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, congenital defects, and progeroid pathologies. To investigate the mechanisms underlying this disorder and its phenotypic heterogeneity, we mimicked the BUBR1^L1012P mutation in mice (BubR1^L1002P) and combined it with 2 other MVA variants, BUBR1^X753 and BUBR1^H, generating a truncated protein and low amounts of wild-type protein, respectively. Whereas BubR1^X753/L1002P and BubR1^H/X753 mice died prematurely, BubR1^H/L1002P mice were viable and exhibited 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 reduction in total BUBR1 and spectrum of MVA phenotypes similar to that of BubR1^H/H mice, several progeroid pathologies were attenuated in severity, which in skeletal muscle coincided with reduced senescence-associated secretory phenotype complexity. Additionally, mice carrying monoallelic BubR1 mutations were prone to select MVA-related pathologies later in life, with predisposition to sarcopenia correlating with mTORC1 hyperactivity. 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.

中文翻译：

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BubR1等位基因效应驱动镶嵌变异的非整倍性早衰综合征的表型异质性

马赛克斑状非整倍性（MVA）综合征是一种罕见的儿童疾病，其特征是双等位基因BUBR1，CEP57或TRIP13畸变。染色体错位增加；以及广泛的临床特征，包括各种癌症，先天性缺陷和早衰症。为了研究这种疾病及其表型异质性的潜在机制，我们模拟了小鼠中的BUBR1 ^L1012P突变（BubR1 ^L1002P），并将其与2个其他MVA变体BUBR1 ^X753和BUBR1 ^H结合，产生了截短的蛋白和少量的野生型蛋白质。而BubR1^{X753 / L1002P}和BubR1 ^{H / X753}小鼠过早死亡，BubR1 ^{H / L1002P}小鼠存活并表现出许多MVA功能，包括癌症易感性和各种早衰表型，例如寿命短，侏儒症，脂肪营养不良，肌肉减少症和低心脏压力耐受性。令人惊讶的是，尽管这些小鼠的总BUBR1和MVA表型的谱图与BubR1 ^{H / H}小鼠相似，但几种早衰症的严重程度有所减轻，这在骨骼肌中与衰老相关的分泌表型复杂性降低了。此外，携带单等位基因BubR1的小鼠突变倾向于在以后的生活中选择与MVA相关的病理，易患肌减少症的原因与mTORC1过度活跃有关。总之，这些数据表明，BUBR1等位基因效应超出蛋白质水平和非整倍性，在MVA患者和MVA突变的杂合子携带者中均导致疾病异质性。