Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by capillary malformation (port-wine stains), and choroidal and leptomeningeal vascular malformations. Previously, the recurrent ...somatic mutation c.548G>A (p.R183Q) in the G-α q gene (GNAQ) was identified as causative in SWS and non-syndromic port-wine stain patients using whole-genome sequencing. In this study, we investigated somatic mutations in GNAQ by next-generation sequencing. We first performed targeted amplicon sequencing of 15 blood-brain-paired samples in sporadic SWS and identified the recurrent somatic c.548G>A mutation in 80% of patients (12 of 15). The percentage of mutant alleles in brain tissues of these 12 patients ranged from 3.6 to 8.9%. We found no other somatic mutations in any of the seven GNAQ exons in the remaining three patients without c.548G>A. These findings suggest that the recurrent somatic GNAQ mutation c.548G>A is the major determinant genetic factor for SWS and imply that other mutated candidate gene(s) may exist in SWS.
Spiky strings in de Sitter space Kato, Mitsuhiro; Nishii, Kanji; Noumi, Toshifumi ...
The journal of high energy physics,
05/2021, Letnik:
2021, Številka:
5
Journal Article
Recenzirano
Odprti dostop
A
bstract
We study semiclassical spiky strings in de Sitter space and the corresponding Regge trajectories, generalizing the analysis in anti-de Sitter space. In particular we demonstrate that each ...Regge trajectory has a maximum spin due to de Sitter acceleration, similarly to the folded string studied earlier. While this property is useful for the spectrum to satisfy the Higuchi bound, it makes a nontrivial question how to maintain mildness of high-energy string scattering which we are familiar with in flat space and anti-de Sitter space. Our analysis implies that in order to have infinitely many higher spin states, one needs to consider infinitely many Regge trajectories with an increasing folding number.
Vacuolar H
-ATPases (V-ATPases) transport protons across cellular membranes to acidify various organelles. ATP6V0A1 encodes the a1-subunit of the V0 domain of V-ATPases, which is strongly expressed ...in neurons. However, its role in brain development is unknown. Here we report four individuals with developmental and epileptic encephalopathy with ATP6V0A1 variants: two individuals with a de novo missense variant (R741Q) and the other two individuals with biallelic variants comprising one almost complete loss-of-function variant and one missense variant (A512P and N534D). Lysosomal acidification is significantly impaired in cell lines expressing three missense ATP6V0A1 mutants. Homozygous mutant mice harboring human R741Q (Atp6v0a1
) and A512P (Atp6v0a1
) variants show embryonic lethality and early postnatal mortality, respectively, suggesting that R741Q affects V-ATPase function more severely. Lysosomal dysfunction resulting in cell death, accumulated autophagosomes and lysosomes, reduced mTORC1 signaling and synaptic connectivity, and lowered neurotransmitter contents of synaptic vesicles are observed in the brains of Atp6v0a1
mice. These findings demonstrate the essential roles of ATP6V0A1/Atp6v0a1 in neuronal development in terms of integrity and connectivity of neurons in both humans and mice.
AADC deficiency causes severe motor and intellectual disability as a result of reduced catecholamine levels. Kojima et al. report beneficial effects of gene therapy in six patients with heterogeneous ...genetic backgrounds. Gene delivery into putamen improved motor function in all patients, plus verbal and cognitive skills in one moderate-phenotype patient.
Abstract
In patients with aromatic l-amino acid decarboxylase (AADC) deficiency, a decrease in catecholamines and serotonin levels in the brain leads to developmental delay and movement disorders. The beneficial effects of gene therapy in patients from 1 to 8 years of age with homogeneous severity of disease have been reported from Taiwan. We conducted an open-label phase 1/2 study of population including adolescent patients with different degrees of severity. Six patients were enrolled: four males (ages 4, 10, 15 and 19 years) and one female (age 12 years) with a severe phenotype who were not capable of voluntary movement or speech, and one female (age 5 years) with a moderate phenotype who could walk with support. The patients received a total of 2 × 1011 vector genomes of adeno-associated virus vector harbouring DDC via bilateral intraputaminal infusions. At up to 2 years after gene therapy, the motor function was remarkably improved in all patients. Three patients with the severe phenotype were able to stand with support, and one patient could walk with a walker, while the patient with the moderate phenotype could run and ride a bicycle. This moderate-phenotype patient also showed improvement in her mental function, being able to converse fluently and perform simple arithmetic. Dystonia disappeared and oculogyric crisis was markedly decreased in all patients. The patients exhibited transient choreic dyskinesia for a couple of months, but no adverse events caused by vector were observed. PET with 6-18Ffluoro-l-m-tyrosine, a specific tracer for AADC, showed a persistently increased uptake in the broad areas of the putamen. In our study, older patients (>8 years of age) also showed improvement, although treatment was more effective in younger patients. The genetic background of our patients was heterogeneous, and some patients suspected of having remnant enzyme activity showed better improvement than the Taiwanese patients. In addition to the alleviation of motor symptoms, the cognitive and verbal functions were improved in a patient with the moderate phenotype. The restoration of dopamine synthesis in the putamen via gene transfer provides transformative medical benefit across all patient ages, genotypes, and disease severities included in this study, with the most pronounced improvements noted in moderate patients.
10.1093/brain/awy331_video1
awy331media1
5991361892001
Symptomatic West syndrome has heterogeneous backgrounds. Recently, two novel genes,
ARX and
CDKL5, have been found to be responsible for cryptogenic West syndrome or infantile spasms. Both are ...located in the human chromosome Xp22 region and are mainly expressed and play roles in fetal brain. Moreover, several genes responsible for brain malformations including lissencephaly, which is frequently associated with West syndrome or infantile spasms, have been found, and the mechanisms responsible for the neural network disorders in these brain malformations are rapidly being determined. Findings of animal and in vitro studies and mutation analyses in humans are delineating the molecular and cellular basis of West syndrome.
Mutations of the
ARX gene controlling the development of GABAergic interneurons exhibit pleiotropic effects including lissencephaly with a strong genotype–phenotype correlation. An expansion mutation of the first polyalanine tract of
ARX is more strongly related to infantile spasms than is that of the second polyalanine tract. Although the phenotype of
CDKL5 mutation is similar to Rett syndrome caused by
MECP2 mutation, the former is characterized by early-onset seizures and association with West syndrome. Lissencephaly caused by
LIS1 or
DCX mutation frequently results in West syndrome, while lissencephaly due to
ARX mutation is associated with the most severe form of epilepsy but never results in West syndrome nor infantile spasms. Both LIS1 and DCX participate in the development of GABAergic interneurons as well as pyramidal neurons, while ARX participates only in that of interneurons. Individuals with lissencephaly due to
ARX mutation lack non-pyramidal or GABAergic interneurons. ARX is crucial for the development of GABAergic interneuron, so abnormal interneurons in patients with ARX mutation are thought to be implicated in the pathological mechanism, even though brain MRI is normal. Abnormal interneurons appear to play an essential role in the pathogenesis of West syndrome or infantile spasms, which can be considered an interneuronopathy.
Abstract
Covariant quantization of a multi-pronged open bosonic string junction is studied beyond static analysis. Its excited states are described by a set of ordinary bosons as well as some sets of ...twisted bosons on the worldsheet. The system is characterized by a certain large algebra of twisted type that includes a single Virasoro algebra as a subalgebra. By properly defining the physical states, one can show that there are no ghosts in the Hilbert space.
Objective
Focal cortical dysplasia (FCD) type IIb is a cortical malformation characterized by cortical architectural abnormalities, dysmorphic neurons, and balloon cells. It has been suggested that ...FCDs are caused by somatic mutations in cells in the developing brain. Here, we explore the possible involvement of somatic mutations in FCD type IIb.
Methods
We collected a total of 24 blood‐brain paired samples with FCD, including 13 individuals with FCD type IIb, 5 with type IIa, and 6 with type I. We performed whole‐exome sequencing using paired samples from 9 of the FCD type IIb subjects. Somatic MTOR mutations were identified and further investigated using all 24 paired samples by deep sequencing of the entire gene's coding region. Somatic MTOR mutations were confirmed by droplet digital polymerase chain reaction. The effect of MTOR mutations on mammalian target of rapamycin (mTOR) kinase signaling was evaluated by immunohistochemistry and Western blotting analyses of brain samples and by in vitro transfection experiments.
Results
We identified four lesion‐specific somatic MTOR mutations in 6 of 13 (46%) individuals with FCD type IIb showing mutant allele rates of 1.11% to 9.31%. Functional analyses showed that phosphorylation of ribosomal protein S6 in FCD type IIb brain tissues with MTOR mutations was clearly elevated, compared to control samples. Transfection of any of the four MTOR mutants into HEK293T cells led to elevated phosphorylation of 4EBP, the direct target of mTOR kinase.
Interpretation
We found low‐prevalence somatic mutations in MTOR in FCD type IIb, indicating that activating somatic mutations in MTOR cause FCD type IIb. Ann Neurol 2015;78:375–386
Heterozygous variants in TUBB encoding one of β-tubulin isotypes are known to cause two overlapping developmental brain disorders, complex cortical dysplasia with other brain malformations (CDCBM) ...and congenital symmetric circumferential skin creases (CSCSC). To date, six cases of CSCSC and eight cases of CDCBM caused by nine heterozygous variants have been reported. Here we report two cases with novel de novo missense TUBB variants (NM_178014.4:c.863A>G, p.(Glu288Gly) and c.869C>T, p.(Thr290Ile)). Case 1 presented brain malformations consistent with tubulinopathies including abnormalities in cortex, basal ganglia, corpus callosum, brain stem, and cerebellum along with other systemic features such as coloboma, facial dysmorphisms, vesicoureteral reflux, hypoplastic kidney, and cutis laxa-like mild skin loosening. Another case presented abnormalities of the corpus callosum, brain stem, and cerebellum along with facial dysmorphisms. We reviewed previous literature and suggest the diversity of clinical findings of TUBB-related disorders.
We construct a class of quadratic gauge invariant actions for extended string fields defined on the tensor product of open superstring state space for multiple open string Neveu–Schwarz (NS) sectors ...with or without one Ramond (R) sector. The basic idea is the same as for the bosonic extended string field theory developed by the authors 1. The theory for NSn sector and NSn−1–R sector contains general n-th rank tensor fields and (n−1)-th rank spinor–tensor fields in the massless spectrum respectively. In principle, consistent gauge invariant actions for any generic type of 10-dimensional massive or massless tensor or spinor–tensor fields can be extracted from the theory. We discuss some simple examples of bosonic and fermionic massless actions.
By exome sequencing, we found de novo SMARCB1 mutations in two of five individuals with typical Coffin-Siris syndrome (CSS), a rare autosomal dominant anomaly syndrome. As SMARCB1 encodes a subunit ...of the SWItch/Sucrose NonFermenting (SWI/SNF) complex, we screened 15 other genes encoding subunits of this complex in 23 individuals with CSS. Twenty affected individuals (87%) each had a germline mutation in one of six SWI/SNF subunit genes, including SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID1A and ARID1B.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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