4,894 research outputs found
Perrault syndrome with neurological features in a compound heterozygote for two TWNK mutations : Overlap of TWNK-related recessive disorders
Altres ajuts: This research was supported with cofounding from the European Regional Development Fund (ERDF), "A way to make Europe") (to IdC); S2017/BMD‑3721‑RAREGENOMICS‑CM from the Consejería de Educación e Investigación de la Comunidad de Madrid (to MAMP).Background: Perrault syndrome is a rare autosomal recessive disorder that is characterized by the association of sensorineural hearing impairment and ovarian dysgenesis in females, whereas males have only hearing impairment. In some cases, patients present with a diversity of neurological signs. To date, mutations in six genes are known to cause Perrault syndrome, but they do not explain all clinically-diagnosed cases. In addition, the number of reported cases and the spectra of mutations are still small to establish conclusive genotype-phenotype correlations. Methods: Affected siblings from family SH19, who presented with features that were suggestive of Perrault syndrome, were subjected to audiological, neurological and gynecological examination. The genetic study included genotyping and haplotype analysis for microsatellite markers close to the genes involved in Perrault syndrome, whole-exome sequencing, and Sanger sequencing of the coding region of the TWNK gene. Results: Three siblings from family SH19 shared similar clinical features: childhood-onset bilateral sensorineural hearing impairment, which progressed to profound deafness in the second decade of life; neurological signs (spinocerebellar ataxia, polyneuropathy), with onset in the fourth decade of life in the two females and at age 20 years in the male; gonadal dysfunction with early cessation of menses in the two females. The genetic study revealed two compound heterozygous pathogenic mutations in the TWNK gene in the three affected subjects: c.85C>T (p.Arg29∗), previously reported in a case of hepatocerebral syndrome; and a novel missense mutation, c.1886C>T (p.Ser629Phe). Mutations segregated in the family according to an autosomal recessive inheritance pattern. Conclusions: Our results further illustrate the utility of genetic testing as a tool to confirm a tentative clinical diagnosis of Perrault syndrome. Studies on genotype-phenotype correlation from the hitherto reported cases indicate that patients with Perrault syndrome caused by TWNK mutations will manifest neurological signs in adulthood. Molecular and clinical characterization of novel cases of recessive disorders caused by TWNK mutations is strongly needed to get further insight into the genotype-phenotype correlations of a phenotypic continuum encompassing Perrault syndrome, infantile-onset spinocerebellar ataxia, and hepatocerebral syndrome
Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane
Tecta is a modular, non-collagenous protein of the tectorial membrane, an extracellular matrix of the cochlea essential for normal hearing. Missense mutations in Tecta cause dominant forms of nonsyndromic deafness and a genotype-phenotype correlation has been reported in humans, with mutations in different Tecta domains causing mid- or high-frequency hearing impairments that are either stable or progressive. Three mutant mice were created as models for human Tecta mutations; the TectaL1820F, G1824D/+ mouse for zona pellucida (ZP) domain mutations causing stable mid-frequency hearing loss in a Belgian family, the TectaC1837G/+ mouse for a ZP-domain mutation underlying progressive mid-frequency hearing loss in a Spanish family, and the TectaC1619S/+ mouse for a zonadhesin-like (ZA) domain mutation responsible for progressive, high-frequency hearing loss in a French family. Mutations in the ZP and ZA domains generate distinctly different changes in the structure of the tectorial membrane. ABR thresholds in the 8-40 kHz range are elevated by 30-40 dB in the ZP-domain mutants, whilst those in the ZA-domain mutant are elevated by 20-30 dB. The phenotypes are stable and no evidence has been found for a progressive deterioration in tectorial membrane structure or auditory function. Despite elevated auditory thresholds, the Tecta mutant mice all exhibit an enhanced tendency to have audiogenic seizures in response to white noise stimuli at low sound pressure levels (≤84 dB SPL), revealing a previously unrecognised consequence of Tecta mutations. These results, together with those from previous studies, establish an allelic series for Tecta unequivocally demonstrating an association between genotype and phenotype
Constraining the Ratio in TeV Cosmic Rays with Observations of the Moon Shadow by HAWC
An indirect measurement of the antiproton flux in cosmic rays is possible as
the particles undergo deflection by the geomagnetic field. This effect can be
measured by studying the deficit in the flux, or shadow, created by the Moon as
it absorbs cosmic rays that are headed towards the Earth. The shadow is
displaced from the actual position of the Moon due to geomagnetic deflection,
which is a function of the energy and charge of the cosmic rays. The
displacement provides a natural tool for momentum/charge discrimination that
can be used to study the composition of cosmic rays. Using 33 months of data
comprising more than 80 billion cosmic rays measured by the High Altitude Water
Cherenkov (HAWC) observatory, we have analyzed the Moon shadow to search for
TeV antiprotons in cosmic rays. We present our first upper limits on the
fraction, which in the absence of any direct measurements, provide
the tightest available constraints of on the antiproton fraction for
energies between 1 and 10 TeV.Comment: 10 pages, 5 figures. Accepted by Physical Review
All-particle cosmic ray energy spectrum measured by the HAWC experiment from 10 to 500 TeV
We report on the measurement of the all-particle cosmic ray energy spectrum
with the High Altitude Water Cherenkov (HAWC) Observatory in the energy range
10 to 500 TeV. HAWC is a ground based air-shower array deployed on the slopes
of Volcan Sierra Negra in the state of Puebla, Mexico, and is sensitive to
gamma rays and cosmic rays at TeV energies. The data used in this work were
taken from 234 days between June 2016 to February 2017. The primary cosmic-ray
energy is determined with a maximum likelihood approach using the particle
density as a function of distance to the shower core. Introducing quality cuts
to isolate events with shower cores landing on the array, the reconstructed
energy distribution is unfolded iteratively. The measured all-particle spectrum
is consistent with a broken power law with an index of prior to
a break at ) TeV, followed by an index of . The
spectrum also respresents a single measurement that spans the energy range
between direct detection and ground based experiments. As a verification of the
detector response, the energy scale and angular resolution are validated by
observation of the cosmic ray Moon shadow's dependence on energy.Comment: 16 pages, 11 figures, 4 tables, submission to Physical Review
Observation of the Crab Nebula with the HAWC Gamma-Ray Observatory
The Crab Nebula is the brightest TeV gamma-ray source in the sky and has been
used for the past 25 years as a reference source in TeV astronomy, for
calibration and verification of new TeV instruments. The High Altitude Water
Cherenkov Observatory (HAWC), completed in early 2015, has been used to observe
the Crab Nebula at high significance across nearly the full spectrum of
energies to which HAWC is sensitive. HAWC is unique for its wide field-of-view,
nearly 2 sr at any instant, and its high-energy reach, up to 100 TeV. HAWC's
sensitivity improves with the gamma-ray energy. Above 1 TeV the
sensitivity is driven by the best background rejection and angular resolution
ever achieved for a wide-field ground array.
We present a time-integrated analysis of the Crab using 507 live days of HAWC
data from 2014 November to 2016 June. The spectrum of the Crab is fit to a
function of the form . The data is well-fit with values of
, , and
log when
is fixed at 7 TeV and the fit applies between 1 and 37 TeV. Study of the
systematic errors in this HAWC measurement is discussed and estimated to be
50\% in the photon flux between 1 and 37 TeV.
Confirmation of the Crab flux serves to establish the HAWC instrument's
sensitivity for surveys of the sky. The HAWC survey will exceed sensitivity of
current-generation observatories and open a new view of 2/3 of the sky above 10
TeV.Comment: Submitted 2017/01/06 to the Astrophysical Journa
The 2HWC HAWC Observatory Gamma Ray Catalog
We present the first catalog of TeV gamma-ray sources realized with the
recently completed High Altitude Water Cherenkov Observatory (HAWC). It is the
most sensitive wide field-of-view TeV telescope currently in operation, with a
1-year survey sensitivity of ~5-10% of the flux of the Crab Nebula. With an
instantaneous field of view >1.5 sr and >90% duty cycle, it continuously
surveys and monitors the sky for gamma ray energies between hundreds GeV and
tens of TeV.
HAWC is located in Mexico at a latitude of 19 degree North and was completed
in March 2015. Here, we present the 2HWC catalog, which is the result of the
first source search realized with the complete HAWC detector. Realized with 507
days of data and represents the most sensitive TeV survey to date for such a
large fraction of the sky. A total of 39 sources were detected, with an
expected contamination of 0.5 due to background fluctuation. Out of these
sources, 16 are more than one degree away from any previously reported TeV
source. The source list, including the position measurement, spectrum
measurement, and uncertainties, is reported. Seven of the detected sources may
be associated with pulsar wind nebulae, two with supernova remnants, two with
blazars, and the remaining 23 have no firm identification yet.Comment: Submitted 2017/02/09 to the Astrophysical Journa
Search for very-high-energy emission from Gamma-ray Bursts using the first 18 months of data from the HAWC Gamma-ray Observatory
The High Altitude Water Cherenkov (HAWC) Gamma-ray Observatory is an
extensive air shower detector operating in central Mexico, which has recently
completed its first two years of full operations. If for a burst like GRB
130427A at a redshift of 0.34 and a high-energy component following a power law
with index -1.66, the high-energy component is extended to higher energies with
no cut-off other than from extragalactic background light attenuation, HAWC
would observe gamma rays with a peak energy of 300 GeV. This paper
reports the results of HAWC observations of 64 gamma-ray bursts (GRBs) detected
by and , including three GRBs that were also
detected by the Large Area Telescope (-LAT). An ON/OFF analysis
method is employed, searching on the time scale given by the observed light
curve at keV-MeV energies and also on extended time scales. For all GRBs and
time scales, no statistically significant excess of counts is found and upper
limits on the number of gamma rays and the gamma-ray flux are calculated. GRB
170206A, the third brightest short GRB detected by the Gamma-ray Burst Monitor
on board the satellite (-GBM) and also
detected by the LAT, occurred very close to zenith. The LAT measurements can
neither exclude the presence of a synchrotron self-Compton (SSC) component nor
constrain its spectrum. Instead, the HAWC upper limits constrain the expected
cut-off in an additional high-energy component to be less than
for reasonable assumptions about the energetics and redshift of the burst.Comment: 19 pages, 6 figures, published in Ap
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