BubR1 allelic effects drive phenotypic heterogeneity in MVA progeria syndrom

Mosaic-variegated aneuploidy (MVA) syndrome is a rare childhood disorder characterized by biallelic BUBR1, CEP57, or TRIP13 aberrations, increased chromosome missegregation, and a broad spectrum of clinical features, including various cancers, congential defects, and progeroid pathologies. To investigate mechanisms underlying this disorder and its phenotypic heterogeneity, we mimicked the BUBR1 L1012P mutation in mice (BubR1 L1002P) and combined it with two other MVA variants, BUBR1X753 and BUBR1H, generating a truncated protein and low amounts of wildtype protein, respectively. Wheras BuBR1X753/L1002P and BuBR1H/X753 mice die prematurelt, BuBR1H/L1002P mice are viable and exhibit many MVA features, including cancer predisposition and various progeroid phenotypes, such as short lifespan, dwarfism, lipodystrophy, sarcopenia, and low cardiac stress tolerance. Strikingly, although these mice had a similar reduction in total BuBR1 and spectrum of MVA phenotypes as BuBR1H/H mice, several progeroid pathologies were attenuated in severity, which in skeletal muscle coincided with reduced senescence-associated secretory phenotype (SASP) complexity. Additionally, mice carrying monoallelic BUBR1 MVA mutations developed distinct pathologies later in life and had different mTORC1 activities. Together these data demonstrate that BUBR1 allelic effects beyond protein level and aneuploidy contribute to disease heterogeneity in both MVA patients and heterozygous carriers of MVA mutations.