84 research outputs found
GENETIC AND FUNCTIONAL ANALYSIS OF A NOVEL CONGENITAL SYNDROME AFFECTING CRANIOFACIAL DEVELOPMENT AND ONTOGENY OF MULTIPLE ORGANS
Ph.DDOCTOR OF PHILOSOPH
A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome
Background: Endocrine-cerebro-osteodysplasia (ECO) syndrome [MIM:612651] caused by a recessive mutation (p.R272Q) in Intestinal cell kinase (ICK) shows significant clinical overlap with ciliary disorders. Similarities are strongest between ECO syndrome, the Majewski and Mohr-Majewski short-rib thoracic dysplasia (SRTD) with polydactyly syndromes, and hydrolethalus syndrome. In this study, we present a novel homozygous ICK mutation in a fetus with ECO syndrome and compare the effect of this mutation with the previously reported ICK variant on ciliogenesis and cilium morphology. Results: Through homozygosity mapping and whole-exome sequencing, we identified a second variant (c.358G\u3eT; p.G120C) in ICK in a Turkish fetus presenting with ECO syndrome. In vitro studies of wild-type and mutant mRFP-ICK (p.G120C and p.R272Q) revealed that, in contrast to the wild-type protein that localizes along the ciliary axoneme and/or is present in the ciliary base, mutant proteins rather enrich in the ciliary tip. In addition, immunocytochemistry revealed a decreased number of cilia in ICK p.R272Q-affected cells. Conclusions: Through identification of a novel ICK mutation, we confirm that disruption of ICK causes ECO syndrome, which clinically overlaps with the spectrum of ciliopathies. Expression of ICK-mutated proteins result in an abnormal ciliary localization compared to wild-type protein. Primary fibroblasts derived from an individual with ECO syndrome display ciliogenesis defects. In aggregate, our findings are consistent with recent reports that show that ICK regulates ciliary biology in vitro and in mice, confirming that ECO syndrome is a severe ciliopathy
Persistent Organic Pollutant Exposure Leads to Insulin Resistance Syndrome
International audienceBackground: the incidence of the insulin resistance syndrome has increased at an alarming rate worldwide, creating a serious challenge to public health care in the 21st century. Recently, epide-miological studies have associated the prevalence of type 2 diabetes with elevated body burdens of persistent organic pollutants (POPs). However, experimental evidence demonstrating a causal link between POPs and the development of insulin resistance is lacking. Objective: We investigated whether exposure to POPs contributes to insulin resistance and meta-bolic disorders. Methods: Sprague-Dawley rats were exposed for 28 days to lipophilic POPs through the con-sumption of a high-fat diet containing either refined or crude fish oil obtained from farmed Atlantic salmon. In addition, differentiated adipocytes were exposed to several POP mixtures that mimicked the relative abundance of organic pollutants present in crude salmon oil. We measured body weight, whole-body insulin sensitivity, POP accumulation, lipid and glucose homeostasis, and gene expres-sion and we performed micro array analysis. Results: Adult male rats exposed to crude, but not refined, salmon oil developed insulin resis-tance, abdominal obesity, and hepatosteatosis. The contribution of POPs to insulin resistance was confirmed in cultured adipocytes where POPs, especially organochlorine pesticides, led to robust inhibition of insulin action. Moreover, POPs induced down-regulation of insulin-induced gene-1 (Insig-1) and Lpin1, two master regulators of lipid homeostasis. Conclusion: Our findings provide evidence that exposure to POPs commonly present in food chains leads to insulin resistance and associated metabolic disorder
De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development
Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD
Linkage disequilibrium mapping of CHEK2: Common variation and breast cancer risk
10.1371/journal.pmed.0030168PLoS Medicine360895-090
ESR1 and EGF genetic variation in relation to breast cancer risk and survival
The main purposes of this thesis were to analyse common genetic variation in candidate
genes and candidate pathways in relation to breast cancer risk, prognosticators and
survival, to develop statistical methods for genetic association analysis for evaluating
the joint importance of genes, and to investigate the potential impact of adding genetic
information to clinical risk factors for projecting individualised risk of developing
breast cancer over specific time periods.
In Paper I we studied genetic variation in the estrogen receptor α and epidermal growth
factor genes in relation to breast cancer risk and survival. We located a region in the
estrogen receptor α gene which showed a moderate signal for association with breast
cancer risk but were unable to link common variation in the epidermal growth factor
gene with breast cancer aetiology or prognosis.
In Paper II we investigated whether suspected breast cancer risk SNPs within genes
involved in androgen-to-estrogen conversion are associated with breast cancer
prognosticators grade, lymph node status and tumour size. The strongest association
was observed for a marker within the CYP19A1 gene with histological grade. We also
found evidence that a second marker from the same gene is associated with histological
grade and tumour size.
In Paper III we developed a novel test of association which incorporates multivariate
measures of categorical and continuous heterogeneity. In this work we described both a
single-SNP and a global multi-SNP test and used simulated data to demonstrate the
power of the tests when genetic effects differ across disease subtypes.
In Paper IV we assessed the extent to which recently associated genetic risk variants
improve breast cancer risk-assessment models. We investigated empirically the
performance of eighteen breast cancer risk SNPs together with mammographic density
and clinical risk factors in predicting absolute risk of breast cancer. We also examined
the usefulness of various prediction models considered at a population level for a
variety of individualised breast cancer screening approaches.
The goal of a genetic association study is to establish statistical associations between
genetic variants and disease states. Each variant linked to a disease can lead the way to
a better understanding of the underlying biological mechanisms that govern the
development of a disease. Increased knowledge of molecular variation provides the
opportunity to stratify populations according to genetic makeup, which in turn has the
potential to lead to improved disease prevention programs and improved patient care
Genetic Association and Expression Studies Indicate a Role of Toll-Like Receptor 8 in Pulmonary Tuberculosis
Despite high rates of exposure, only 5–10% of people
infected with Mycobacterium tuberculosis will develop active
tuberculosis (TB) disease, suggesting a significant role for genetic variation
in the human immune response to this infection. Here, we studied TB association
and expression of 18 genes involved in the Toll-like receptor (TLR) pathways.
Initially, we genotyped 149 sequence polymorphisms in 375 pulmonary TB patients
and 387 controls from Indonesia. We found that four polymorphisms in the
TLR8 gene on chromosome X showed evidence of association
with TB susceptibility in males, including a non-synonymous polymorphism
rs3764880 (Met1Val; P = 0.007,
odds ratio (OR) = 1.8, 95%
c.i. = 1.2–2.7). We genotyped these
four TLR8 polymorphisms in an independent collection of 1,837
pulmonary TB patients and 1,779 controls from Russia and again found evidence of
association in males (for rs3764880
P = 0.03,
OR = 1.2, 95%
c.i. = 1.02–1.48). Combined evidence
for association is
P = 1.2×10−3–6×10−4.
In addition, a quantitative PCR analysis indicated that TLR8
transcript levels are significantly up-regulated in patients during the acute
phase of disease
(P = 9.36×10−5),
relative to baseline levels following successful chemotherapy. A marked increase
in TLR8 protein expression was also observed directly in differentiated
macrophages upon infection with M. bovis bacille
Calmette-Guérin (BCG). Taken together, our results provide evidence,
for the first time, of a role for the TLR8 gene in
susceptibility to pulmonary TB across different populations
Ermin deficiency leads to compromised myelin, inflammatory milieu, and susceptibility to demyelinating insult
Ermin is an actin-binding protein found almost exclusively in the central nervous system (CNS) as a component of myelin sheaths. Although Ermin has been predicted to play a role in the formation and stability of myelin sheaths, this has not been directly examined in vivo. Here, we show that Ermin is essential for myelin sheath integrity and normal saltatory conduction. Loss of Ermin in mice caused de-compacted and fragmented myelin sheaths and led to slower conduction along with progressive neurological deficits. RNA sequencing of the corpus callosum, the largest white matter structure in the CNS, pointed to inflammatory activation in aged Ermin-deficient mice, which was corroborated by increased levels of microgliosis and astrogliosis. The inflammatory milieu and myelin abnormalities were further associated with increased susceptibility to immune-mediated demyelination insult in Ermin knockout mice. Supporting a possible role of Ermin deficiency in inflammatory white matter disorders, a rare inactivating mutation in the ERMN gene was identified in multiple sclerosis patients. Our findings demonstrate a critical role for Ermin in maintaining myelin integrity. Given its near-exclusive expression in myelinating oligodendrocytes, Ermin deficiency represents a compelling “inside-out” model of inflammatory dysmyelination and may offer a new paradigm for the development of myelin stability-targeted therapies
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