A change of heart for MEF2A in coronary artery disease
Coronary artery disease (CAD) is one of the major killers in Western societies. Recently, mutations in a gene called MEF2A on chromosome 15 were reported to be causative of premature CAD. The authors of the report failed to find the mutation in a large number of control individuals and thus concluded that the MEF2A mutation was the cause of the CAD. Only a single family was observed to carry the putative mutation, however.
A new study appearing in the April 1 print issue of The Journal of Clinical Investigation overturns these findings. Len Pennacchio and colleagues from Lawrence Berkeley National Laboratory have sequenced the MEF2A gene in about 300 patients with premature coronary heart disease and fail to find any causative mutations.
The researchers do find the precise mutation (a 21 base pair deletion) that was previously reported to be causative of CAD, but in this new JCI study, this mutation was found in three control subjects who did not have CAD or any other coronary heart disease. Thus, the studies demonstrate that MEF2A mutations are not common cause of heart disease and suggest that another one of 93 genes in that area of chromosome 15 was responsible for heart disease in the original family. These data question the role of MEF2A in CAD. In an accompanying commentary, David Altshuler and Joel Hirschhorn write, "the genetic evidence available to date does not demonstrate that these mutations play a causal role in CAD in humans….These [new] studies remind us that replication and multiplicity in human genetic research are critically important."
TITLE: Lack of MEF2A mutations in coronary artery disease
AUTHOR CONTACT:
Len A. Pennacchio
Lawrence Berkeley National Laboratory, Berkeley, California, USA.
Phone: (510) 486-7498; Fax: (510) 486-4229; E-mail: LAPennacchio@lbl.gov
View the PDF of this article at: https://www.the-jci.org/article.php?id=24186
ACCOMPANYING COMMENTARY:
TITLE: MEF2A sequence variants and coronary artery disease: a change of heart?
AUTHOR CONTACT:
David Altshuler
Massachusetts General Hospital, Boston, Massachusetts, USA.
Phone: (617) 726-5940; Fax: (617) 726-5937; E-mail: altshuler@molbio.mgh.harvard.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=24715
EDITOR'S PICK
How lupus T cells lose IL-2
Lupus is a chronic, autoimmune disease that causes inflammation, particularly of the skin, joints, blood, and kidneys. Patients with lupus produce antibodies against their own proteins. Patients also have immune T cells that produce a protein called IL-2, which normally usually protects against infection, at lower than typical levels. In a study appearing in the April 1 print edition of The Journal of Clinical Investigation, George Tsokos and colleagues from the Walter Reed Army Institute of Research explore the mechanisms underlying this decreased IL-2 production.
The researchers find that sera from lupus patients contains antibodies that bind to T cells and activate a complex cellular signaling cascade that ultimately results in decreased IL-2 production. This deficiency in IL-2 could result in the autoantibody production that occurs in lupus.
In an accompanying commentary, Gary Kammer of Arthritis Associates, Inc points out "the contribution by Tsokos and his colleagues…provides a new appreciation and insight into how the microenvironment in lupus can further impinge on a defective T cell to inhibit IL-2 production. From such studies will come the inspiration and novel approaches necessary to develop therapeutic tools to abate disease and improve the quality of life of our patients."
TITLE: Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV
AUTHOR CONTACT:
George C. Tsokos
Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
Phone: (301) 319-9911; Fax: (301) 319-9133; E-mail: gtsokos@usuhs.mil
View the PDF of this article at: https://www.the-jci.org/article.php?id=22854
ACCOMPANYING COMMENTARY:
TITLE: Altered regulation of IL-2 production in systemic lupus erythematosus: an evolving paradigm
AUTHOR CONTACT:
Gary M. Kammer
Arthritis Associates Inc., Willoughby, Ohio, USA.
Phone: (440) 953-8700; Fax: (440) 953-8796; E-mail: gmkammer@hotmail.com
View the PDF of this article at:
IMMUNOLOGY
Ikaros integrates stress and immunity
The immune system and the stress system have evolved together and there is much crosstalk between them. In a study appearing in the April 1 issue of the Journal of Clinical Investigation, Sylvia Asa and colleagues from the University of Toronto present the first evidence that Ikaros, a factor previously thought to be restricted to the lymph and blood, is involved in integrating the stress and immune systems. The authors use mice lacking Ikaros to show that Ikaros affects the development and function of the stress systems in the brain. This function of Ikaros parallels its already known role in immune cells. In an accompanying commentary, George Chrousos and Tomoshige Kino write, "the findings of Ezzat, et al…suggest that changes in [Ikaros] may be associated with human disorders that are related to dysfunction of the stress and immune responses."
TITLE: Ikaros integrates endocrine and immune system development
AUTHOR CONTACT:
Sylvia L. Asa
University Health Network, Toronto, Ontario, Canada.
Phone: (416) 946-2099; Fax: (416) 946-6579; E-mail: sylvia.asa@uhn.on.ca
View the PDF of this article at: https://www.the-jci.org/article.php?id=22486
ACCOMPANYING COMMENTARY:
TITLE: Ikaros transcription factors: flying between stress and inflammation
AUTHOR CONTACT:
Tomoshige Kino
National Institute of Child Health and Human Development, Bethesda, Maryland, USA.
Phone: (301) 496-5800; Fax: (301) 402-0884; E-mail: kinot@mail.nih.gov
View the PDF of this article at: https://www.the-jci.org/article.php?id=24886
PULMONOLOGY
A1 lets lungs breathe a sigh of relief
Patients with lung and heart disease are commonly given supplemental oxygen, however very high concentrations of oxygen administered for extended periods of time can trigger lung injury. The mechanism underlying this lung injury has not been characterized. In a study appearing in the April 1 issue of The Journal of Clinical Investigation, Jack Elias and colleagues from Yale University demonstrate that a protein called A1 is a critical regulator in this type of lung injury. The authors also show that high oxygen concentration stimulates A1, that A1 regulates death of cells in the lung, and that it plays a central role in the induction of other proteins that modulate programmed cell death. In mice lacking A1, the harmful effects of oxygen are intensified whereas overexpressing A1 decreases lung cell death in the presence of oxygen. In an accompanying commentary, G.R.Scott Budinger and Jacob Sznajder writes that these studies will "influence future investigations into the molecular mechanisms by which these [A1] pathways become activated to contribute to…lung injury."
TITLE: Bcl-2-related protein A1 is an endogenous and cytokine-stimulated mediator of cytoprotection in hyperoxia acute lung injury
AUTHOR CONTACT:
Jack Elias
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: (203) 785-4163; Fax: (203) 785-3826; E-mail: jack.elias@yale.edu
View the PDF of this article at:
ACCOMPANYING COMMENTARY:
TITLE: To live or die: a critical decision for the lung
AUTHOR CONTACT:
Jacob I. Sznajder
Northwestern University, Chicago, Illinois, USA.
Phone: (312) 908-8163; Fax: (312) 908-4650; E-mail: j-sznajder@northwestern.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=24681
METABOLIC DISEASE
Sifting through the cells responsible for diabetes
Insulin receptor substrate 2 (IRS2) plays a role in energy homeostasis and mice that lack this protein develop diabetes. However, mice that lack IRS2 in only certain cells of the pancreas and brain do not develop diabetes, raising a number of questions. In a study appearing in the April 1 issue of The Journal of Clinical Investigation, Dominic Withers and colleagues from University College London sought to further understand the generation of diabetes and the role of IRS2 in brain cells and the pancreatic cells that produce insulin. The authors have generated three types of mice with specific deletion of IRS2 expression. One line has reduced IRS2 in insulin-producing cells of the pancreas and the hypothalamus of the brain, one line has IRS2 reduced in all neurons and the last line has reduced IRS2 in a particular subset of neurons that regulate feeding behavior. The authors give a detailed and complex analysis of each mouse line, clarifying the role of IRS2 in specific cells of the pancreas and brain. The results suggest that IRS2 may be useful for treating diabetes and obesity.
TITLE: The role of insulin receptor substrate 2 in hypothalamic and beta cell function
AUTHOR CONTACT:
Dominic Withers
University College London, London, UK
Phone: 44-20-7679-6586; Fax: 44-20-7679-6211; E-mail: d.withers@ucl.ac.uk
View the PDF of this article at: https://www.the-jci.org/article.php?id=24445
PHYSIOLOGY
Putting a finger on shortened digits
Brachydactyly is a group of inherited disorders of the hands that are characterized by shortened fingers and abnormal joint formation. In a paper appearing in the April 1 issue of The Journal of Clinical Investigation, Stefan Mundlos and colleagues from the Max Planck Institute for Molecular Genetics describe the analysis of a mouse model with limb mutations called short digits (Dsh). The mice have disrupted Shh expression – a factor that helps skeletal formation. The result is that the mice have symptoms similar to human brachydactyly type A1. This is because the misexpression of Shh disrupts other factors with normally regulate joint development as well as the growth and patterning of the digits
Luis de la Fuente and Jill Helms write, in an accompanying commentary, that this study shows "that removal or expansion of one of the factors that contributes to the establishment of a boundary can cause a multitude of processes, including those that shape and control development of the skeleton, then go awry." The developmental pathology associated with Shh misexpression extends our understanding of the developmental pathology of digit development and thus of human brachydactyly.
TITLE: An inversion involving the mouse Shh locus results in brachydactyly through dysregulation of Shh expression
AUTHOR CONTACT:
Stefan Mundlos
Max Planck Institute for Molecular Genetics, Berlin, Germany.
Phone: +49-30-8413-1267; Fax: +49-30-8413-1385; E-mail: mundlos@molgen.mpg.de
View the PDF of this article at: https://www.the-jci.org/article.php?id=23675
ACCOMPANYING COMMENTARY:
TITLE: The fickle finger of fate
AUTHOR CONTACT:
Jill A. Helms
Stanford University, Stanford, California, USA.
Phone: (650) 736-0919; Fax: (650) 736-4374; E-mail: jhelms@stanford.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=24840
PHYSIOLOGY
The kidney is only part of the blood pressure problem
Abnormal blood pressure is a widespread problem thought to be triggered by changes in the kidney. More recent studies have shown that vascular function can also affect blood pressure. In a paper appearing in the April 1 issue of The Journal of Clinical Investigation, Thomas Coffman and colleagues at the Durham VA Medical Center explore the relationship between the kidney and non-kidney tissues in mice with low blood pressure. The mice lack a receptor (AT1) to a protein called angiotensin, which regulates blood pressure. The authors provide direct evidence that actions of AT1 receptors both inside and outside the kidney each contribute to determining the level of blood pressure. In an accompanying commentary, Michael Mendelsohn states that the findings have "important implications for the ways we diagnose and treat blood pressure disease in humans."
TITLE: Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system
AUTHOR CONTACT:
Thomas M. Coffman
VA Medical Center, Durham, North Carolina, USA.
Phone: (919) 286-6947; Fax: (919) 286-6879; E-mail: tcoffman@acpub.duke.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=23378
ACCOMPANYING COMMENTARY:
TITLE: In hypertension, the kidney is not always the heart of the matter
AUTHOR CONTACT:
Michael E. Mendelsohn
Tufts-New England Medical Center, Boston, Massachusetts, USA.
Phone: (617) 636-9370; Fax: (617) 636-1444; E-mail: MMendelsohn@tufts-nemc.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=24806
PHYSIOLOGY
A cause for skin blistering disease pops up
Pemphigus is a skin blistering disease that causes separation of the layers of the skin, along with inflammation. In a paper appearing in the April 1 issue of The Journal of Clinical Investigation, Zhi Liu and colleagues from the University of North Carolina use a mouse model of pemphigus to unravel the mechanisms of this disease. The researchers show that activity of a protein called plasmin is an essential step in the early phase of blister formation in the mouse model. They further show that plasmin joins another protein, MMP-9, in a pathological signaling pathway during the early phase of disease. According to a related commentary by Kim Yancey of the Medical College of Wisconsin, these results "will facilitate the development of effective interventions that counteract the chronic morbidity and, at times, mortality" of skin blistering diseases.
TITLE: Synergy between a plasminogen cascade and MMP-9 in autoimmune disease
AUTHOR CONTACT:
Zhi Liu
University of North Carolina, Chapel Hill, North Carolina, USA.
Phone: (919) 966-0785; Fax: (919) 966-3898; E-mail: zhiliu@med.unc.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=23977
ACCOMPANYING COMMENTARY:
TITLE: The pathophysiology of autoimmune blistering diseases
AUTHOR CONTACT:
Kim B. Yancey
Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Phone: (414) 456-4081; Fax: (414) 456-6518; E-mail: kyancey@mcw.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=24855
Journal
Journal of Clinical Investigation