Rett syndrome is the most severe of the autism spectrum disorders, and it affects nearly 1 in 10,000 children with symptoms that include progressive loss of speech, stereotypic hand movements, motor deficits and developmental impairment. The disease overwhelmingly affects girls, and it is caused by mutations in the Mecp2 gene on the X chromosome. Mouse strains engineered with mutations in Mecp2 are instrumental for modeling basic aspects of the disease and testing therapies. A 2013 publication in Nature Genetics from the laboratory of Dr. Monica Justice at Baylor College of Medicine provides an elegant example of how genetic screens in mice can reveal surprising new roles for genetic pathways in the development of Rett syndrome and other diseases (Buchovecky, et al. 2013).
The genetic screen was designed to identify dominant mutations that suppressed disease progression in a Mecp2-deficient mouse, B6.129P2(C)-Mecp2tm1.1Bird/J (003890). By 3-8 weeks of age, knockout mice are hypoactive, have an abnormal gait and show stereotypies such as hindlimb clasping. Survival is usually limited to less than two months. Factors that improved disease symptoms in this model were discovered by first creating new mutations at random in C57BL/6J (000664) males with the DNA damaging agent, ENU (N-ethyl-N-nitrosourea), and then mating the mutant mice to Mecp2 heterozygous mice. Screening nearly 700 different Mecp2-deficient males produced in the crosses identified five different mutations that suppressed the disease by prolonging survival and improving neurological symptoms.
Genome sequencing mapped one of the mutations to the Sqle gene encoding squalene epoxidase, which participates in early stages of cholesterol synthesis. Proper cholesterol levels are essential for controlling neuronal functions, and complementary findings suggested that the cholesterol pathway was misregulated in Rett syndrome models: brain cholesterol levels were elevated in two different Mecp2-mutant strains used to model the disease, while the Sqle mutation impaired cholesterol synthesis and suppressed the effects of Mecp2 deficiency.
The misregulated cholesterol metabolism in Rett syndrome mouse models suggested an attractive possibility for therapeutic intervention: statin drugs, which lower cholesterol levels systemically by inhibiting the early stages of cholesterol synthesis. Administering two different statins (fluvastatin and lovastatin) to Mecp2 knockout mice corrected cholesterol imbalances, extended the lifespan and improved neurological symptoms such as motor deficits.
Taken together, the Justice groups’ findings provided genetic evidence that imbalances in cholesterol metabolism can underlie many disease traits in mouse models of Rett syndrome. The promising new role for a widely prescribed class of drugs complement other recent findings that statins improve disease symptoms in a mouse model of another neurological disease, fragile X syndrome (Osterweil, et al. 2013), and offer hope for new treatments of the disease.