1,282 research outputs found
SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome
OBJECTIVE: To describe the genetic and clinical features of a simplex patient with distal hereditary motor neuropathy (dHMN) and lower limb spasticity (Silver-like syndrome) due to a mutation in the sigma nonopioid intracellular receptor-1 gene (SIGMAR1) and review the phenotypic spectrum of mutations in this gene. METHODS: We used whole-exome sequencing to investigate the proband. The variants of interest were investigated for segregation in the family using Sanger sequencing. Subsequently, a larger cohort of 16 unrelated dHMN patients was specifically screened for SIGMAR1 mutations. RESULTS: In the proband, we identified a homozygous missense variant (c.194T>A, p.Leu65Gln) in exon 2 of SIGMAR1 as the probable causative mutation. Pathogenicity is supported by evolutionary conservation, in silico analyses, and the strong phenotypic similarities with previously reported cases carrying coding sequence mutations in SIGMAR1. No other mutations were identified in 16 additional patients with dHMN. CONCLUSIONS: We suggest that coding sequence mutations in SIGMAR1 present clinically with a combination of dHMN and pyramidal tract signs, with or without spasticity, in the lower limbs. Preferential involvement of extensor muscles of the upper limbs may be a distinctive feature of the disease. These observations should be confirmed in future studies
Association between the c.*229C>T polymorphism of the topoisomerase IIb binding protein 1 (TopBP1) gene and breast cancer
Topoisomerase IIb binding protein 1 (TopBP1)
is involved in cell survival, DNA replication, DNA damage
repair and cell cycle checkpoint control. The biological
function of TopBP1 and its close relation with BRCA1
prompted us to investigate whether alterations in the
TopBP1 gene can influence the risk of breast cancer.
The aim of this study was to examine the association
between five polymorphisms (rs185903567, rs116645643,
rs115160714, rs116195487, and rs112843513) located in
the 30UTR region of the TopBP1 gene and breast cancer
risk as well as allele-specific gene expression. Five hundred
thirty-four breast cancer patients and 556 population controls
were genotyped for these SNPs. Allele-specific Top-
BP1 mRNA and protein expressions were determined by
using real time PCR and western blotting methods,
respectively. Only one SNP (rs115160714) showed an
association with breast cancer. Compared to homozygous
common allele carriers, heterozygous and homozygous for
the T variant had significantly increased risk of breast
cancer (adjusted odds ratio = 3.81, 95 % confidence
interval: 1.63–8.34, p = 0.001). Mean TopBP1 mRNA and
protein expression were higher in the individuals with the
CT or TT genotype. There was a significant association
between the rs115160714 and tumor grade and stage. Most
carriers of minor allele had a high grade (G3) tumors
classified as T2-T4N1M0. Our study raises a possibility
that a genetic variation of TopBP1 may be implicated in
the etiology of breast cancer
Establishment of LIF-Dependent Human iPS Cells Closely Related to Basic FGF-Dependent Authentic iPS Cells
Human induced pluripotent stem cells (iPSCs) can be divided into a leukemia inhibitory factor (LIF)-dependent naïve type and a basic fibroblast growth factor (bFGF)-dependent primed type. Although the former are more undifferentiated than the latter, they require signal transduction inhibitors and sustained expression of the transgenes used for iPSC production. We used a transcriptionally enhanced version of OCT4 to establish LIF-dependent human iPSCs without the use of inhibitors and sustained transgene expression. These cells belong to the primed type of pluripotent stem cell, similar to bFGF-dependent iPSCs. Thus, the particular cytokine required for iPSC production does not necessarily define stem cell phenotypes as previously thought. It is likely that the bFGF and LIF signaling pathways converge on unidentified OCT4 target genes. These findings suggest that our LIF-dependent human iPSCs could provide a novel model to investigate the role of cytokine signaling in cellular reprogramming
Effect of changes over time in the performance of a customized SAPS-II model on the quality of care assessment
Purpose: The aim of our study was to explore, using an innovative method, the effect of temporal changes in the mortality prediction performance of an existing model on the quality of care assessment. The prognostic model (rSAPS-II) was a recalibrated Simplified Acute Physiology Score-II model developed for very elderly Intensive Care Unit (ICU) patients. Methods: The study population comprised all 12,143 consecutive patients aged 80 years and older admitted between January 2004 and July 2009 to one of the ICUs of 21 Dutch hospitals. The prospective dataset was split into 30 equally sized consecutive subsets. Per subset, we measured the model's discrimination [area under the curve (AUC)], accuracy (Brier score), and standardized mortality ratio (SMR), both without and after repeated recalibration. All performance measures were considered to be stable if 1 without and after repeated recalibration for the year 2009. Results: For all subsets, the AUCs were stable, but the Brier scores and SMRs were not. The SMR was downtrending, achieving levels significantly below 1. Repeated recalibration rendered it stable again. The proportions of hospitals with SMR>1 and SMR <1 changed from 15 versus 85% to 35 versus 65%. Conclusions: Variability over time may markedly vary among different performance measures, and infrequent model recalibration can result in improper assessment of the quality of care in many hospitals. We stress the importance of the timely recalibration and repeated validation of prognostic models over tim
Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study.
BACKGROUND: Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant death in high-income countries. Central respiratory system dysfunction seems to contribute to these deaths. Excitation that drives contraction of skeletal respiratory muscles is controlled by the sodium channel NaV1.4, which is encoded by the gene SCN4A. Variants in NaV1.4 that directly alter skeletal muscle excitability can cause myotonia, periodic paralysis, congenital myopathy, and myasthenic syndrome. SCN4A variants have also been found in infants with life-threatening apnoea and laryngospasm. We therefore hypothesised that rare, functionally disruptive SCN4A variants might be over-represented in infants who died from SIDS. METHODS: We did a case-control study, including two consecutive cohorts that included 278 SIDS cases of European ancestry and 729 ethnically matched controls without a history of cardiovascular, respiratory, or neurological disease. We compared the frequency of rare variants in SCN4A between groups (minor allele frequency <0·00005 in the Exome Aggregation Consortium). We assessed biophysical characterisation of the variant channels using a heterologous expression system. FINDINGS: Four (1·4%) of the 278 infants in the SIDS cohort had a rare functionally disruptive SCN4A variant compared with none (0%) of 729 ethnically matched controls (p=0·0057). INTERPRETATION: Rare SCN4A variants that directly alter NaV1.4 function occur in infants who had died from SIDS. These variants are predicted to significantly alter muscle membrane excitability and compromise respiratory and laryngeal function. These findings indicate that dysfunction of muscle sodium channels is a potentially modifiable risk factor in a subset of infant sudden deaths. FUNDING: UK Medical Research Council, the Wellcome Trust, National Institute for Health Research, the British Heart Foundation, Biotronik, Cardiac Risk in the Young, Higher Education Funding Council for England, Dravet Syndrome UK, the Epilepsy Society, the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health, and the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program
Genetic defects are common in myopathies with tubular aggregates
Objective: A group of genes have been reported to be associated with myopathies with tubular aggregates (TAs). Many cases with TAs still lack of genetic
clarification. This study aims to explore the genetic background of cases with
TAs in order to improve our knowledge of the pathogenesis of these rare
pathological structures. Methods: Thirty-three patients including two family
members with biopsy confirmed TAs were collected. Whole-exome sequencing
was performed on 31 unrelated index patients and a candidate gene search
strategy was conducted. The identified variants were confirmed by Sanger
sequencing. The wild-type and the mutant p.Ala11Thr of ALG14 were transfected into human embryonic kidney 293 cells (HEK293), and western blot
analysis was performed to quantify protein expression levels. Results: Eleven
index cases (33%) were found to have pathogenic variant or likely pathogenic
variants in STIM1, ORAI1, PGAM2, SCN4A, CASQ1 and ALG14. Among them,
the c.764A>T (p.Glu255Val) in STIM1 and the c.1333G>C (p.Val445Leu) in
SCN4A were novel. Western blot analysis showed that the expression of ALG14
protein was severely reduced in the mutant ALG14 HEK293 cells (p.Ala11Thr)
compared with wild type. The ALG14 variants might be associated with TAs in
patients with complex multisystem disorders. Interpretation: This study
expands the phenotypic and genotypic spectrums of myopathies with TAs. Our
findings further confirm previous hypothesis that genes related with calcium
signalling pathway and N-linked glycosylation pathway are the main genetic
causes of myopathies with TAs
Indirect measurement of pinch and pull forces at the shaft of laparoscopic graspers
The grasping instruments used in minimally invasive surgery reduce the ability of the surgeon to feel the forces applied on the tissue, thereby complicating the handling of the tissue and increasing the risk of tissue damage. Force sensors implemented in the forceps of the instruments enable accurate measurements of applied forces, but also complicate the design of the instrument. Alternatively, indirect estimations of tissue interaction forces from measurements of the forces applied on the handle are prone to errors due to friction in the linkages. Further, the force transmission from handle to forceps exhibits large nonlinearities, so that extensive calibration procedures are needed. The kinematic analysis of the grasping mechanism and experimental results presented in this paper show that an intermediate solution, force measurements at the shaft and rod of the grasper, enables accurate measurements of the pinch and pull forces on tissue with only a limited number of calibration measurements. We further show that the force propagation from the shaft and rod to the forceps can be approximated by a linear two-dimensional function of the opening angle of the grasper and the force on the rod
CAV3 mutations causing exercise intolerance, myalgia and rhabdomyolysis: expanding the phenotypic spectrum of caveolinopathies
Rhabdomyolysis is often due to a combination of environmental trigger(s) and genetic predisposition; however, the underlying genetic cause remains elusive in many cases. Mutations in CAV3 lead to various neuromuscular phenotypes with partial overlap, including limb girdle muscular dystrophy type 1C (LGMD1C), rippling muscle disease, distal myopathy and isolated hyperCKemia. Here we present a series of eight patients from seven families presenting with exercise intolerance and rhabdomyolysis caused by mutations in CAV3 diagnosed by next generation sequencing (NGS) (n=6). Symptoms included myalgia (n=7), exercise intolerance (n=6) and episodes of rhabdomyolysis (n=2). Percussion-induced rapid muscle contractions (PIRCs) were seen in five out of six patients examined. A previously reported heterozygous mutation in CAV3 (p.T78M) and three novel variants (p.V14I, p.F41S, p.F54V) were identified. Caveolin-3 immunolabeling in muscle was normal in 3/4 patients however, immunoblotting showed more than 50% reduction of caveolin-3 in five patients compared with controls. This case series demonstrates that exercise intolerance, myalgia and rhabdomyolysis may be caused by CAV3 mutations and broadens the phenotypic spectrum of caveolinopathies. In our series immunoblotting was a more sensitive method to detect reduced caveolin-3 levels than immunohistochemistry in skeletal muscle. Patients presenting with muscle pain, exercise intolerance and rhabdomyolysis should be routinely tested for PIRCs as this may be an important clinical clue for caveolinopathies, even in the absence of other “typical” features. The use of NGS may expand current knowledge concerning inherited diseases, and unexpected/atypical phenotypes may be attributed to well-known human disease genes
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