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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.sup.L1012P] mutation in mice ([BubR1.sup.L1002P]) and combined it with 2 other MVA variants, [BUBR1.sup.X753] and [BUBR1.sup.H], generating a truncated protein and low amounts of wild-type protein, respectively. Whereas [BubR1.sup.X753/L1002P] and [BubR1.sup.H/X753] mice died prematurely, [BubR1.sup.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.sup.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 BubRI 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., Introduction Mosaic-variegated aneuploidy (MVA) syndrome is an autosomal recessive syndrome characterized by near-diploid aneuploidies involving multiple tissues and chromosomes (1-4). A wide variety of additional clinical features are associated with [...]

Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of [SF3B1.sup.MUT] xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against [SF3B1.sup.MUT] cancers., Introduction Since their identification in 2011, mutations in spliceosome genes have been found in numerous human malignancies (1). Among the most broadly implicated genes is SF3B1, recurrently mutated in myelodysplastic [...]

Background: Maternal tobacco smoke exposure has been associated with altered DNA methylation. However, previous studies largely used methylation arrays, which cover a small fraction of CpGs, and focused on whole cord blood. Objectives: The current study examined the impact of in utero exposure to maternal tobacco smoke on the cord blood [CD4.sup.+] DNA methylome. Methods: The methylomes of 20 Hispanic white newborns (n = 10 exposed to any maternal tobacco smoke in pregnancy; n = 10 unexposed) from the Maternal and Child Health Study (MACHS) were profiled by whole-genome bisulfite sequencing (median coverage: 6.5 X). Statistical analyses were conducted using the Regression Analysis of Differential Methylation (RADMeth) program because it performs well on low-coverage data (minimizes false positives and negatives). Results: We found that 10,381 CpGs were differentially methylated by tobacco smoke exposure [neighbor-adjusted p-values that are additionally corrected for multiple testing based on the Benjamini-Hochberg method for controlling the false discovery rate (FDR) ([p.sub.FDR]) Conclusions: Maternal tobacco smoke exposure in pregnancy is associated with cord blood [CD4.sup.+] DNA methylation in key regulatory regions, including enhancers. While we used a method that performs well on low-coverage data, we cannot exclude the possibility that some results may be false positives. However, we identified a differentially methylated CpG in amino acid transporter SLC7A8 that is highly reproducible, which may be sensitive to cigarette smoke in both cord blood and adult [CD4.sup.+] cells. https://doi.org/10.1289/EHP3398, Introduction Maternal smoking during pregnancy is one of the most prevalent and modifiable risk factors affecting newborn health (Curtin and Matthews 2016). In the United States, >8% of women smoke [...]