Browsing by Subject "Aneuploidy"

Now showing 1 - 8 of 8
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    Approaches to Studying Outcomes in Patients With Congenital Heart Disease With Genetic Syndromes: What Down Syndrome Can Teach Us
    (American Heart Association, 2024) Ware, Stephanie M.; Medical and Molecular Genetics, School of Medicine
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    Bottom-up, integrated -omics analysis identifies broadly dosage-sensitive genes in breast cancer samples from TCGA
    (PLOS, 2019-01-17) Kechavarzi, Bobak D.; Wu, Huanmei; Doman, Thompson N.; Biohealth Informatics, School of Informatics and Computing
    The massive genomic data from The Cancer Genome Atlas (TCGA), including proteomics data from Clinical Proteomic Tumor Analysis Consortium (CPTAC), provides a unique opportunity to study cancer systematically. While most observations are made from a single type of genomics data, we apply big data analytics and systems biology approaches by simultaneously analyzing DNA amplification, mRNA and protein abundance. Using multiple genomic profiles, we have discovered widespread dosage compensation for the extensive aneuploidy observed in TCGA breast cancer samples. We do identify 11 genes that show strong correlation across all features (DNA/mRNA/protein) analogous to that of the well-known oncogene HER2 (ERBB2). These genes are generally less well-characterized regarding their role in cancer and we advocate their further study. We also discover that shRNA knockdown of these genes has an impact on cancer cell growth, suggesting a vulnerability that could be used for cancer therapy. Our study shows the advantages of systematic big data methodologies and also provides future research directions.
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    A Child With Radius Aplasia, Cleft of Lip and Palate, Microcephaly, and Unusual Chromosome Findings
    (Wiley, 1982-12) Butler, Merlin G.; Russell, Laura J.; Palmer, Catherine G.; Bull, Marilyn; Hodes, M.E.; Medical and Molecular Genetics, School of Medicine
    We report a child with malformation syndrome of microcephaly, asymmetrical radius aplasia, and cleft of lip and palate, who was mosaic for a chromosome marker and/or ring of unknown origin. In view of the reported cases of limb deficiency with chromosome abnormalities and the unlikelihood that the patient has a recognized genetic syndrome, the cause of the patient’s syndrome may well be the extra chromosomal material.
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    Elimination of protein aggregates prevents premature senescence in human trisomy 21 fibroblasts
    (PLOS, 2019) Nawa, Nobutoshi; Hirata, Katsuya; Kawatani, Keiji; Nambara, Toshihiko; Omori, Sayaka; Banno, Kimihiko; Kokubu, Chikara; Takeda, Junji; Nishimura, Ken; Ohtaka, Manami; Nakanishi, Mahito; Okuzaki, Daisuke; Taniguchi, Hidetoshi; Arahori, Hitomi; Wada, Kazuko; Kitabatake, Yasuji; Ozono, Keiichi; Pediatrics, School of Medicine
    Chromosome abnormalities induces profound alterations in gene expression, leading to various disease phenotypes. Recent studies on yeast and mammalian cells have demonstrated that aneuploidy exerts detrimental effects on organismal growth and development, regardless of the karyotype, suggesting that aneuploidy-associated stress plays an important role in disease pathogenesis. However, whether and how this effect alters cellular homeostasis and long-term features of human disease are not fully understood. Here, we aimed to investigate cellular stress responses in human trisomy syndromes, using fibroblasts and induced pluripotent stem cells (iPSCs). Dermal fibroblasts derived from patients with trisomy 21, 18 and 13 showed a severe impairment of cell proliferation and enhanced premature senescence. These phenomena were accompanied by perturbation of protein homeostasis, leading to the accumulation of protein aggregates. We found that treatment with sodium 4-phenylbutyrate (4-PBA), a chemical chaperone, decreased the protein aggregates in trisomy fibroblasts. Notably, 4-PBA treatment successfully prevented the progression of premature senescence in secondary fibroblasts derived from trisomy 21 iPSCs. Our study reveals aneuploidy-associated stress as a potential therapeutic target for human trisomies, including Down syndrome.
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    The Fanconi anemia signaling network regulates the mitotic spindle assembly checkpoint
    (2014) Enzor, Rikki S.; Clapp, D. Wade; Broxmeyer, Hal E.; Haneline, Laura S.; Srour, Edward F.
    Fanconi anemia (FA) is a heterogenous genetic syndrome characterized by progressive bone marrow failure, aneuploidy, and cancer predisposition. It is incompletely understood why FA-deficient cells develop gross aneuploidy leading to cancer. Since the mitotic spindle assembly checkpoint (SAC) prevents aneuploidy by ensuring proper chromosome segregation during mitosis, we hypothesized that the FA signaling network regulates the mitotic SAC. A genome-wide RNAi screen and studies in primary cells were performed to systematically evaluate SAC activity in FA-deficient cells. In these experiments, taxol was used to activate the mitotic SAC. Following taxol challenge, negative control siRNA-transfected cells appropriately arrested at the SAC. However, knockdown of fourteen FA gene products resulted in a weakened SAC, evidenced by increased formation of multinucleated, aneuploid cells. The screen was independently validated utilizing primary fibroblasts from patients with characterized mutations in twelve different FA genes. When treated with taxol, fibroblasts from healthy controls arrested at the mitotic SAC, while all FA patient fibroblasts tested exhibited weakened SAC activity, evidenced by increased multinucleated cells. Rescue of the SAC was achieved in FANCA patient fibroblasts by genetic correction. Importantly, SAC activity of FANCA was confirmed in primary CD34+ hematopoietic cells. Furthermore, analysis of untreated primary fibroblasts from FA patients revealed micronuclei and multinuclei, reflecting abnormal chromosome segregation. Next, microscopy-based studies revealed that many FA proteins localize to the mitotic spindle and centrosomes, and that disruption of the FA pathway results in supernumerary centrosomes, establishing a role for the FA signaling network in centrosome maintenance. A mass spectrometry-based screen quantifying the proteome and phospho-proteome was performed to identify candidates which may functionally interact with FANCA in the regulation of mitosis. Finally, video microscopy-based experiments were performed to further characterize the mitotic defects in FANCA-deficient cells, confirming weakened SAC activity in FANCA-deficient cells and revealing accelerated mitosis and abnormal spindle orientation in the absence of FANCA. These findings conclusively demonstrate that the FA signaling network regulates the mitotic SAC, providing a mechanistic explanation for the development of aneuploidy and cancer in FA patients. Thus, our study establishes a novel role for the FA signaling network as a guardian of genomic integrity.
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    INPP5E Preserves Genomic Stability through Regulation of Mitosis
    (American Society for Microbiology, 2017-03-15) Sierra Potchanant, Elizabeth A.; Cerabona, Donna; Sater, Zahi Abdul; He, Ying; Sun, Zejin; Gehlhausen, Jeff; Nalepa, Grzegorz; Department of Pediatrics, IU School of Medicine
    The partially understood phosphoinositide signaling cascade regulates multiple aspects of cellular metabolism. Previous studies revealed that INPP5E, the inositol polyphosphate-5-phosphatase that is mutated in the developmental disorders Joubert and MORM syndromes, is essential for the function of the primary cilium and maintenance of phosphoinositide balance in nondividing cells. Here, we report that INPP5E further contributes to cellular homeostasis by regulating cell division. We found that silencing or genetic knockout of INPP5E in human and murine cells impairs the spindle assembly checkpoint, centrosome and spindle function, and maintenance of chromosomal integrity. Consistent with a cell cycle regulatory role, we found that INPP5E expression is cell cycle dependent, peaking at mitotic entry. INPP5E localizes to centrosomes, chromosomes, and kinetochores in early mitosis and shuttles to the midzone spindle at mitotic exit. Our findings identify the previously unknown, essential role of INPP5E in mitosis and prevention of aneuploidy, providing a new perspective on the function of this phosphoinositide phosphatase in health and development.
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    Medical and surgical interventions and outcomes for infants with trisomy 18 (T18) or trisomy 13 (T13) at children's hospitals neonatal intensive care units (NICUs)
    (Springer Nature, 2021) Acharya, Krishna; Leuthner, Steven R.; Zaniletti, Isabella; Niehaus, Jason Z.; Bishop, Christine E.; Coghill, Carl H.; Datta, Ankur; Dereddy, Narendra; DiGeronimo, Robert; Jackson, Laura; Ling, Con Yee; Matoba, Nana; Natarajan, Girija; Pritha Nayak, Sujir; Brown Schlegel, Amy; Seale, Jamie; Shah, Anita; Weiner, Julie; Williams, Helen O.; Wojcik, Monica H.; Fry, Jessica T.; Sullivan, Kevin; Palliative Care and Ethics Focus Group of the Children’s Hospital Neonatal Consortium (CHNC); Pediatrics, School of Medicine
    Objectives: To examine characteristics and outcomes of T18 and T13 infants receiving intensive surgical and medical treatment compared to those receiving non-intensive treatment in NICUs. Study design: Retrospective cohort of infants in the Children's Hospitals National Consortium (CHNC) from 2010 to 2016 categorized into three groups by treatment received: surgical, intensive medical, or non-intensive. Results: Among 467 infants admitted, 62% received intensive medical treatment; 27% received surgical treatment. The most common surgery was a gastrostomy tube. Survival in infants who received surgeries was 51%; intensive medical treatment was 30%, and non-intensive treatment was 72%. Infants receiving surgeries spent more time in the NICU and were more likely to receive oxygen and feeding support at discharge. Conclusions: Infants with T13 or T18 at CHNC NICUs represent a select group for whom parents may have desired more intensive treatment. Survival to NICU discharge was possible, and surviving infants had a longer hospital stay and needed more discharge supports.