| First Author | Szelenyi ER | Year | 2024 |
| Journal | Cell Rep | Volume | 43 |
| Issue | 4 | Pages | 114068 |
| PubMed ID | 38614085 | Mgi Jnum | J:347690 |
| Mgi Id | MGI:7626181 | Doi | 10.1016/j.celrep.2024.114068 |
| Citation | Szelenyi ER, et al. (2024) Distributed X chromosome inactivation in brain circuitry is associated with X-linked disease penetrance of behavior. Cell Rep 43(4):114068 |
| abstractText | The precise anatomical degree of brain X chromosome inactivation (XCI) that is sufficient to alter X-linked disorders in females is unclear. Here, we quantify whole-brain XCI at single-cell resolution to discover a prevalent activation ratio of maternal to paternal X at 60:40 across all divisions of the adult brain. This modest, non-random XCI influences X-linked disease penetrance: maternal transmission of the fragile X mental retardation 1 (Fmr1)-knockout (KO) allele confers 55% of total brain cells with mutant X-active, which is sufficient for behavioral penetrance, while 40% produced from paternal transmission is tolerated. Local XCI mosaicism within affected maternal Fmr1-KO mice further specifies sensorimotor versus social anxiety phenotypes depending on which distinct brain circuitry is most affected, with only a 50%-55% mutant X-active threshold determining penetrance. Thus, our results define a model of X-linked disease penetrance in females whereby distributed XCI among single cells populating brain circuitries can regulate the behavioral penetrance of an X-linked mutation. |
