Weatherall Institute of Molecular Medicine

Oxford, United Kingdom

Weatherall Institute of Molecular Medicine

Oxford, United Kingdom
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Sezgin E.,Weatherall Institute of Molecular Medicine
Nature Reviews Molecular Cell Biology | Year: 2017

Cellular plasma membranes are laterally heterogeneous, featuring a variety of distinct subcompartments that differ in their biophysical properties and composition. A large number of studies have focused on understanding the basis for this heterogeneity and its physiological relevance. The membrane raft hypothesis formalized a physicochemical principle for a subtype of such lateral membrane heterogeneity, in which the preferential associations between cholesterol and saturated lipids drive the formation of relatively packed (or ordered) membrane domains that selectively recruit certain lipids and proteins. Recent studies have yielded new insights into this mechanism and its relevance in vivo, owing primarily to the development of improved biochemical and biophysical technologies. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Wilkie A.O.M.,Weatherall Institute of Molecular Medicine
Nature Genetics | Year: 2017

The chromatin scaffolding protein SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) was previously shown to have diverse roles in X-chromosome inactivation, imprinting and double-strand break repair, and mutations in SMCHD1 contribute to a type of muscular dystrophy. Now, development of the nose and eyes is added to its list of functions. © 2017 Nature America, Inc., part of Springer Nature.

Goriely A.,Weatherall Institute of Molecular Medicine | Wilkie A.O.M.,Weatherall Institute of Molecular Medicine
American Journal of Human Genetics | Year: 2012

Advanced paternal age has been associated with an increased risk for spontaneous congenital disorders and common complex diseases (such as some cancers, schizophrenia, and autism), but the mechanisms that mediate this effect have been poorly understood. A small group of disorders, including Apert syndrome (caused by FGFR2 mutations), achondroplasia, and thanatophoric dysplasia (FGFR3), and Costello syndrome (HRAS), which we collectively term "paternal age effect" (PAE) disorders, provides a good model to study the biological and molecular basis of this phenomenon. Recent evidence from direct quantification of PAE mutations in sperm and testes suggests that the common factor in the paternal age effect lies in the dysregulation of spermatogonial cell behavior, an effect mediated molecularly through the growth factor receptor-RAS signal transduction pathway. The data show that PAE mutations, although arising rarely, are positively selected and expand clonally in normal testes through a process akin to oncogenesis. This clonal expansion, which is likely to take place in the testes of all men, leads to the relative enrichment of mutant sperm over time - explaining the observed paternal age effect associated with these disorders - and in rare cases to the formation of testicular tumors. As regulation of RAS and other mediators of cellular proliferation and survival is important in many different biological contexts, for example during tumorigenesis, organ homeostasis and neurogenesis, the consequences of selfish mutations that hijack this process within the testis are likely to extend far beyond congenital skeletal disorders to include complex diseases, such as neurocognitive disorders and cancer predisposition. © 2012 The American Society of Human Genetics.

Rehwinkel J.,Weatherall Institute of Molecular Medicine
Cellular and molecular life sciences : CMLS | Year: 2014

Infection of cells with human immunodeficiency virus 1 (HIV-1) is controlled by restriction factors, host proteins that counteract a variety of steps in the life cycle of this lentivirus. These include SAMHD1, APOBEC3G and tetherin, which block reverse transcription, hypermutate viral DNA and prevent progeny virus release, respectively. These and other HIV-1 restriction factors are conserved and have clear orthologues in the mouse. This review summarises studies in knockout mice lacking HIV-1 restriction factors. In vivo experiments in such animals have not only validated in vitro data obtained from cultured cells, but have also revealed new findings about the biology of these proteins. Indeed, genetic ablation of HIV-1 restriction factors in the mouse has provided evidence that restriction factors control retroviruses and other viruses in vivo and has led to new insights into the mechanisms by which these proteins counteract infection. For example, in vivo experiments in knockout mice demonstrate that virus control exerted by restriction factors can shape adaptive immune responses. Moreover, the availability of animals lacking restriction factors opens the possibility to study the function of these proteins in other contexts such as autoimmunity and cancer. Further in vivo studies of more recently identified HIV-1 restriction factors in gene targeted mice are, therefore, justified.

Higgs D.R.,Weatherall Institute of Molecular Medicine
Cold Spring Harbor perspectives in medicine | Year: 2013

The globin gene disorders including the thalassemias are among the most common human genetic diseases with more than 300,000 severely affected individuals born throughout the world every year. Because of the easy accessibility of purified, highly specialized, mature erythroid cells from peripheral blood, the hemoglobinopathies were among the first tractable human molecular diseases. From the 1970s onward, the analysis of the large repertoire of mutations underlying these conditions has elucidated many of the principles by which mutations occur and cause human genetic diseases. This work will summarize our current knowledge of the α-thalassemias, illustrating how detailed analysis of this group of diseases has contributed to our understanding of the general molecular mechanisms underlying many orphan and common diseases.

Crawford G.,Weatherall Institute of Molecular Medicine
Blood | Year: 2013

Patients with the dedicator of cytokinesis 8 (DOCK8) immunodeficiency syndrome suffer from recurrent viral and bacterial infections, hyper-immunoglobulin E levels, eczema, and greater susceptibility to cancer. Because natural killer T (NKT) cells have been implicated in these diseases, we asked if these cells were affected by DOCK8 deficiency. Using a mouse model, we found that DOCK8 deficiency resulted in impaired NKT cell development, principally affecting the formation and survival of long-lived, differentiated NKT cells. In the thymus, DOCK8-deficient mice lack a terminally differentiated subset of NK1.1(+) NKT cells expressing the integrin CD103, whereas in the liver, DOCK8-deficient NKT cells express reduced levels of the prosurvival factor B-cell lymphoma 2 and the integrin lymphocyte function-associated antigen 1. Although the initial NKT cell response to antigen is intact in the absence of DOCK8, their ongoing proliferative and cytokine responses are impaired. Importantly, a similar defect in NKT cell numbers was detected in DOCK8-deficient humans, highlighting the relevance of the mouse model. In conclusion, our data demonstrate that DOCK8 is required for the development and survival of mature NKT cells, consistent with the idea that DOCK8 mediates survival signals within a specialized niche. Accordingly, impaired NKT cell numbers and function are likely to contribute to the susceptibility of DOCK8-deficient patients to recurrent infections and malignant disease.

Weatherall D.J.,Weatherall Institute of Molecular Medicine
Annual Review of Genomics and Human Genetics | Year: 2013

Although the inherited hemoglobin disorders were the first genetic diseases to be explored at the molecular level, they still have important messages for the future of medical genetics. In particular, they can offer a better understanding of the evolutionary and population biology of genetic disease, the mechanisms that underlie the phenotypic diversity of monogenic disease, and how, by developing appropriate partnerships, richer countries can help low-income countries to evolve programs for the control and management of these diseases where, in many cases, they are particularly common. Copyright © 2013 by Annual Reviews. All rights reserved.

Weatherall D.J.,Weatherall Institute of Molecular Medicine
Blood | Year: 2010

It is estimated that in excess of 300 000 children are born each year with a severe inherited disorder of hemoglobin and that approximately 80% of these births occur in low- or middle-income countries. As these countries go through an epidemiologic transition, with a reduction in childhood and infant mortality due to improved public health measures, babies who would have previously died of these diseases before they were recognized are now surviving to present for diagnosis and treatment. Hence, they are presenting an increasing global health burden. Because of their uneven distribution in high-frequency populations, reflecting their complex population genetics, the true magnitude of this burden is still unknown. In many poor countries there are virtually no facilities for the diagnosis and management of these conditions, and even in richer countries there are limited data about their frequency, clinical course, or mortality. Without this information, it will be impossible to persuade governments about the increasing importance of these diseases. The situation will only be improved by concerted action on the part of the hematology community of the richer countries together with input from the major international health organizations and funding agencies. © 2010 by The American Society of Hematology.

Mead A.J.,Weatherall Institute of Molecular Medicine
Blood | Year: 2013

The association between somatic JAK2 mutation and myeloproliferative neoplasms (MPNs) is now well established. However, because JAK2 mutations are associated with heterogeneous clinical phenotypes and often occur as secondary genetic events, some aspects of JAK2 mutation biology remain to be understood. We recently described a germline JAK2V617I mutation in a family with hereditary thrombocytosis and herein characterize the hematopoietic and signaling impact of JAK2V617I. Through targeted sequencing of MPN-associated mutations, exome sequencing, and clonality analysis, we demonstrate that JAK2V617I is likely to be the sole driver mutation in JAK2V617I-positive individuals with thrombocytosis. Phenotypic hematopoietic stem cells (HSCs) were increased in the blood and bone marrow of JAK2V617I-positive individuals and were sustained at higher levels than controls after xenotransplantation. In signaling and transcriptional assays, JAK2V617I demonstrated more activity than wild-type JAK2 but substantially less than JAK2V617F. After cytokine stimulation, JAK2V617I resulted in markedly increased downstream signaling compared with wild-type JAK2 and comparable with JAK2V617F. These findings demonstrate that JAK2V617I induces sufficient cytokine hyperresponsiveness in the absence of other molecular events to induce a homogeneous MPN-like phenotype. We also provide evidence that the JAK2V617I mutation may expand the HSC pool, providing insights into both JAK2 mutation biology and MPN disease pathogenesis.

Weatherall D.J.,Weatherall Institute of Molecular Medicine
Blood Reviews | Year: 2012

Inherited hemoglobin-related disorders, which include the structural variants (hemoglobin S, C, and E) and the alpha (α)- and beta (β)-thalassemias, affect more than 300,000 children annually, particularly in malaria-endemic regions stretching from sub-Saharan Africa and the Mediterranean to Southeast Asia. Screening for carriers of these traits is important to provide prenatal genetic counseling and to accurately estimate the true prevalence and public health burden of these disorders. The clinical course of thalassemias, which affect nearly 70,000 children annually, is highly variable depending on the mixture of inherited alleles. The primary forms of non-transfusion-dependent thalassemia include β-thalassemia intermedia, hemoglobin E β-thalassemia, and hemoglobin H disease. Early clinical recognition of these disorders is essential to prevent affected children from being mistakenly placed on life-long transfusion therapy. © 2012 Elsevier Ltd.

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