Commentary
Abstract
Rare mutations in MEF2A have been proposed as a cause of coronary artery disease (CAD) and myocardial infarction (MI). In this issue of the JCI, Pennacchio and colleagues report sequencing MEF2A in 300 patients with premature CAD and in controls. Only 1 CAD patient was found to carry a missense mutation not found in controls. The specific 21-bp deletion in MEF2A previously proposed as causal for CAD and/or MI was observed in unaffected individuals and did not segregate with CAD in families. These results do not support the hypothesis that mutations in MEF2A are a cause of CAD and/or MI but do illustrate general principles regarding the difficulty of connecting genetic variation to common diseases.
Authors
David Altshuler, Joel N. Hirschhorn
Abstract
In this issue of the JCI, Niedermaier and colleagues demonstrate that a chromosomal inversion in mice results in dysregulation of Sonic hedgehog (Shh), such that Shh is ectopically expressed in a skeletogenic domain typically occupied by Indian hedgehog (Ihh). This molecular reversal eliminates phalangeal joint spaces, and consequently, Short digits (Dsh) heterozygotes (Dsh/+) have brachydactyly (shortened digits). Ihh is normally downregulated in regions that will become the joint space, but in Dsh/+ mice, Shh bypasses this regulatory control and persists; accordingly, cells maintain their chondrogenic fate and the developed digits are shorter than normal. The significance of these data extends far beyond the field of skeletal biology: they hint at the very real possibility that the endogenous Shh regulatory region contains a repressor designed to segregate the activity of Shh from Ihh. The existence of such a repressor provides a window into the distant past, revealing that Shh and Ihh must once have shared responsibilities in establishing tissue boundaries and orchestrating vertebrate tissue morphogenesis.
Authors
Luis de la Fuente, Jill A. Helms
Abstract
In systemic lupus erythematosus (SLE), IL-2 production by T lymphocytes in vitro is impaired. Deficient IL-2 production may be an outcome of a primary SLE T cell disorder that is due to impaired signal transduction. In this issue of the JCI, evidence is presented that an anti-TCR/CD3 complex autoantibody present in SLE sera can bind to T cells and activate the Ca2+-calmodulin kinase IV (CaMKIV) signaling cascade, resulting in downregulation of IL-2 transcription and IL-2 production. Because IL-2 may contribute to the maintenance of T cell tolerance, deficient IL-2 production could promote a breach of T cell tolerance that results in autoantibody production in SLE.
Authors
Gary M. Kammer
Abstract
Blood pressure abnormalities are thought to originate from intrinsic changes in the kidney, a concept that has been largely unchallenged for more than 4 decades. However, recent molecular, cellular, and transgenic mouse studies support an alternative hypothesis: primary abnormalities in vascular cell function can also directly cause abnormalities of blood pressure. In this issue of the JCI, Crowley and coworkers describe the application of an elegant cross-renal transplant model to type 1A angiotensin (AT1A) receptor–deficient mice and their wild-type littermates to explore the relative contributions of renal and extrarenal tissues to the low blood pressure seen in the AT1A receptor–deficient animals. Their studies further support the emerging paradigm that primary abnormalities of the vasculature can make unique, nonredundant contributions to blood pressure regulation; the findings have potentially important implications for the ways we diagnose and treat blood pressure diseases in humans.
Authors
Michael E. Mendelsohn
Abstract
The hypothalamic-pituitary-adrenal axis (a major component of the stress system) and the immune system contribute to the maintenance of homeostasis at rest and during stress. Because of their essential roles for the survival of self and species, the activities of these systems have evolutionarily developed in parallel and are intertwined at many levels. In this issue of the JCI, Ezzat et al. demonstrate that Ikaros, a differentiation factor of leukocyte lineage, also influences the maturation of the fetal pituitary corticotroph and, hence, the secretion of adrenocorticotropic hormone before and after birth. These results indicate that Ikaros is an ontogenetic and phylogenetic integrator of the stress and immune systems and that abnormalities in its function may produce endocrine and/or immune pathologies.
Authors
George P. Chrousos, Tomoshige Kino
Abstract
The causative genes for essential tremor (ET), one of the most common genetic neurological disorders, have eluded scientists despite intensive search. Two gene loci linked to ET, one on chromosome 3q13 and another on chromosome 2p24.1, have been identified, and a missense mutation in the HS1-BP3 gene on the 2p has been suggested as the cause of the disorder in about 10% of American ET patients. Therefore, the genetic basis for the vast majority of familial ET is still unknown. In this issue of the JCI, the gene coding for the γ-aminobutyric acidA (GABAA) receptor α1 subunit is suggested as a potential candidate gene for ET, as mice lacking the gene express a phenotype that overlaps with some clinical characteristics of the human condition.
Authors
Joseph Jankovic, Jeffrey L. Noebels
Abstract
Recently, type I interferons IFN-α and IFN-β (IFN-α/β) have been evaluated in pilot clinical trials for the treatment of active ulcerative colitis. However, the underlying mechanisms that may contribute to a potential therapeutic effect are incompletely understood. A new study in this issue demonstrates a protective role for IFN-α/β, induced by activation of a Toll-like receptor 9–dependent pathway, in a rodent model of experimental colitis.
Authors
Stefan Wirtz, Markus F. Neurath
Abstract
Remodeling of the arterial wall occurs mainly as a consequence of increased wall stress caused by hypertension. In this issue of the JCI, Azizi et al. report that in humans with a kallikrein gene polymorphism that lowers kallikrein activity, the brachial artery undergoes eutrophic inward remodeling in the absence of hypertension or other hemodynamic changes. It has also been reported that alterations of the kallikrein-kinin system are associated with formation of aortic aneurysms. Conversely, after vascular injury, kinins mediate the beneficial effect of angiotensin-converting enzyme inhibitors that prevent neointima formation. These findings raise the intriguing possibility that decreased kallikrein-kinin system activity may play an important role in the pathogenesis of vascular remodeling and disease, while increased activity may have a beneficial effect.
Authors
Oscar A. Carretero
Abstract
Numerous viruses cause latent infections in humans, and reactivation often results in pain and suffering. While vaccines for several of these viruses are available or currently being studied in clinical trials, and antiviral therapies have been successful in preventing or treating active infection, therapy to eradicate latent infection has lagged behind. A new study reported in this issue of the JCI shows that treatment of cells latently infected with Kaposi sarcoma–associated herpesvirus (KSHV) with glycyrrhizic acid, a component of licorice, reduces synthesis of a viral latency protein and induces apoptosis of infected cells. This finding suggests a novel way to interrupt latency.
Authors
Jeffrey I. Cohen
Abstract
The DEAD-box RNA helicases are enzymes involved in many critical aspects of RNA metabolism within both eukaryotic and prokaryotic organisms. Several studies have shown that these proteins may have important functions in mediating microbial pathogenesis. A new study in this issue of the JCI identifies the first DEAD-box RNA helicase in the pathogenic fungus Cryptococcus neoformans and proposes novel roles for this family of proteins in the development and progression of cryptococcosis.
Authors
Lena J. Heung, Maurizio Del Poeta
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