Rett Syndrome: Postnatal Neurological and Growth Disorder
Rett syndrome (RTT) is a rare disorder that is characterized by a deceleration of postnatal development, particularly neurological maturation, and is often associated with increasing motor impairments. Impaired grey matter cell development and function leads to challenges with learning, speech, movement, breathing, and cardiac function among others. Patients are predominantly female, but males can be affected, too. Patients typically are identified at 6-18 months by impaired developmental progression, as well as by small hand, foot, and head size. They may also display stereotypical hand movements (putting hands to mouth or wringing), gastrointestinal disorders, and a high proportion of those affected also experience seizures. Patients, also, commonly have decreased bone mass and density, which puts them at higher risk for fractures and early-onset osteoporosis. Consequences of RTT itself, such as immobility and diet challenges, as well as side effects from anti-seizure medications, have been proposed as contributing to RTT-associated osteoporosis, but the underlying etiology of this phenomenon is not completely understood.
Loss-of-function mutations in the X-linked MECP2 (Methyl CpG binding protein 2) gene drive RTT. MECP2 protein regulates gene expression in many cell types, and is required for normal nerve cell activity. In a recent study published in Bone, a group led by Drs. Mary Blue and Jay Shapiro of the Hugo W. Moser Research Institute at Kennedy Krieger Institute examined the role of MECP2 deficiency in osteoblast function and bone development. Their work suggests that MECP2 deficiency contributes to pathology that extends beyond the neurological developmental disorder.
Mutant Mecp2 mice have decreased osteoblast activity
Bone histological analyses in RTT mouse models and of biopsies from RTT patients have demonstrated that MECP2 mutations are associated with abnormal bone formation. To investigate the direct role of MECP2 on bone cell function, the authors examined the activity of osteoblasts and osteoclasts in the Mecp2-deficient mouse, B6.129P2(C)-Mecp2tm1.1Bird/J (003890). Compared to wild-type (WT) mice, Mecp2-null male mice have significantly reduced bone volume and density, including less tightly spaced trabeculae. Bone structure and organization in female Mecp2 heterozygous (HET) mutant mice, however, are not significantly different from female WT mice. In contrast, features of bone remodeling and mineralization rates are altered in both null males and HET females. Although bone-resorbing osteoclast numbers are similar to WT in both null males and HET females, fewer bone-rebuilding osteoblasts are observed in the Mecp2 mutants. Additionally, cultured osteoblasts from Mecp2-null male mutants show altered expression of the characteristic bone markers Runx2, Osterix (Sp7), and type I collagen mRNA compared to WT osteoblasts. These results demonstrate that MECP2 deficiency results in impaired osteoblast function, a finding which helps to explain the high rate of early-onset osteoporosis in RTT patients. This new appreciation for the direct linkage between osteoporosis and MECP2-deficiency may help researchers develop better-targeted therapies for the different pathologies of this disorder.