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JCI table of contents, November 15 2004

JCI Journals

New gene mutation found to cause "bubble boy disease"

Approximately one in every million people develop a group of inherited disorders known as severe combined immunodeficiency (SCID) or "bubble boy disease". Characterized by inherited abnormal changes in B and T cells of their immune system, these individuals often suffer from numerous serious or life-threatening infections that are often fatal in early life. The condition became widely known in the 1970's when the world learned of David Vetter, a boy with SCID who lived for 12 years in a plastic, germ-free bubble.

A number of genetic abnormalities can cause SCID. The two most common forms are linked to the X chromosome. Patients with abnormalities on this chromosome either lack an enzyme called adenosine deaminase, or lack the ability to produce IL-2 receptor gamma chain, a molecule that T cells need to communicate with B cells. In some cases of SCID, doctors have been unable to identify the underlying cause.

In the November 15 issue of the Journal of Clinical Investigation, Françoise Le Deist and colleagues from INSERM, Paris, describe how a complete deficiency in the CD3 epsilon chain of the T cell receptor, which binds foreign antigens and thus targets them for destruction, causes SCID.

The authors studied 3 families with, or having had lost, infants with SCID of an unknown molecular type. All of these individuals had normal B cells but no T cells. The authors found that the absence of CD3 epsilon completely blocks T cell development at a specific stage in the thymus.

In an accompanying commentary, Rebecca H. Buckley, a pediatrician at Duke University Medical Center, discusses the importance of the identification of this new mutation. "If the diagnosis is made at birth or shortly thereafter, definitive therapy in the form of bone marrow stem cell transplantation can result in a survival rate as high as 97%, regardless of the molecular type of SCID." Dr. Buckley cautions that while stem cell transplantation (involving transplanting bone marrow from a healthy sibling or other donor whose tissue type closely matches that of the patient's) is not a perfect therapy, there has been remarkable success in reestablishing the B and T cell population in SCID patients. However, gene therapy cannot be performed unless the abnormal gene for the specific patient is known. At Duke University alone, approximately 6% of recorded SCID cases have an unknown molecular basis. Identification of this new mutation in the CD3 epsilon chain will prompt doctors to examine such individuals for this mutation and hopefully allow suitable therapeutic steps, such as gene therapy, to be considered.

TITLE: Severe combined immunodeficiency caused by deficiency in either the delta or epsilon subunit of CD3.

AUTHOR CONTACT: Françoise Le Deist
INSERM and Hôpital Necker-Enfants Malades, Paris, France.
Phone: 33-1-44-49-50-88; Fax: 33-1-42-73-06-40; E-mail:

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TITLE: The multiple causes of human SCID

AUTHOR CONTACT: Rebecca H. Buckley
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
Phone: 919-684-2922; Fax: 919-681-7979; E-mail:

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Aging affects susceptibility to type 2 diabetes

Earlier research has reported a small but significant decrease in the levels of the transcription factors PGC-1alpha and PGC-1beta (which activate the conversion of protein to glucose) in the skeletal muscle of individuals with type 2 diabetes mellitus (T2DM) and in first degree relatives who do not have diabetes. However it was previously unknown whether this was an inherited genetic defect or the result of environmental triggers.

T2DM is caused by the development of insulin resistance in muscle and liver coupled with the progressive failure of beta cells in the pancreas to produce sufficient quantities of insulin to overcome the increasing resistance.

In the November 15 issue of the Journal of Clinical Investigation, a study by Charlotte Ling and colleagues from Lund University, Sweden, addresses whether the dysregulation of PGC-1 expression is due to environmental or genetic factors. The authors examined the effects of insulin on muscle PGC levels in young and old, identical and fraternal, non-diabetic twins.

The authors demonstrate that the expression levels of PGC-1alpha and PGC-1beta in muscle are increased by insulin stimulation and decreased by aging. The age-dependent decrease was found to be partially heritable and only observed in individuals with a mutation in the gene encoding PGC-1alpha. This may explain the significant variation in susceptibility of individuals to T2DM as we age. The study also demonstrated that PGC-1alpha and PGC-1beta were found to each influence different aspects of glucose metabolism, lending insights into the complex interaction between genetic and environmental influences such as age on the development of insulin resistance and T2DM.

The finding that the age-dependent decrease in expression of these key genes regulating glucose metabolism is under genetic control could provide an explanation by which an environmental trigger like aging modifies genetic susceptibility to type 2 diabetes.

In an accompanying commentary, Alan R. Shuldiner and John C. McLenithan from the University of Maryland School of Medicine discuss these results and how aging, diet, exercise, and other factors can affect our susceptibility to T2DM.

TITLE: Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins.

AUTHOR CONTACT: Charlotte Ling
Department of Endocrinology, Lund University, Malmö, Sweden
Phone: 46-4-033-6066; Fax: 46-4-033-7042; E-mail:

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TITLE: Genes and pathophysiology of type 2 diabetes: more than just the Randle cycle all over again.

AUTHOR CONTACT: Alan R. Shuldiner
Division of Endocrinology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Phone: 410-706-1623; Fax: 410-706-1622; E-mail:

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Inactive form of scatter factor protein found to suppress tumor growth and spread

Scatter factor (SF) is a growth factor that controls the proliferation and survival of many tissues by promoting invasive growth in both normal and disease-related biological processes. Produced in a precursor form, pro-SF must be cleaved in order to activate its receptor, Met tyrosine kinase. In the November 15 issue of the Journal of Clinical Investigation, Paolo Michieli and colleagues developed an uncleavable form of pro-SF and used it in a gene therapy approach in mice to inhibit invasive tumor growth. Administration of the uncleavable pro-SF at the site of the tumor prevented the development of new blood vessels to the tumor, tumor growth, and tumor spread to other tissues, without affecting any normal physiological functions. The study demonstrates that the cleavage of pro-SF is an important step in the progression of tumor development and also suggests that drugs that inhibit this cleavage may lead to successful anti-cancer therapies.

TITLE: An uncleavable form of pro-scatter factor suppresses tumor growth and dissemination in mice.

AUTHOR CONTACT: Paolo Michieli
Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo, Italy.
Phone: 39-011-9933-219; Fax: 39-011-9933-225; E-mail:

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Researchers piece together the puzzle of Hailey-Hailey skin disease

Hailey-Hailey disease is a blistering skin disorder, usually inherited, and is characterized by a painful erosive skin rash that appears on the body in an unusual pattern of lines (Figure 1). The rash appears in a linear pattern on the extremities, S-shaped on the chest and abdomen, and V-shaped on the back. These lines are thought to trace the pathway of development of the ectoderm, one of the three layers of cells of the early human embryo and that which gives rise to skin and neural tissue.

It has been thought that individuals with Hailey-Hailey disease possess not one, but two or more genetically different populations of cells that originate from the one fertilized cell after fusion of the sperm and ovum during fertilization. This condition is known as mosaicism. In most cases of clinical mosaicism, the linear patterns of abnormal skin are surrounded by normal skin - termed type 1 mosacism. Several patients have been described whom experience both patterned lesions and, in remaining areas of skin, also show a milder form of the disorder - termed type 2 mosaicism.

In the November 15 issue of the Journal of Clinical Investigation, German researcher Jorge Frank and colleagues reveal the molecular basis of type 2 mosaicism in Hailey-Hailey disease. The authors isolated skin cells from severely affected areas of a female patient and found that skin cells from patterned skins lesions possessed a defect in the gene ATP2C1, which encodes a calcium pump protein, present on the chromosome derived from the patients mother. Normally, the chromosome obtained from the father and presumably containing a normal form of this gene, would compensate for this defect and result in the remaining skin cells being normal. However, in this case, the chromosome obtained from the father had been lost. Therefore, skin cells isolated from other areas of the skin possessed the same defect and in effect the patient had received a "double dose" of the mutant gene in severely affected areas.

In an accompanying commentary, Amy S. Paller, from the Department of Dermatology at Northwestern University discusses this novel genetic concept and asserts that "the discovery of the basis for type 2 mosaicism contributes to our understanding of gene mosaicism as well as of embryologic development of the ectoderm." This study will prompt further examination of the mechanisms of embryologic development of the ectoderm and the causes of other patterned epidermal and dermal disorders.

TITLE: Allelic loss underlies type 2 segmental Hailey-Hailey disease, proving molecular confirmation of a novel genetic concept.


Department of Dermatology and Allergology, University Clinic of the RWTH, Aachen, Germany.

Phone: 49-241-808-9162; Fax: 49-241-808-2413; E-mail:

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TITLE: Piecing together the puzzle of cutaneous mosaicism.

Department of Dermatology. Northwestern University, Chicago, Illinois, USA.
Phone: 312-695-0197; Fax: 312-695-0664; E-mail:

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Understanding the development of wasting in disused muscles

For people with immobilized limbs, sedentary lifestyles or subject to extended periods of bed rest, muscle disuse often leads to the loss of muscle tissue known as muscle atrophy. Earlier studies have implicated three proteins - NF-kappaB, p50, and Bcl3 - in the development of atrophy, however the precise mechanisms involved have remained unknown. In the November 15 issue of the Journal of Clinical Investigation, Susan Kandarian and R. Bridge Hunter from Boston University examined mice deficient in the proteins p105/p50 (encoded by the gene Nfkb1) or Bcl3 (encoded by the gene Bcl3) and had their hind limbs suspended for 10 days. The authors found that these mice lost soleus muscle mass. While normal mice showed greatest loss of their fast contracting muscle fibers in comparison to slow contracting fibers, the fast contracting fibers in Nfkb1- and Bcl3-deficient mice appeared to be resistant to atrophy. The results demonstrate that muscular inactivity triggers the activation of P50 and Bcl3, which in turn may activate genes necessary for the development of atrophy.

TITLE: Disruption of either the Nfkb1 or Bcl3 gene inhibits skeletal muscle atrophy.

AUTHOR CONTACT: Susan C. Kandarian
Department of Health Sciences, Boston University, Boston, Massachusetts, USA.
Phone: 617-353-5169; Fax: 617-353-7567; E-mail:

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New structure described for kidney filter: the slit diaphragm

One of the main functions of the kidney is the formation of urine by filtration of the plasma. The size-selective kidney filter, known as the slit diaphragm (SD), prevents plasma proteins from leaking into the urine. This filtration barrier consists of layers of specialized cells, including podocytes, which are connected by the interdigitating zipper-like structure of the SD, and defects in the SD are associated with a number of kidney diseases. In 1974, the zipper-like SD structure was first described, however this model was later questioned and the molecular nature of the SD has since remained obscure.

In the November 15 issue of the Journal of Clinical Investigation, Karl Tryggvason and colleagues from the Karolinska Institute used electron tomography to obtain detailed images of the SD that were previously impossible to obtain. They found that some elements of the proposed zipper-like structure hold true but the pores of this filtration structure appear to be more irregularly shaped that previously proposed. The authors also demonstrated a crucial role for the protein nephrin, expressed by the podocytes and localized in the area of the SD, in the formation of this structure. Indeed, the fibers that constitute the SD appear to be formed largely by the association of extracellular nephrin strands. The authors examined a Finnish population of individuals lacking the nephrin protein due to a mutation in then nephrin gene, and also examined nephrin-deficient mice and found that in all cases the ordered SD structure was no longer evident and excessive protein levels were found in the urine.

In an accompanying commentary, William M. Deen from the Massachusetts Institute of Technology, discusses how the many parts of the glomerular capillary wall function to determine the permeability of this living ultrafiltration membrane.

TITLE: Nephrin strands contribute to a porous slit diaphragm scaffold as revealed by electron tomography.

AUTHOR CONTACT: Karl Tryggvason
Department of Medical Biochemistry and Biophysics, Karolinksa Institute, Stockholm, Sweden.
Phone: 46-8-7287720; Fax: 46-8-316165; E-mail:

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TITLE: What determines glomerular capillary permeability?

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Phone: 617-253-4535; Fax: 617-253-2072; E-mail:

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Identifying the cellular sensor at work in polycystic kidney disease

Approximately 1 in 1,000 individuals are affected by polycystic kidney disease, characterized by the development of multiple cysts in the kidney and end-stage renal disease in late middle age. Resulting from mutations in 1 of 2 genes, PKD1 or PKD2, previous studied have presupposed that the proteins encoded by these two genes, polycystin-1 and -2, physically interact to initiate a number of cell signaling cascades. However, recent studies have shown that these two proteins are located in different compartments with the cell, begging the question - how can they interact?

In the November 15 issue of the Journal of Clinical Investigation, Michael Caplan and colleagues provide the first evidence that the tail of the cell surface receptor polycystin-1 is cleaved and released from the cell membrane by a process known as regulated intramembrane proteolysis where it then travels to the nucleus in a polycystin-2-dependent manner to modulate gene expression. This explains how polycystin-1-polycystin-2 interactions occur without colocalization of these proteins in the same membrane compartment.

In an accompanying commentary, Lisa Guay-Woodford from the University of Alabama at Birmingham discusses how this highly choreographed cellular crosstalk may affect other signaling pathways within the cell that ultimately define and maintain normal kidney cell architecture.

TITLE: Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus.

AUTHOR CONTACT: Michael J. Caplan
Department of Cellular and Molecular Physiology, Yale University, New Haven, Connecticut, USA.
Phone: 203-785-7316; Fax: 203-785-4951; E-mail:

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TITLE: RIP-ed and ready to dance: new mechanisms for polycystin-1 signaling

AUTHOR CONTACT: Lisa M. Guay-Woodford
Department of Medicine, Genetics, and Pediatrics, University of Alabama at Birmingham, Atlanta, USA.
Phone: 205-934-7308; Fax: 205-975-5689; E-mail:

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Hobbling free of alpha-hemoglobin in beta-thalassemia

Hemoglobin carries oxygen throughout the body and is comprised of four subunits: two alpha-hemoblobins (alpha-Hb) and two beta-hemoglobins (beta-Hb). Hempoglobin synthesis is carefully coordinated to avoid accumulation of free alpha-Hb or beta-Hb subunits, which can be toxic. In the disease beta-thalassemia, characterized by severe anemia, loss of beta-Hb leaves alpha-Hb subunits unpaired and alpha-Hb production of toxic oxygen molecules reduces the lifespan of circulating red blood cells.

In the November 15 issue of the Journal of Clinical Investigation, Mitchell Weiss and colleagues investigated the role of the alpha-Hb-stabilizing protein (AHSP) in limiting the damage caused by free alpha-Hb. The authors developed mice deficient in AHSP and found that their red blood cells were short-lived due to increased levels of toxic reactive oxygen species and free Hb. Providing purified AHSP in culture inhibited toxic alpha-Hb oxygen production. The study indicates an essential role for AHSP during Hb production and red blood cell production. The authors propose that developing means to alter human AHSP expression could reduce the severity of beta-thalassemia.

TITLE: Loss of alpha-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates beta-thalassemia

AUTHOR CONTACT: Mitchell J. Weiss
The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 215-590-0565; Fax: 215-590-4834; E-mail:

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Desmoglein 4 shown to have no role in disrupted adhesion of skin cells in the skin-blistering disease pemphigus

Data disproves early theory

Pemphigus is a group of rare blistering diseases of the skin and/or mucous membranes that occur when the immune system produces antibodies that mistakenly perceive cells of the skin or mucous membranes as foreign, and attacks them. Desmogleins, a family of proteins that function to attach one cell to its neighbor, when attacked by autoantobodies, become separated from each other causing burn-like lesions or blisters that do not heal. To date, four types of desmogleins have been described - Dsg1-4 - and in the November 15 issue of the Journal of Clinical Investigation, Masayuki Amagai and colleagues from Keio University in Tokyo investigated the involvement of Dsg4, expressed in the superficial layer of the skin, in pemphigus and staphylococcal scalded skin syndrome (SSSS).

Surprisingly, and in contrast to earlier work suggesting a role for Dsg4 in pemphigus, the authors found that although autoantobodies that recognize Dsg4 are present in the sera of pemphigus patients, these antibodies cross-react with Dsg1 and removal of anti-Dsg4 antibodies did not affect the pathogenicity of the remaining Dsg1 autoantobodies. Is SSSS, Dsg1 is targeted for cleavage by exfoliative toxins (ETs) of Staphylococcus aureus, however Amagai et al. found that ETs did not cleave Dsg4, suggesting that Dsg4 could not compensate for the loss of Dsg1 after ET cleavage. In sum, the authors concluded that Dsg4 must play a role other that adhesion in the development of pemphigus and SSSS.

TITLE: Defining the pathogenic involvement of desmoglein 4 in pemphigus and staphylococcal scalded skin syndrome.

AUTHOR CONTACT: Masayuki Amagai
Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
Phone: 81-3-5363-3425; Fax: 81-3-3351-6880; E-mail:

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Par1 for the course in inflammatory bowel disease

An estimated more than 1 million Americans suffer from ulcerative colitis or Crohn's disease, the two most common forms of inflammatory bowel disease (IBD), which cause painful and debilitating chronic inflammation of the digestive tract. Thought to result from a variety of genetic and environmental factors, scientists have yet to gain a complete picture of the mechanisms of this disease. In the November 15 issue of the Journal of Clinical Investigation, Nathalie Vergnolle and colleagues found that IBD patients have increased levels of protein-activated receptor-1 (PAR1) in the colon. In mice, activation of PAR1 resulted in increased severity and duration of inflammation requiring T and B cells. Conversely, drugs that inhibit PAR1 activity were shown to greatly reduce inflammation. The results point to the importance of PAR1 activity in IBD and indicate that PAR1 inhibition may be useful in treating IBD and other chronic intestinal inflammatory conditions.

TITLE: A role for proteinase-activated receptor-1 in inflammatory bowel diseases.

AUTHOR CONTACT: Nathalie Vergnolle
Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada.
Phone: 403-220-4588; Fax: 403-210-8195; E-mail:

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OutFOXing high lipid levels in diabetes

TITLE: Foxo1 mediates insulin action on apoC-III and triglyceride metabolism. AUTHOR CONTACT: Hengjian Henry Dong
Department of Pediatrics, Children's Hospital of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Phone: 412-692-6577; Fax: 412-692-5809; E-mail:

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