Found! First gene associated with myeloproliferative diseases
Myelodysplastic / myeloproliferative diseases (MDS/MPD) are blood stem cell disorders characterized by ineffective formation and development of blood cells in the bone marrow, resulting in abnormal development of bone marrow precursor cells and a reduction in the number of blood cells. The broad spectrum of symptoms makes MDS/MPD difficult to treat, and there are no good prognostic markers available. No single gene defect has been found for these diseases, and no animal model was available to study them.
A common anomaly associated with these myeloid malignancies is a chromosomal deletion, suggesting the presence of one or more tumor suppressor genes in the long arm of chromosome 20. In a paper appearing online on August 25 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Carlos Martinez-A and colleagues create a new mouse model of MDS/MPD, based on the production of mutant mice in which the Dido gene, mapped to the long arm of human chromosome 20, has been deleted.
The authors also examined human MDS/MPD patients and find 100% of them have Dido expression abnormalities. Furthermore, a substantial number of patients with other hematological myeloid disorders showed significant loss of Dido expression. Thus, Dido might be one of the tumor suppressor genes at chromosome 20q associated with MDS/MPD.
TITLE:Dido gene expression alterations are implicated in the induction of hematological myeloid neoplasms.
AUTHOR CONTACT:
Carlos Martinez-A
Centro Nacional Biotecnologia, Madrid, Spain
Phone: 34-91 585-4850; Fax: 34-91 585-4401; E-mail: cmartineza@cnb.uam.es
View the PDF of this article at: https://www.the-jci.org/article.php?id=24177
EDITOR'S PICK
Insulin sensitivity gets a kick out of SOCS-7
Insulin resistance is a fundamental factor in non-insulin-dependent diabetes. Prolonged activation of the insulin receptor, inflammation, and excessive insulin levels can induce insulin resistance by decreasing levels of insulin receptor substrate (IRS) proteins. However, the mechanism(s) underlying the destruction of IRS proteins and subsequent resistance to insulin have not been well defined. Proteins of the SOCS family have been implicated in the negative regulation of insulin signaling and also regulate cytokine signaling by targeting proteins for degradation by the proteasome. In particular, the function for the SOCS-7 protein was previously unclear.
In a study appearing online on August 25 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Paul Rothman and colleagues from the University of Iowa demonstrate that SOCS-7 regulates insulin signaling by associating with several components of the insulin-signaling cascade.
The researchers generate SOCS-7-deficient mice and show that cells lacking SOCS-7 have increased IRS protein levels and prolonged IRS activation. SOCS-7 deficient mice are more insulin sensitive as measured by a glucose tolerance test and an insulin tolerance test. In addition, SOCS-7-deficient mice exhibit increased growth of pancreatic islets with increased fasting insulin levels and hypoglycemia. As one of the only mouse knockout models featuring increased insulin sensitivity, these data suggest that SOCS-7 is a potent regulator of glucose homeostasis and insulin signaling.
TITLE: Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of langerhans
AUTHOR CONTACT:
Paul B. Rothman
University of Iowa, Iowa City, IA USA
Phone: 319 384 5424; Fax: 319 356 8608; E-mail: paul-rothman@uiowa.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=23853
METABOLIC DISEASE
A spoonful of sugar is sufficient for diabetic atherosclerosis
People with diabetes are more likely to develop atherosclerosis, leading to more heart attacks and strokes in this population. But evidence that hyperglycemia in these patients contributes to atherosclerosis was lacking. In a study appearing online on August 25 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Ira Goldberg and colleagues from Columbia University show that hyperglycemia alone can accelerate atherosclerosis.
The researchers create mice lacking a gene called aldose reductase (AR) that mediates the generation of toxic products from glucose and cross these mice with atherosclerosis-prone mice lacking a protein called Ldlr. They found that AR expression modulates atherosclerosis development in the diabetic animals. Thus, inhibitors of AR or other proteins that mediate glucose toxicity may be useful for treating diabetic atherosclerosis.
TITLE:Human aldose reductase expression accelerates diabetic atherosclerosis in transgenic mice
AUTHOR CONTACT:
Ira J. Goldberg
Columbia University, New York, NY USA
Phone: 212 305 5961; Fax: 212 305 5484; E-mail: ijg3@columbia.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=24819
NEUROSCIENCE
Unlocking Alzheimer's: Cholesterol and copper chemistry could be the key
The risk for Alzheimer Disease (AD) is related to high levels of cholesterol and copper, but the mechanisms underlying this association were unclear. In a study appearing online on August 25 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Ashley Bush and colleagues from Massachusetts General Hospital show that beta-amyloid, the protein culprit in AD, possesses cholesterol oxidase activity. They show that this activity is exaggerated in patients with AD.
The scientists show that beta-amyloid peptides form a complex with copper ions in the AD brain. This complex generates hydrogen peroxide from oxygen and leads to oxidative stress. The researchers show that the substrate for this chemical reaction is cholesterol, which is abundant in the brain and in amyloid plaques. They show that beta-amyloid/copper complexes convert cholesterol into a cell death-enhancing toxin. Levels of this toxin were elevated in AD transgenic mice and in brains from AD patients, but not from brains of patients with other neurological diseases.
This chemical reaction may explain why high cholesterol is a risk factor for AD, and may explain why copper-binding drugs and statins have been shown to be useful for the treatment of AD.
TITLE:Cholesterol oxidase activity mimics that of Alzheimer disease beta-amyloid
AUTHOR CONTACT:
Ashley Bush
Massachusetts General Hospital, Charlestown, MA USA
Phone: 617-726-8244; Email: bush@helix.mgh.harvard.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=23610
PHYSIOLOGY
Small molecule correction for cystic fibrosis
Cystic fibrosis is one of the most common genetically transmitted diseases. In a study appearing online on August 25 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Alan Verkman and colleagues from UCSF report the discovery and characterization of small molecule 'correctors' of defective cystic fibrosis conductance regulator (CFTR) cellular processing. A deletion in phenylalanine 508 is a mutation that disrupts the function of this cellular channel and causes cystic fibrosis.
The authors screen 150,000 compounds using a cell-based functional assay, and test structural analogs of active compounds. Compounds were identified that effectively corrected the mutant CFTR cellular processing biochemically and functionally, and conferred proper channel function to human bronchial cells from cystic fibrosis patients. This work represents a strategy to treat cystic fibrosis, by treating the underlying CFTR defect.
TITLE:Small molecule correctors of defective deltaF508-CFTR cellular processing identified by high-throughput screening
AUTHOR CONTACT:
Alan Verkman
University of California at San Francisco, San Francisco, CA USA
Phone: 415 476 8530; Fax: 415 665 3847; E-mail: verkman@itsa.ucsf.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=24898
PHYSIOLOGY
A targeted complement will cure what ails you
The pathogenesis of many inflammatory, autoimmune and ischemic diseases are due to inappropriate activation of the complement system - proteins found in blood that help destroy bacteria and other foreign cells. Complement inhibitors are now used therapeutically but there are unresolved questions regarding their clinical use. Complement activation products are important for host defense and regulation of the immune system, and thus complement inhibition may compromise this protection.
In a study appearing online on August 25 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Stephen Tomlinson and colleagues from the Medical University of South Carolina show that appropriate targeting of complement inhibition to sites of complement activation and disease can improve bioavailability and increase efficacy without systemically inhibiting complement. They do this by using mouse models of intestinal ischemia/reperfusion (I/R) injury and of acute infection.
By not systemically inhibiting complement, complement-dependent host defense is not compromised. The targeting strategy involved a novel technique and provided protection from injury in the lung, where complement-dependent injury occurs following intestinal I/R. Currently available complement inhibitory drugs systemically inhibit complement and are not optimal. This new targeting strategy is a step forward for developing better complement inhibitors.
TITLE:Targeted complement inhibition by C3d recognition ameliorates tissue injury without apparent increase in susceptibility to infection
AUTHOR CONTACT:
Stephen Tomlinson
Medical University of South Carolina, Charleston, SC USA
Phone: 843-792-1450; Fax: 843-792-2464; E-mail: tomlinss@musc.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=25208
IMMUNOLOGY
Acquired defects confer susceptibility to mycobacteria infection
Susceptibility to mycobacterial infection can be caused by mutations in the interferon gamma receptor gene. In a study appearing online on August 25 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Beate Kampmann and colleagues from Imperial College report a syndrome of disseminated mycobacterial infection caused not by genetic defect in the type 1 cytokine pathways, but instead by an acquired defect mediated by autoantibodies against interferon gamma.
These autoantibodies produce the same phenotype as seen in the genetically determined defect in the interferon gamma response pathway. Identification of the mechanisms responsible for susceptibility to mycobacteria in these patients has important implications for our understanding of immunity to tuberculosis and other mycobacteria.
TITLE:Acquired predisposition to mycobacterial disease due to auto-antibodies to IFN gamma.
AUTHOR CONTACT:
Beate Kampmann
Imperial College, London, Great Britain
Phone: 0044-207886-6377; Fax: 0044-207886-6284; E-mail: b.kampmann@imperial.ac.uk
View the PDF of this article at: https://www.the-jci.org/article.php?id=19316
ALSO IN THIS ISSUE:
Thoughts on thyroid biology
In a study appearing online on August 25 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Ana Luiza Maia and colleagues from Harvard have developed a novel system to address a long- standing question in thyroid biology – the relative contribution of Type 1 (D1) and Type 2 (D2) 5'-deiodinase to circulating T3 in humans. They show that D2 accounts for a higher fraction of T3 production in hypothyroidism and D1 in hyperthyroidism. D2 generated T3 is shown to have a greater effect on T3-dependent gene expression.
TITLE:Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans.
AUTHOR CONTACT:
Ana Luiza Maia
Harvard Medical School, Boston, MA USA
Phone: 617-525-5520; Fax: 617-731-4718; E-mail: amaia@rics.bwh.harvard.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=25083
GDF5 lends a hand to finger abnormalities
In a study appearing online on August 25 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Petra Seemann and colleagues describe two mutations in Growth and Differentiation Factor 5 (GDF5), a signaling molecule, that result in altered binding affinities to the BMP type 1 receptors giving rise to opposing phenotypes, brachydactyly type A2 (unusually short digits) and symphalangism (fusion of the hand joints). The authors propose a model for normal joint formation.
TITLE:Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2.
AUTHOR CONTACT:
Petra Seemann
Institute for Molekulare Genetik, Berlin, Germany
Phone: 0049 30 8413 1263; E-mail: seemann@molgen.mpg.de
View the PDF of this article at: https://www.the-jci.org/article.php?id=25118
Journal
Journal of Clinical Investigation