Rett syndrome modeling goes simian

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Science Translational Medicine  07 Jun 2017:
Vol. 9, Issue 393, eaan8196
DOI: 10.1126/scitranslmed.aan8196


Rett syndrome modeling in monkey mirrors the human disorder.

Last year marked the 50th anniversary since a Viennese pediatrician, Andreas Rett, reported the cases of 22 children, all females, presenting with loss of previously acquired skills, such as practical hand usage and communicative behaviors. The severe neurodevelopmental disorder, now bearing Rett’s name, manifests in girls and in the majority of the cases is caused by mutations in the X-linked gene MECP2. Females carrying heterozygous MECP2 mutations show a constellation of symptoms—such as seizures, intellectual disability, compromised social and motor skills—whereas in males, hemizygous MECP2 mutations result in neonatal encephalopathy and, most often, embryonic lethality.

The delineation of MECP2 mutations behind the majority of Rett syndrome (RS) cases represented a critical step toward the understanding of RS etiology and led to the generation of valid models. Mecp2-mutant mice show a number of neurological issues affecting behavior, breathing, and movements. However, Mecp2 deficiency in mice causes a less severe phenotype than in humans, as mutant male mice are viable and heterozygous females show symptoms only into adulthood.

In this study, Chen et al. characterize the phenotype of a recently developed MECP2 mutant cynomolgus monkey model of RS. The disease is embryonic lethal in male monkeys, as it is in humans, and unlike in mice; mutant females develop an early-onset Rett-like phenotype, with abnormal sleep pattern, decreased social contact, and increased stereotyped and repetitive behaviors. When assessed with eye-tracking tests, mutant monkeys exhibit interest in socially weighted stimuli, such as monkey faces, but difficulties in recognizing emotional expressions, in line with RS patients and implying that eye tracking may be a reliable and accessible test for studying the progression of RS individuals.

MRI scanning of the monkeys’ brains indicates reduction of subregional gray and white matter volumes and decreased cortical surface and thickness, similar to RS patients. In this respect, monkeys offer a great opportunity to perform informative longitudinal studies to assess changes in brain structures over time, a task much less compelling in rodents. Additionally, the work of Chen and colleagues reminds us that although very valuable, the mouse data have to be considered carefully. It would be important to compare mouse and monkey gene expression to better evaluate species-specific differences.

Unfortunately, this study fails to clearly report whether MECP2 mutant monkeys display progressive loss of previously acquired skills, as well as other hallmarks of RS in humans such as seizures and severe cognitive deficits. Last, although it remains to be seen if this model can actually generate new insights into the human condition and lead to the development of potential treatments for RS patients, Chen and colleagues clearly show that MECP2 mutant monkeys display features that are never observed in rodents and can be used to assess and study the progression of RS.

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