Nature Genetics pp 383 - 391

People are not born equal when it comes to susceptibility to disease and response to treatment. The anesthetic drug midozolam, for example, lingers longer in the blood streams of some people than those of others. The reason for this is thought to lie, at least in part, in the genetic variation between people. For any given stretch of a human chromosome, it is estimated that two individuals will show variation at about 1 in every 1,000 bases of DNA sequence. One of the great challenges now faced by geneticists is to identify how the variable bases (called 'single nucleotide polymorphisms' (SNPs)) influence traits, such as drug response. The way in which genotype (defined, for example, by a particular SNP or combination of SNPs) governs and correlates with drug response has been dubbed 'pharmacogenetics', and received a great deal of fanfare, albeit with scant support from the research laboratory.

A group led by Erin Schuetz (of St Jude Children's Research Hospital, Memphis, Tennessee) has now found a major genetic determinant of drug clearance in humans. They characterized the genes encoding the cytochrome P450 (CYP) proteins, which chemically modify and thus inactivate many toxic molecules—whether produced by the body itself or supplied by the environment. They focused on the CYP3A family, members of which account for the inactivation of 50% of all drugs—including HIV protease inhibitors, immunosuppressants, and anti-cancer and cholesterol-lowering chemicals. Using the DNA of people in different groups, they identified the most common SNPs in the CYP3A genes and then looked for possible associations between these SNPs and differences in drug detoxification.

Among several significant associations, they found one SNP (CYP3A5*3) that results in a shorter, and presumably less active, CYP3A5 protein. By measuring the rate at which different individuals break down midazolam, Schuetz and colleagues were able to draw a correlation between type of SNP (or genotype) and ability to metabolize the drug. Consistent with prediction, people with the CP3A5*3 allele break down the drug midazolam more slowly than those carrying the CYP3A5*1 allele, which encodes a full-length protein. They are therefore more likely to respond more efficiently to standard doses of many therapeutic agents. They may also have a higher risk of developing diseases promoted by other CYP3A target molecules-such as the hormone estrogen, which can promote breast cancer.

As the full-length CYP3A5*1 allele typically accounts for over 50% of total CYP3A activity when intact, it may be that the CYP3A5 alleles contribute substantially to the clearance of drugs and other relevant targets. The study by Schuetz and colleagues opens the door to a more accurate assessment of risk of disease and improvements in tailoring the prescription of drugs.

Nature Genetics pp 399 - 405 and pp 354 - 355

Type 1 neurofibromatosis (NF1) is a prevalent genetic disorder, affecting about 1 in 3,500 newborns. The syndrome is characterized by tumors of the nervous system and blood; about half of people with NF1 also have learning impairments. The disease is caused by mutations in the gene NF1, which encodes neurofibromin. Neurofibromin is a signaling protein that coordinates information relayed from the cell surface and appropriate cellular response to that information. But, as illustrated by NF1 syndrome, the inactivation of one signaling molecule can result in the disruption of many cellular processes. The challenge, therefore, is to sort out which signaling pathways are responsible for the different aspects of the NF1 syndrome.

A study by Alcino Silva and colleagues (of the University of California, Los Angeles) provides some insight into how neurofibromin mediates the learning process. Silva and colleagues engineered mutant mice in which a specific portion of Nf1-exon 23a-has been removed. These mice develop normally, in contrast with those lacking Nf1 (which die in utero). And they do not develop tumors, unlike people with NF1 (who are born with only one copy of functioning NF1) But when Silva and colleagues tested the learning ability of 23a-deficient mice, they observed impairments similar to those affecting people with NF1. As these mice developed normally, it would seem that the learning deficits of NF1 patients are caused by aberrations in brain biochemistry, rather than aberrant development-rendering the prospect of treatment a more realistic one than in the case of developmental glitches. Consistent with this is the finding that the learning impairments of both 23a-deficient mice and NF1 patients can be overcome by extensive training. As pointed out by Yuan Zhu and Luis Parada (of University of Texas Southwestern, Dallas) in an accompanying News & Views article, exon 23 encodes a region of the protein that is likely to disrupt signaling of in a particular pathway, known as the Ras-GAP pathway.

Nature Genetics pp 439 - 441

Leprosy is a disfiguring disease that has endured since the ancient civilizations of China, Egypt and India. It is a chronic infectious disease caused by the bacterium Mycobacterium leprae, a relative of the bacterium that causes tuberculosis. Leprosy tends to run in families; some families don't seem susceptible to the disease whereas others do, indicating that there may be genes that influence susceptibility.

An international collaborative effort, led by Adrian Hill (of Oxford University, UK) with collaborators in India, has resulted in the first identification of a chromosomal region that is associated with susceptibility to the leprosy. The researchers evaluated 224 families from South India and 245 pairs of siblings with leprosy. They searched for polymorphic DNA markers that correlate with the incidence of disease. After zeroing in on chromosome 10, they narrowed the search to a region on the short arm of the chromosome, 10p13. Establishing that susceptibility to leprosy has a major genetic component should hasten the discovery of the gene or genes that underlie the influence of the 10p13 locus.