Abstract
Rett syndrome (RTT) is a severe genetic disorder resulting from mutations in the X-linked MECP2 gene. MeCP2 protein is highly expressed in the nervous system and deficiency in the mouse central nervous system alone recapitulates many features of the disorder. This suggests that RTT is primarily a neurological disorder, although the protein is reportedly widely expressed throughout the body. To determine whether aspects of the RTT phenotype that originate in non-neuronal tissues might have been overlooked, we generated mice in which Mecp2 remains at near normal levels in the nervous system, but is severely depleted elsewhere. Comparison of these mice with wild type and globally MeCP2-deficient mice showed that the majority of RTT-associated behavioural, sensorimotor, gait and autonomic (respiratory and cardiac) phenotypes are absent. Specific peripheral phenotypes were observed, however, most notably hypo-activity, exercise fatigue and bone abnormalities. Our results confirm that the brain should be the primary target for potential RTT therapies, but also strongly suggest that some less extreme but clinically significant aspects of the disorder arise independently of defects in the nervous system.
Highlights
Rett Syndrome (RTT) is an X-linked genetic disorder that is a leading cause of intellectual disability in girls and women [1]
In the vast majority of cases Rett syndrome (RTT) is caused by de novo mutations in the MECP2 gene, which encodes methyl-CpG binding protein 2 (MeCP2) [6], an abundant nuclear protein that is considered to be important in chromatin-level regulation of transcription [7]
Abnormal breathing patterns, including breath holding and apnoea, are common features of RTT [47] and are observed in Mecp2 KO mice [34,48,49,50,51]. They are typically attributed to disruption of autonomic or brainstem function, but as MeCP2 protein is expressed in lung, albeit at modest levels, and clinical studies suggest that pulmonary lesions are common in RTT [20], we looked for a peripheral contribution to respiratory pathologies
Summary
Rett Syndrome (RTT) is an X-linked genetic disorder that is a leading cause of intellectual disability in girls and women [1]. Diagnostic features of typical RTT include a highly characteristic developmental regression involving loss or impairment of mobility and loss of learnt speech and skilled intentional hand movements, accompanied by stereotypic hand movement automatisms. Associated features, such as microcephaly, respiratory/autonomic abnormalities, seizures, growth deficits and early hypotonia are highly prevalent [1,2]. In the vast majority of cases RTT is caused by de novo mutations in the MECP2 gene, which encodes methyl-CpG binding protein 2 (MeCP2) [6], an abundant nuclear protein that is considered to be important in chromatin-level regulation of transcription [7]. Other reports suggest MeCP2 may function as an activator of transcription [15] amongst other functions [7]
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