Aberrant lung lipids cause respiratory impairment in a Mecp2-deficient mouse model of Rett syndrome.

Severe respiratory impairment is a prominent feature of Rett syndrome, an X-linked disorder caused by mutations in methyl CpG-binding protein 2 (MECP2). Despite MECP2's ubiquitous expression, respiratory anomalies are attributed to neuronal dysfunction. Here, we show that neutral lipids accumulate in mouse Mecp2-mutant lungs, whereas surfactant phospholipids decrease. Conditional deletion of Mecp2 from lipid-producing alveolar epithelial 2 (AE2) cells causes aberrant lung lipids and respiratory symptoms, whereas deletion of Mecp2 from hindbrain neurons results in distinct respiratory abnormalities. Single-cell RNA sequencing of AE2 cells suggests lipid production and storage increase at the expense of phospholipid synthesis. Lipid production enzymes are confirmed as direct targets of MECP2-directed nuclear receptor co-repressor 1/2 transcriptional repression. Remarkably, lipid-lowering fluvastatin improves respiratory anomalies in Mecp2-mutant mice. These data implicate autonomous pulmonary loss of MECP2 in respiratory symptoms for the first time and have immediate impacts on patient care.

Treating Rett syndrome: from mouse models to human therapies.

Rare diseases are very difficult to study mechanistically and to develop therapies for because of the scarcity of patients. Here, the rare neuro-metabolic disorder Rett syndrome (RTT) is discussed as a prototype for precision medicine, demonstrating how mouse models have led to an understanding of the development of symptoms. RTT is caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). Mecp2-mutant mice are being used in preclinical studies that target the MECP2 gene directly, or its downstream pathways. Importantly, this work may improve the health of RTT patients. Clinical presentation may vary widely among individuals based on their mutation, but also because of the degree of X chromosome inactivation and the presence of modifier genes. Because it is a complex disorder involving many organ systems, it is likely that recovery of RTT patients will involve a combination of treatments. Precision medicine is warranted to provide the best efficacy to individually treat RTT patients.

Rett syndrome: a neurological disorder with metabolic components.

Rett syndrome (RTT) is a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2), a ubiquitously expressed transcriptional regulator. Despite remarkable scientific progress since its discovery, the mechanism by which MECP2 mutations cause RTT symptoms is largely unknown. Consequently, treatment options for patients are currently limited and centred on symptom relief. Thought to be an entirely neurological disorder, RTT research has focused on the role of MECP2 in the central nervous system. However, the variety of phenotypes identified in Mecp2 mutant mouse models and RTT patients implicate important roles for MeCP2 in peripheral systems. Here, we review the history of RTT, highlighting breakthroughs in the field that have led us to present day. We explore the current evidence supporting metabolic dysfunction as a component of RTT, presenting recent studies that have revealed perturbed lipid metabolism in the brain and peripheral tissues of mouse models and patients. Such findings may have an impact on the quality of life of RTT patients as both dietary and drug intervention can alter lipid metabolism. Ultimately, we conclude that a thorough knowledge of MeCP2's varied functional targets in the brain and body will be required to treat this complex syndrome.

Genetic markers of inflammation may not contribute to metabolic traits in Mexican children.

BACKGROUND: Low-grade chronic inflammation is a common feature of obesity and its cardio-metabolic complications. However, little is known about a possible causal role of inflammation in metabolic disorders. Mexico is among the countries with the highest obesity rates in the world and the admixed Mexican population is a relevant sample due to high levels of genetic diversity. METHODS: Here, we studied 1,462 Mexican children recruited from Mexico City. Six genetic variants in five inflammation-related genes were genotyped: rs1137101 (leptin receptor (LEPR)), rs7305618 (hepatocyte nuclear factor 1 alpha (HNF1A)), rs1800629 (tumor necrosis factor alpha (TNFA)), rs1800896, rs1800871 (interleukin-10 (IL-10)), rs1862513 (resistin (RETN)). Ten continuous and eight binary traits were assessed. Linear and logistic regression models were used adjusting for age, sex, and recruitment centre. RESULTS: We found that one SNP displayed a nominal evidence of association with a continuous trait: rs1800871 (IL-10) with LDL (beta = -0.068 ± 1.006, P = 0.01). Subsequently, we found one nominal association with a binary trait: rs7305618 (HNF1A) with family history of hypertension (odds-ratio = 1.389 [1.054-1.829], P = 0.02). However, no P-value passed the Bonferroni correction for multiple testing. DISCUSSION: Our data in a Mexican children population are consistent with previous reports in European adults in failing to demonstrate an association between inflammation-associated single nucleotide polymorphisms (SNPs) and metabolic traits.