CMT2Q-causing mutation in the Dhtkd1 gene lead to sensory defects, mitochondrial accumulation and altered metabolism in a knock-in mouse model

AbstractRett syndrome (RTT) is a regressive neurodevelopmental disorder in girls, characterized by multisystem complications including gut dysbiosis and altered metabolism. While RTT is known to be caused by mutations in the X-linked gene MECP2, the intermediate molecular pathways of progressive disease phenotypes are unknown. Mecp2 deficient rodents used to model RTT pathophysiology in most prior studies have been male. Thus, we utilized a patient-relevant mouse model of RTT to longitudinally profile the gut microbiome and metabolome across disease progression in both sexes. Fecal metabolites were altered in Mecp2e1 mutant females before onset of neuromotor phenotypes and correlated with lipid deficiencies in brain, results not observed in males. Females also displayed altered gut microbial communities and an inflammatory profile that were more consistent with RTT patients than males. These findings identify new molecular pathways of RTT disease progression and demonstrate the relevance of further study in female Mecp2 animal models.

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Sex disparate gut microbiome and metabolome perturbations precede disease progression in a mouse model of Rett syndrome

10.21203/rs.3.rs-478134/v1 ◽

2021 ◽

Author(s):

Kari Neier ◽

Tianna Grant ◽

Rebecca Palmer ◽

Demario Chappell ◽

Sophia Hakam ◽

...

Keyword(s):

Mouse Model ◽

Disease Progression ◽

Rett Syndrome ◽

Gut Microbiome ◽

Progressive Disease ◽

Neurodevelopmental Disorder ◽

Linked Gene ◽

Disease Phenotypes ◽

Gut Dysbiosis ◽

Altered Metabolism

Abstract Rett syndrome (RTT) is a severe regressive neurodevelopmental disorder in girls, characterized by multisystem complications including gut dysbiosis and altered metabolism. While RTT is known to be caused by mutations in the X-linked gene MECP2, the intermediate molecular pathways of progressive disease phenotypes are unknown. Mecp2 knockout rodents used to model RTT pathophysiology in most prior studies have been male. Thus, we utilized a patient-relevant mouse model of RTT to longitudinally profile the gut microbiome and metabolome across disease progression in both sexes. Fecal metabolite alterations in Mecp2e1 mutant females occurred prior to onset of neuromotor phenotypes and correlated with lipid deficiencies in brain, results not observed in males. Females also displayed altered gut microbial communities, including those belonging to Clostridia, that were more consistent with RTT patients than males. These findings suggest new potential therapeutic targets for RTT and demonstrate the importance of further study in female animal models.

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Regenerating myofibers in tibialis anterior muscles of young ‘MDX’ mice

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100127943 ◽

1987 ◽

Vol 45 ◽

pp. 726-727

Author(s):

H. D. Geissinge ◽

L.D. Rhodes

Keyword(s):

Muscular Dystrophy ◽

Mouse Model ◽

Tibialis Anterior ◽

Physiological Activity ◽

Mdx Mice ◽

Mode Of Inheritance

A recently discovered mouse model (‘mdx’) for muscular dystrophy in man may be of considerable interest, since the disease in ‘mdx’ mice is inherited by the same mode of inheritance (X-linked) as the human Duchenne (DMD) muscular dystrophy. Unlike DMD, which results in a situation in which the continual muscle destruction cannot keep up with abortive regenerative attempts of the musculature, and the sufferers of the disease die early, the disease in ‘mdx’ mice appears to be transient, and the mice do not die as a result of it. In fact, it has been reported that the severely damaged Tibialis anterior (TA) muscles of ‘mdx’ mice seem to display exceptionally good regenerative powers at 4-6 weeks, so much so, that these muscles are able to regenerate spontaneously up to their previous levels of physiological activity.

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