Details

Autor(en) / Beteiligte

• Szelenyi, Eric R.
• Fisenne, Danielle
• Knox, Joseph E.
• Harris, Julie A.
• Gornet, James A.
• Palaniswamy, Ramesh
• Kim, Yongsoo
• Venkataraju, Kannan Umadevi
• Osten, Pavel

Titel

Distributed X chromosome inactivation in brain circuitry is associated with X-linked disease penetrance of behavior

Ist Teil von

• Cell reports (Cambridge), 2024-04, Vol.43 (4), p.114068-114068, Article 114068

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Adult brain XCI favors maternal X-active cells at 60:40 ratios across all regions•Local XCI mosaicism shapes individual variability beyond whole-brain status by 20%•X-linked Fmr1-KO allele is penetrant in maternal carriers with biased brain XCI•XCI within intact brain circuitry distinguishes individual phenotypic outcomes Szelenyi et al. demonstrate that adult brain XCI is systematically biased toward maternal X-active cells, which is sufficient for disease penetrance of the X-linked Fmr1-KO allele. Furthermore, local XCI mosaicism distinguishes phenotypic outcomes of individuals based on mutant X-active cells populating distinct brain circuits.