky
Frequency of the different mutations causing spinocerebellar ataxia (SCA1, SCA2, MJD/SCA3 and DRPLA) in a large group of Brazilian patients
Clinical and genetic epidemiological study of 16q22.1-linked autosomal dominant cerebellar ataxia in western Japan
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