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JCI online early table of contents: Aug. 10, 2009

JCI Journals

EDITOR'S PICK: New gene linked to muscular dystrophy

Muscular dystrophy, a group of inherited diseases characterized by progressive skeletal muscle weakness, can be caused by mutations in any one of a number of genes. Another gene can now be added to this list, as Yukiko Hayashi and colleagues, at the National Center of Neurology and Psychiatry, Japan, have now identified mutations in a gene not previously linked to muscular dystrophy as causative of a form of the disease in five nonconsanguineous Japanese patients.

Mutations in the caveolin-3 gene have previously been linked to muscular dystrophy. In this study, the authors identified five nonconsanguineous Japanese patients with muscular dystrophy and degeneration of their fat tissue (a condition known as lipodystrophy) whose muscles were deficient in caveolin-3 protein in the absence of mutations in their caveolin-3 gene. Detailed genetic analysis revealed that these individuals had mutations in their PTRF gene, which is responsible for making a protein thought to influence caveolin protein stabilization. Further investigation confirmed this as a function for the PTRF protein, as the mutated forms of the PTRF gene generated mutant PTRF proteins that could not localize correctly or associate with caveolin proteins. The authors therefore conclude that disease in the five patients studied is likely to be a result of caveolin deficiencies secondary to the PTRF gene mutations.

TITLE: Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy

Yukiko K. Hayashi
National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Phone: 81-42-341-2711; Fax: 81-42-346-1742; E-mail:

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EDITOR'S PICK: How mice and humans differ immunologically

Edith Hessel and colleagues, at Dynavax Technologies Corporation, Berkeley, have identified the reason that humans and rodents respond differently to a molecule that is being developed to treat allergic diseases.

Molecules that trigger the protein TLR9 are being developed as a potential therapeutic for allergic diseases. While they have been shown to be safe and well-tolerated when inhaled by people, they cause severe lung inflammation and toxicity when inhaled by rodents. In the study, the toxicity of one of the molecules under development was found to depend on TLR9 and the soluble immune molecule TNF-alpha in mice. Importantly, TLR9 is expressed on many immune cell types in the mouse (monocyte/macrophage cells, B cells, and pDCs) and only on B cells and pDCs in humans. The toxicity in mice was found to be independent of B cells and pDCs, meaning that other immune cells expressing TLR9 were responsible for TNF-alpha production. As human TLR9-expressing cells did not produce TNF-alpha in response to stimulation by the molecules under development, the authors conclude that the differential pattern of TLR9 expression is important in determining the nontoxicity of molecules that target TLR9 in humans and that toxicity in rodents is a result of TNF-alpha production.

TITLE: CpG-containing immunostimulatory DNA sequences elicit TNF-alpha-dependent toxicology in rodents but not in humans

Edith M. Hessel
Dynavax Technologies Corporation, Berkeley, California, USA.
Phone: (510) 665-7255; Fax: (510) 848-1327; E-mail:

John D. Campbell
Dynavax Technologies Corporation, Berkeley, California, USA.
Phone: (510) 665-7281; Fax: (510) 848-1327; E-mail:

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EDITOR'S PICK: Bone cell control of energy generation is regulated by the protein Atf4

Bone cells known as osteoblasts were recently shown to have a role in controlling the biochemical reactions that generate energy via secretion of the molecule osteocalcin. Gerard Karsenty and colleagues, at Columbia University College of Physicians and Surgeons, New York, therefore hypothesized that osteoblasts express a regulatory gene(s) that controls this osteoblast function and then identified Atf4 as this regulatory gene in mice.

Atf4 is a protein expressed predominantly in osteoblasts that is known to regulate many osteoblast functions. The researchers therefore analyzed mice lacking Atf4 and found that they have lower fat mass and blood glucose (a major source of energy) levels than control mice. The lower blood glucose levels were due to increased expression and secretion of the hormone insulin, which promotes liver, fat, and muscle cells to take up glucose. Sensitivity to insulin in the liver, fat, and muscle was also enhanced. Several genetic experiments established that lack of Atf4 in osteoblasts was central to these abnormal characteristics of mice lacking Atf4 and further analysis indicated the underlying mechanism. Specifically, Atf4 directly increased expression of the Esp gene, which makes a protein that decreases the activity of osteocalcin. As Atf4 in osteoblasts was already known to regulate bone formation and mineralization, the authors conclude that Atf4 regulates many, but not all, osteoblast functions.

TITLE: The transcription factor ATF4 regulates glucose metabolism in mice through its expression in osteoblasts

Gerard Karsenty
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: (212) 305-4011; Fax: (212) 923-2090; E-mail:

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ONCOLOGY: New toxin carrier helps kill off tumor cells

TITLE: Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth

Samuel A. Wickline
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 454-8635; Fax: (314) 454-5265; E-mail:

Paul H. Schlesinger
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 362-2223; Fax: (314) 362-7463; E-mail:

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CARDIOLOGY: Micromanaging heart function

TITLE: MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice

Da-Zhi Wang
Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 919-4768; Fax: (617) 731-0787; E-mail:

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HEMATOLOGY: Cells galore: new way to make large numbers of patient-specific myelomonocytic cells

TITLE: Generation of mature human myelomonocytic cells through expansion and differentiation of pluripotent stem cell-derived lin-CD34+CD43+CD45+ progenitors

Igor I. Slukvin
Wisconsin National Primate Research Center, University of Wisconsin, Madison, Wisconsin, USA.
Phone: (608) 263-0058; Fax: (608) 265-8984; E-mail:

David Tenenbaum
Writer, University Communications, University of Wisconsin, Madison, Wisconsin, USA.
Phone: (608) 265-8549; E-mail:

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HEMATOLOGY: Immune response to transfused platelets later causes bone marrow-transplant rejection

TITLE: Transfusion of minor histocompatibility antigen-mismatched platelets induces rejection of bone marrow transplants in mice

James C. Zimring
Emory University School of Medicine, Atlanta, Georgia, USA.
Phone: (404) 712-2174; Fax: (404) 727-5764; E-mail:

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METABOLIC DISEASE: Effects of high-fat diets are mediated via PKC-theta in the brain

TITLE: Palmitic acid mediates hypothalamic insulin resistance by altering PKC-theta subcellular localization in rodents

Deborah J. Clegg
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-3401; Fax: (214) 648-8720; E-mail:

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