Nature Genetics pp 434 - 439

Focussing one's attention requires the brain to filter sensory input and hone in on selective stimuli, a neurological process called 'sensorimotor gating'. This process is disrupted in patients with psychiatric disorders who, as a consequence, register all sensory input with the same intensity, suffering 'sensory overload' and attention difficulties. Maria Karayiorgou, of the Rockefeller University (New York), and colleagues now reveal that the amino acid proline is critical to sensorimotor gating. The researchers found that mice with a mutation in the Prodh gene, which encodes an enzyme involved in proline metabolism, suffer from the same defects in sensorimotor gating as patients with neuropsychiatric disorders.

A sudden loud sound instinctively causes one to startle, but this reaction is normally reduced if another sound is heard immediately before the 'startling' stimulus. This is called 'prepulse inhibition' and can be used to test sensorimotor gating function in both humans and rodents. Karayiorgou and colleagues demonstrate that mice lacking Prodh have abnormal prepulse inhibition: the mice get almost as startled after a prepulse warning signal as they do if they receive the startling stimulus alone. This behaviour of Prodh-deficient mice is similar to that observed in psychiatric patents and, together with the finding that the human PRODH gene is located in a chromosomal region deleted in some psychiatric patients, suggests that PRODH may be involved in human behavioural disorders.

Nature Genetics pp 424 - 428

High density lipoprotein (HDL) cholesterol is often thought of as the good kind of cholesterol--the kind you want to have--as opposed to low density lipoprotein (LDL), which is associated with increased risk of cardiovascular disease. Higher levels of HDL are correlated with a reduced risk of atherosclerosis, a condition characterized by the accumulation of cholesterol on the interior walls of arteries which leads to clogging of the blood vessels. As nearly everyone with a relative suffering from elevated LDL cholesterol levels knows, there is a strong genetic component involved in determining cholesterol levels, but the picture of what genetic factors influence cholesterol and HDL metabolism is far from complete. Two triacylglycerol (TG) lipase enzymes have overlapping roles in modulating HDL levels; nevertheless, the action of the two enzymes cannot account for all of the variation in HDL cholesterol levels.

Daniel Rader, of the University of Pennsylvania, and colleagues have now discovered a new TG lipase involved in cholesterol metabolism. Unlike the two known TG lipases, endothelial lipase (EL) is produced in endothelial cells (the cells that line the wall of blood vessels) and other tissues, such as lung and kidney, where expression of the other lipases is low. Rader and colleagues demonstrate that injection of EL into mice leads to a dramatic reduction in plasma levels of HDL, suggesting that EL may be responsible for trafficking HDL from the plasma to tissues. These findings indicate that EL is a key regulator of cholesterol metabolism and raise the possibility that elevated EL levels may reduce the levels of HDL in plasma and lead to an increased risk of heart disease.

Nature Genetics pp 370 - 378 and pp 345 - 346

Different mycobacteria species vary in the severity of disease they inflict on humans, depending both on the virulence of the particular species and the host's susceptibility. Tuberculosis, caused by the highly virulent Mycobacterium tuberculosis, is one of the most infectious diseases in the world. Less virulent myobacteria, such as non-tuberculous mycobacteria (NTM) and the Bacille Calmette-Guerin (BCG) substrain (which is used as a live vaccine for tuberculosis and leprosy) do no harm to the general population, with the exception of rare individuals who succumb to severe and sometimes fatal infections. Jean-Laurent Casanova, of INSERM (France) and colleagues have now discovered that a mutation in the IFNGR1 gene is what makes otherwise healthy individuals susceptible to NTM and BCG infections.

IFNGR1 encodes the receptor for interferon (IFN), a key player in our immune defense against bacterial infections. When the host's surveillance cells detect a bacterial invader, they release chemical signals called cytokines, which trigger other cells of the immune system to produce IFN. IFN, in turn, activates macrophages (the 'scavengers' of the immune system) to kill the invading bacterium. Casanova and colleagues have found that mutation of only one of the two copies of IFNGR1 is sufficient to render an individual vulnerable to NTM and BCG infections. This is the first example where susceptibility to mycobacterial infection is inherited in a 'dominant' manner--that is, any family member who inherits even a single copy of the mutation will be susceptible. The mutant IFNGR1 receptor still makes its way to the surface of the cell and is able to bind IFN, but it lacks the region needed to activate the signalling pathways that enable a cell to respond to IFN. Although normal copies of IFNGR1 are also present in these cells, the mutated receptors compete for binding to IFN and clog up the cell surface, leaving no room for normal receptors.

It is surprising that a defect in IFN signalling, a critical component of the host's immune system, results in vulnerability to only a small range of normally innocuous mycobacteria. These findings, discussed by Simon Foote, of the Walter and Eliza Hall Institute of Medical Research, Australia, in an accompanying News & Views article, provide clues as to how genetic makeup can determine susceptibility and resistance to infectious diseases.