Nature Genetics pp 185 - 188 and pp 127 - 128

Rett syndrome is a progressive neurodegenerative disorder that is unusual in that it almost exclusively affects females. It is one of the most common forms of mental retardation in females, affecting approximately 1 in 10,000 births. Girls with this disorder develop normally until 6-18 months of age, but then gradually lose speech and purposeful use of the hands, suffer from seizures and develop autism and severe dementia. Huda Zoghbi (of the Howard Hughes Medical Institute at Baylor College of Medicine) and colleagues have now discovered the gene defective in Rett syndrome.

Their findings provide insight into a disorder that has confused and frustrated researchers because of its unusual pattern of inheritance and the difficulty in finding families where multiple members are affected. Geneticists typically map the location of a disease gene by studying the way the genetic defect is inherited in families, and then concentrate their search for the gene in this region. Most cases of Rett syndrome, however, are sporadic, which means that the gene mutation is new and absent in earlier generations. There are a few rare families, however, with affected sisters and half-sisters; these enabled researchers to map the gene to a region on the X chromosome. As females have two X chromosomes and males have an XY pair, and the discovery that the 'Rett syndrome' gene maps to the X chromosome was surprising because most other forms of X-linked mental retardation affect mostly males, who lack a 'back-up' copy that can compensate for the defect.

Zoghbi and colleagues now report that mutations in the X-linked gene MECP2 cause Rett syndrome. This discovery sheds light on why Rett syndrome affects mainly girls. Mice defective in the mouse version of MECP2 die before birth; it is therefore likely that human male fetuses with MECP2 mutations are never born. But why do females, who have a normal copy of MECP2, suffer from the disease? This can be explained by X inactivation in females, a process whereby one of the X chromosomes is inactivated to keep the dosage of gene expression equivalent to that of a male (who has only one X). As X inactivation is random, the functional copy of MECP2 is active in some cells of Rett syndrome females but inactive in others. This partial deficiency allows survival and apparently normal infant development, but later leads to the disease.

MECP2 encodes a repressor of gene expression and it cooperates with a process called DNA methylation to turn off expression and keep genes 'silent'. Some cells in Rett-syndrome patients lack a functional copy of this gene and therefore may abnormally express other genes that affect neuronal function. Rett syndrome is the first human disease found to be caused by defects in a gene involved in DNA methylation. Hunt Willard (of Case Western Reserve University) and Brian Hendrich (of the University of Edinburgh) discuss, in an accompanying News & Views article, ways in which disruption of gene silencing could lead to the severe neurodevelopmental defects and mental retardation observed in the patients. Quite a bit is known about the function of MECP2 and these findings raise hopes that a treatment could be developed for people with Rett syndrome. The window of apparently normal development in early infancy affords an opportunity for affected girls to be treated before symptoms appear.

Nature Genetics pp 189 - 193

Vascular cavities killed the American runner Florence Griffith Joyner in her sleep. They were also responsible for the seizure that struck down Larry Dierker, the manager of the Houston Astros baseball team, and forced him to be carried off the field and into surgery. These cavities, called cavernous angiomas, are abnormal enlargements of blood vessels in the central nervous system that swell and take up space normally occupied by brain tissue. While many cavernous angiomas have no clinical effect, others cause epileptic seizures, brain haemorrhages or neurological deficit. Cavernous angiomas have a high incidence; they occur in approximately 0.5% of the population and, in up to 50% of cases, the condition is inherited. Elisabeth Tournier-Lasserve (of INSERM U25) and colleagues have now discovered that hereditary cavernous angiomas are caused by mutations in the gene CCM1.

As much of the human genome is still uncharacterized, the identification of the genetic defects underlying a particular disease often uncovers new genes of unknown function. In this case, however, a few things are known about CCM1 that implicate other players in the development of cavernous angiomas. The protein product of CCM1 interacts with RAP1A, a factor that is part of the well-characterized RAS signalling pathway. This report therefore links the RAS pathway, which is known to be involved in the formation of blood vessels, with brain vascular malformations, and suggests that members of this pathway could be potential targets for therapeutic intervention.

Nature Genetics pp 142 - 144

Hereditary nonpolyposis colorectal cancer (HNPCC)--a common form of inherited early onset colorectal cancer--is caused by mutations in a particular class of DNA repair genes. All three billion base pairs that make up the human genome need to be copied every time a cell divides. The copying process is remarkably reliable, but given the magnitude of the task, mistakes inevitably occur. If uncorrected, some of these mistakes, or 'mutations', could kill a cell or, alternatively, put it on the pathway to cancer. Given the pivotal importance of the repair systems, it is easy to see why mutations in DNA repair genes are frequently associated with human cancer syndromes such as HNPCC. Mutations in two repair genes, MLH1 and MSH2, cause typical HNPCC (as defined by specific clinical characteristics, the so-called 'Amsterdam criteria'). A study by Riccardo Fodde (of Leiden University Medical Center) and colleagues now reveals that mutation of another DNA repair gene, MSH6, is the frequent cause of atypical HNPCC. In their study, they found that many women suffering from HNPCC caused by mutations in MSH6 also have endometrial tumours (73%), suggesting that mutations in MSH6, independently of HNPCC, may also predispose towards this very common cancer.