409 research outputs found
Oto‐spondylo‐megaepiphyseal dysplasia (OSMED): Clinical description of three patients homozygous for a missense mutation in the COL11A2 gene
Single hole dynamics in the t-J model on two- and three-leg ladders
The dynamics of a single hole in the t-J model on two- (2LL) and three- (3LL)
leg ladders is studied using a recently developed quantum Monte Carlo
algorithm. For the 2LL it is shown that in addition to the most pronounced
features of the spectral function, well described by the limit of strong
coupling along the rungs, a clear shadow band appears in the antibonding
channel. Moreover, both the bonding band and its shadow have a finite
quasiparticle (QP) weight in the thermodynamic limit. For strong coupling along
the rungs of the 3LL, the low-energy spectrum in the antisymmetric channel is
similar to a one-dimensional chain, whereas in the two symmetric channels it
resembles the 2LL. The QP weight vanishes in the antisymmetric channel, but is
finite in the symmetric one
Получение полуизолирующего кремния для высоковольтных приборов
Исследовано влияние условий осаждения на структуру и электрофизические свойства пленок поликристаллического кремния, легированного кислородом. Результаты использованы при изготовлении изделий силовой электроники
Genotype versus phenotype in families with androgen insensitivity syndrome
Androgen insensitivity syndrome encompasses a wide range of phenotypes,
which are caused by numerous different mutations in the AR gene. Detailed
information on the genotype/phenotype relationship in androgen
insensitivity syndrome is important for sex assignment, treatment of
androgen insensitivity syndrome patients, genetic counseling of their
families, and insight into the functional domains of the AR. The commonly
accepted concept of dependence on fetal androgens of the development of
Wolffian ducts was studied in complete androgen insensitivity syndrome
(CAIS) patients. In a nationwide survey in The Netherlands, all cases (n =
49) with the presumptive diagnosis androgen insensitivity syndrome known
to pediatric endocrinologists and clinical geneticists were studied. After
studying the clinical phenotype, mutation analysis and functional analysis
of mutant receptors were performed using genital skin fibroblasts and in
vitro expression studies. Here we report the findings in families with
multiple affected cases. Fifty-nine percent of androgen insensitivity
syndrome patients had other affected relatives. A total of 17 families
were studied, seven families with CAIS (18 patients), nine families with
partial androgen insensitivity (24 patients), and one family with female
prepubertal phenotypes (two patients). No phenotypic variation was
observed in families with CAIS. However, phenotypic variation was observed
in one-third of families with partial androgen insensitivity resulting in
different sex of rearing and differences in requirement of reconstructive
surgery. Intrafamilial phenotypic variation was observed for mutations
R846H, M771I, and deletion of amino acid N682. Four newly identified
mutations were found. Follow-up in families with different AR gene
mutations provided information on residual androgen action in vivo and the
development of the prepubertal and adult phenotype. Patients with a
functional complete defective AR had some pubic hair, Tanner stage P2, and
vestigial Wolffian duct derivatives despite absence of AR expression.
Vaginal length was functional in most but not all CAIS patients. The
minimal incidence of androgen insensitivity syndrome in The Netherlands,
based on patients with molecular proof of the diagnosis is 1:99,000.
Phenotypic variation was absent in families with CAIS, but distinct
phenotypic variation was observed relatively frequent in families with
partial androgen insensitivity. Molecular observations suggest that
phenotypic variation had different etiologies among these families. Sex
assignment of patients with partial androgen insensitivity cannot be based
on a specific identified AR gene mutation because distinct phenotypic
variation in partial androgen insensitivity families is relatively
frequent. In genetic counseling of partial androgen insensitivity
families, this frequent occurrence of variable expression resulting in
differences in sex of rearing and/or requirement of reconstructive surgery
is important information. During puberty or normal dose androgen therapy,
no or only minimal virilization may occur even in patients with
significant (but still deficient) prenatal virilization. Wolffian duct
remnants remain detectable but differentiation does not occur in the
absence of a functional AR. In many CAIS patients, surgical elongation of
the vagina is not indicated
POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome
Background: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration, which causes a cobblestone cortex. Ocular abnormalities include cataract, microphthalmia, buphthalmos, and Peters anomaly. WWS patients show defective O-glycosylation of α-dystroglycan (α-DG), which plays a key role in bridging the cytoskeleton of muscle and CNS cells with extracellular matrix proteins, important for muscle integrity and neuronal migration. In 20% of the WWS patients, hypoglycosylation results from mutations in either the protein O-mannosyltransferase 1 (POMT1), fukutin, or fukutin related protein (FKRP) genes. The other genes for this highly heterogeneous disorder remain to be identified. Objective: To look for mutations in POMT2 as a cause of WWS, as both POMT1 and POMT2 are required to achieve protein O-mannosyltransferase activity. Methods: A candidate gene approach combined with homozygosity mapping. Results: Homozygosity was found for the POMT2 locus at 14q24.3 in four of 11 consanguineous WWS families. Homozygous POMT2 mutations were present in two of these families as well as in one patient from another cohort of six WWS families. Immunohistochemistry in muscle showed severely reduced levels of glycosylated α-DG, which is consistent with the postulated role for POMT2 in the O-mannosylation pathway. Conclusions: A fourth causative gene for WWS was uncovered. These genes account for approximately one third of the WWS cases. Several more genes are anticipated, which are likely to play a role in glycosylation of α-DG
Avaliação sorológica da vacina oral, tipo Sabin, contra a poliomielite em região semi - rural: II - Aspectos quantitativos dos anticorpos formados e anticorpos para outros enterovirus
Cellular interference in craniofrontonasal syndrome: Males mosaic for mutations in the x-linked EFNB1 gene are more severely affected than true hemizygotes
Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundariesa process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5 untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69. The 5 UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females. © The Author 2013. Published by Oxford University Press. All rights reserved
Relations between the milnor and quillen K-theory of fields
De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles
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