Public Release:  JCI online early table of contents: July 17, 2008

Journal of Clinical Investigation

EDITOR'S PICK: Loss of stability of the AHI1-HAP1 complex an issue in Joubert syndrome

Joubert syndrome is an inherited disorder that affects the area of the brain that controls balance and coordination; it is characterized by symptoms such as loss of muscle tone, developmental delay, and mental retardation. Mutations in several genes have been associated with Joubert syndrome. The mutations in one of these, AHI1, are known to generate truncated forms of the AHI1 protein but how this contributes to the development of disease has not been determined. However, Xiao-Jiang Li and colleagues have now provided insight into this issue by showing that mouse Ahi1 interacts with the protein Hap1, which is critical for neonatal development.

In the study, it was found that Ahi1 binds tightly to Hap1 and that they form a stable complex in the mouse brain. Further analysis indicated that the two proteins stabilize each other and that truncated mouse Ahi1 that resembled the truncated AHI1 protein observed in individuals with Joubert syndrome was unable to stabilize mouse Hap1. The ability of Hap1 and Ahi1 to stabilize each other was important for maintaining levels of the protein TrkB, which is critical for the generation of nerves and brain development. These data have provided insight into the mechanisms underlying disease in individuals with Joubert syndrome associated with AHI1 mutations and might provide new targets for the development of novel therapeutic approaches.

TITLE: Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice

Xiao-Jiang Li
Emory University School of Medicine, Atlanta, Georgia, USA.
Phone: (404) 727-3290; Fax: (404) 727-3949; E-mail:

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MICROBIOLOGY: Human fats: a link between leprosy and atherosclerosis?

Leprosy is caused by the microbe Mycobacterium leprae, which lives inside cells and survives by both evading the immune system and using human fat molecules (lipids) to promote its growth and virulence. A link between these two factors influencing M. leprae survival in the lesions that characterize disease in individuals with the lepromatous form of human leprosy (L-lep) has now been uncovered by Robert Modlin and colleagues, at UCLA David Geffen School of Medicine, Los Angeles.

In the study, expression of genes containing the information for making proteins involved in lipid metabolism (the production and breakdown of lipids) was observed in human L-lep lesions. Consistent with this, the lipid-laden cells (specifically macrophages) in human L-lep lesions that are known to harbor M. leprae were found to accumulate human lipids known as oxidized phospholipids. Further in vitro analysis indicated that some of these oxidized phospholipids inhibited innate immune responses. The accumulation of macrophages laden with human oxidized phospholipids in L-lep lesions is strikingly similar to what is observed in the lesions that narrow the blood vessels in the disease atherosclerosis -- a common disease of the major arterial blood vessels that can result in heart attack or stroke. These similarities have led the authors to suggest that in both microbial infection and atherosclerosis there is a link between innate immunity and human lipid metabolism.

TITLE: Host-derived oxidized phospholipids and HDL regulate innate immunity in human leprosy

Robert L. Modlin
UCLA David Geffen School of Medicine, Los Angeles, California, USA.
Phone: (310) 825-6214; Fax: (310) 267-2121; E-mail:

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VASCULAR BIOLOGY: The protein MRP4 regulates disease-associated smooth muscle cell proliferation

The proteins MRP4 and MRP5 are expressed in several tissues and cell types, including smooth muscle cells, but their function has not been clearly determined. However, new insight into the function of these proteins has now been provided by Jean-Sébastien Hulot and colleagues, at INSERM U621, France, who have shown that MRP4 regulates the amount of two signaling molecules known as cAMP and cGMP inside smooth muscle cells from the wall of human and rat arteries in disease-associated situations.

In the study, expression of MRP4, but not MRP5, was found to be increased in proliferating human smooth muscle cells from arteries and rat smooth muscle cells from damaged arteries. Inhibiting MRP4 in the rat smooth muscle cells blocked proliferation associated with damage and this was coupled with increased amounts of cAMP and cGMP inside the smooth muscle cells. The authors therefore suggest that MRP4 acts as regulator of levels of cAMP and cGMP inside smooth muscle cells. Further, as excessive smooth muscle cell proliferation in arteries is associated with several diseases, including a form of high blood pressure and atherosclerosis (the disease that is one of the most common causes of heart attack and stroke), it is suggested that MRP4 inhibition might have therapeutic potential.

TITLE: Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation

Jean-Sébastien Hulot
INSERM U621, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
Phone: 33-1-40-77-95-84; Fax: 33-1-40-77-96-45; E-mail:

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CARDIOLOGY: The protein CAR is essential for normal heart function

The adhesion protein CAR is expressed in a region of the adult heart known as the intercalated disc (which supports synchronized contraction of the heart), but its function there is unknown. However, a new study, by Kirk Knowlton and colleagues, at the University of California, San Diego, has revealed that CAR is essential for normal heart function in mice.

In the study, adult mice lacking CAR in the heart exhibited a complete block in conduction of electrical impulses from the upper chambers of the heart (the atria) to the lower chambers (the ventricles) (a process known as atrioventricular [AV] conduction), meaning that the heart did not beat synchronously. The complete block in AV conduction occurred for varying lengths of time in the different mice analyzed. Furthermore, the mice developed heart disease by 21 weeks of age, and this was associated with disorganization of the intercalated disc structure. Detailed analysis indicated that in the absence of CAR in the heart, cell-cell junctions at both the site of AV conduction and the intercalated disc were abnormal. The authors therefore conclude that CAR is essential for the adult mouse heart to function normally and suggest that these results have implications for the development of therapeutics for genetic and acquired heart diseases.

TITLE: Coxsackievirus and adenovirus receptor (CAR) mediates atrioventricular-node function and connexin 45 localization in the murine heart

Kirk U. Knowlton
University of California, at San Diego, La Jolla, California, USA.
Phone: (858) 822-1364; Fax: (858) 822-3027; E-mail:

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IMMUNOLOGY: Revising what B cells see

New insight into mechanisms that operate to diminish an ongoing immune response targeting the body's own tissues has been provided by Ying-Hua Wang, at Columbia University Medical Center, New York, and Betty Diamond, at North Shore Long Island Jewish Health System, Manhasset, who performed research using a mouse model of the autoimmune disease systemic lupus erythematosus (SLE), a disease commonly known as lupus.

B cells are immune cells that recognize microbes through a protein on their cell surface known as the BCR. In lupus, BCR interactions with normal components of the body mistakenly trigger B cells to attack. In the study, B cells responding to the normal components of the body were found to have increased expression of a protein known as RAG, which modifies the BCR such that it now recognizes different things. This ability of RAG to revise what the BCR recognizes was found to help dampen the ongoing immune response targeting the normal components of the mouse. The authors therefore suggest that perturbation of BCR revision might contribute to the development of autoimmune disease.

TITLE: B cell receptor revision diminishes the autoreactive B cell response after antigen activation in mice

Betty Diamond
The Feinstein Institute for Medical Research, North Shore Long Island Jewish Health System, Manhasset, New York, USA.
Phone: (516) 562-3830; Fax: (516) 562-2953; E-mail:

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