| First Author | Vashi N | Year | 2021 |
| Journal | Hum Mol Genet | Volume | 30 |
| Issue | 22 | Pages | 2161-2176 |
| PubMed ID | 34230964 | Mgi Jnum | J:320693 |
| Mgi Id | MGI:6871837 | Doi | 10.1093/hmg/ddab182 |
| Citation | Vashi N, et al. (2021) Aberrant lung lipids cause respiratory impairment in a Mecp2-deficient mouse model of Rett syndrome. Hum Mol Genet 30(22):2161-2176 |
| abstractText | 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. |
