378 research outputs found
ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease
Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for similar to 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot-Marie-Tooth disease type 2H on chromosome 8q13-21.1 was excluded by linkage analysis. Pedigrees originated in Italy, Brazil, Canada, England, Iran, and Japan. Interestingly, we identified 15 ALS5/SPG11/KIAA1840 mutations in 12 families (two sequence variants were never reported before, p.Gln198* and p.Pro2212fs*5). No large deletions/duplications were detected in these patients. The novel mutations seemed to be pathogenic since they co-segregated with the disease in all pedigrees and were absent in 300 unrelated controls. Furthermore, in silico analysis predicted their pathogenic effect. Our results indicate that ALS5/SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease
Frameshift mutations at the C-terminus of HIST1H1E result in a specific DNA hypomethylation signature
BACKGROUND: We previously associated HIST1H1E mutations causing Rahman syndrome with a specific genome-wide methylation pattern. RESULTS: Methylome analysis from peripheral blood samples of six affected subjects led us to identify a specific hypomethylated profile. This "episignature" was enriched for genes involved in neuronal system development and function. A computational classifier yielded full sensitivity and specificity in detecting subjects with Rahman syndrome. Applying this model to a cohort of undiagnosed probands allowed us to reach diagnosis in one subject. CONCLUSIONS: We demonstrate an epigenetic signature in subjects with Rahman syndrome that can be used to reach molecular diagnosis
Study of Z Boson Pair Production in e+e- Collisions at LEP at \sqrt{s}=189 GeV
The pair production of Z bosons is studied using the data collected by the L3
detector at LEP in 1998 in e+e- collisions at a centre-of-mass energy of 189
GeV. All the visible final states are considered and the cross section of this
process is measured to be 0.74 +0.15 -0.14 (stat.) +/- 0.04 (syst.) pb. Final
states containing b quarks are enhanced by a dedicated selection and their
production cross section is found to be 0.18 +0.09 -0.07 (stat.) +/- 0.02
(syst.) pb. Both results are in agreement with the Standard Model predictions.
Limits on anomalous couplings between neutral gauge bosons are derived from
these measurements
Search for Scalar Leptons in e+e- collisions at \sqrt{s}=189 GeV
We report the result of a search for scalar leptons in e+e- collisions at 189
GeV centre-of-mass energy at LEP. No evidence for such particles is found in a
data sample of 176 pb^{-1}. Improved upper limits are set on the production
cross sections for these new particles. New exclusion contours in the parameter
space of the Minimal Supersymmetric Standard Model are derived, as well as new
lower limits on the masses of these supersymmetric particles. Under the
assumptions of common gaugino and scalar masses at the GUT scale, we set an
absolute lower limit on the mass of the lightest scalar electron of 65.5 Ge
Search for Low Scale Gravity Effects in e+e- Collisions at LEP
Recent theories propose that quantum gravity effects may be observable at LEP
energies via gravitons that couple to Standard Model particles and propagate
into extra spatial dimensions. The associated production of a graviton and a
photon is searched for as well as the effects of virtual graviton exchange in
the processes: e+e- -> gamma gamma, ZZ, WW, mu mu, tau tau, qq and ee No
evidence for this new interaction is found in the data sample collected by the
L3 detector at LEP at centre-of-mass energies up to 183 GeV. Limits close to 1
TeV on the scale of this new scenario of quantum gravity are set
Formation of the in Two-Photon Collisions at LEP
The two-photon width of the meson has been
measured with the L3 detector at LEP. The is studied in the decay
modes , KK, KK,
KK, , , and
using an integrated luminosity of 140 pb at GeV and
of 52 pb at GeV. The result is
(BR) keV. The dependence of the cross section is studied for
GeV. It is found to be better described by a Vector Meson
Dominance model form factor with a J-pole than with a -pole. In addition,
a signal of events is observed at the mass. Upper limits
for the two-photon widths of the , , and are also
given
Search for Charginos with a Small Mass Difference with the Lightest Supersymmetric Particle at \sqrt{s} = 189 GeV
A search for charginos nearly mass-degenerate with the lightest
supersymmetric particle is performed using the 176 pb^-1 of data collected at
189 GeV in 1998 with the L3 detector. Mass differences between the chargino and
the lightest supersymmetric particle below 4 GeV are considered. The presence
of a high transverse momentum photon is required to single out the signal from
the photon-photon interaction background. No evidence for charginos is found
and upper limits on the cross section for chargino pair production are set. For
the first time, in the case of heavy scalar leptons, chargino mass limits are
obtained for any \tilde{\chi}^{+-}_1 - \tilde{\chi}^0_1 mass difference
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