Browsing by Subject "Genetic disorders"

Now showing 1 - 7 of 7
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    An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia
    (Ferrata Storti Foundation, 2017-06) Zhou, Yuan; He, Yongzheng; Xing, Wen; Zhang, Peng; Shi, Hui; Chen, Shi; Shi, Jun; Bai, Jie; Rhodes, Steven D.; Zhang, Fengqui; Yuan, Jin; Yang, Xianlin; Zhu, Xiaofan; Li, Yan; Hanenberg, Helmut; Xu, Mingjiang; Robertson, Kent A.; Yuan, Weiping; Nalepa, Grzegorz; Cheng, Tao; Clapp, D. Wade; Yang, Feng-Chun; Pediatrics, School of Medicine
    Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation.
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    Emerging Role of Clinical Genetics in CKD
    (Elsevier, 2022-02-11) Devarajan, Prasad; Chertow, Glenn M.; Susztak, Katalin; Levin, Adeera; Agarwal, Rajiv; Stenvinkel, Peter; Chapman, Arlene B.; Warady, Bradley A.; Medicine, School of Medicine
    Chronic kidney disease (CKD) afflicts 15% of adults in the United States, of whom 25% have a family history. Genetic testing is supportive in identifying and possibly confirming diagnoses of CKD, thereby guiding care. Advances in the clinical genetic evaluation include next-generation sequencing with targeted gene panels, whole exome sequencing, and whole genome sequencing. These platforms provide DNA sequence reads with excellent coverage throughout the genome and have identified novel genetic causes of CKD. New pathologic genetic variants identified in previously unrecognized biological pathways have elucidated disease mechanisms underlying CKD etiologies, potentially establishing prognosis and guiding treatment selection. Molecular diagnoses using genetic sequencing can detect rare, potentially treatable mutations, avoid misdiagnoses, guide selection of optimal therapy, and decrease the risk of unnecessary and potentially harmful interventions. Genetic testing has been widely adopted in pediatric nephrology; however, it is less frequently used to date in adult nephrology. Extension of clinical genetic approaches to adult patients may achieve similar benefits in diagnostic refinement and treatment selection. This review aimed to identify clinical CKD phenotypes that may benefit the most from genetic testing, outline the commonly available platforms, and provide examples of successful deployment of these approaches in CKD.
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    Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels
    (Nature Publishing Group, 2018-01-17) Jiang, Xia; O’Reilly, Paul F.; Aschard, Hugues; Hsu, Yi-Hsiang; Richards, J. Brent; Dupuis, Josée; Ingelsson, Erik; Karasik, David; Pilz, Stefan; Berry, Diane; Kestenbaum, Bryan; Zheng, Jusheng; Luan, Jianan; Sofianopoulou, Eleni; Streeten, Elizabeth A.; Albanes, Demetrius; Lutsey, Pamela L.; Yao, Lu; Tang, Weihong; Econs, Michael J.; Wallaschofski, Henri; Völzke, Henry; Zhou, Ang; Power, Chris; McCarthy, Mark I.; Michos, Erin D.; Boerwinkle, Eric; Weinstein, Stephanie J.; Freedman, Neal D.; Huang, Wen-Yi; Van Schoor, Natasja M.; Velde, Nathalie van der; de Groot, Lisette C. P. G. M.; Enneman, Anke; Cupples, L. Adrienne; Booth, Sarah L.; Vasan, Ramachandran S.; Liu, Ching-Ti; Zhou, Yanhua; Ripatti, Samuli; Ohlsson, Claes; Vandenput, Liesbeth; Lorentzon, Mattias; Eriksson, Johan G.; Shea, M. Kyla; Houston, Denise K.; Kritchevsky, Stephen B.; Liu, Yongmei; Lohman, Kurt K.; Ferrucci, Luigi; Peacock, Munro; Gieger, Christian; Beekman, Marian; Slagboom, Eline; Deelen, Joris; Heemst, Diana van; Kleber, Marcus E.; März, Winfried; de Boer, Ian H.; Wood, Alexis C.; Rotter, Jerome I.; Rich, Stephen S.; Robinson-Cohen, Cassianne; Heijer, Martin den; Jarvelin, Marjo-Riitta; Cavadino, Alana; Joshi, Peter K.; Wilson, James F.; Hayward, Caroline; Lind, Lars; Michaëlsson, Karl; Trompet, Stella; Zillikens, M. Carola; Uitterlinden, Andre G.; Rivadeneira, Fernando; Broer, Linda; Zgaga, Lina; Campbell, Harry; Theodoratou, Evropi; Farrington, Susan M.; Timofeeva, Maria; Dunlop, Malcolm G.; Valdes, Ana M.; Tikkanen, Emmi; Lehtimäki, Terho; Lyytikäinen, Leo-Pekka; Kähönen, Mika; Raitakari, Olli T.; Mikkilä, Vera; Ikram, M. Arfan; Sattar, Naveed; Jukema, J. Wouter; Wareham, Nicholas J.; Langenberg, Claudia; Forouhi, Nita G.; Gundersen, Thomas E.; Khaw, Kay-Tee; Butterworth, Adam S.; Danesh, John; Spector, Timothy; Wang, Thomas J.; Hyppönen, Elina; Kraft, Peter; Kiel, Douglas P.; Medicine, School of Medicine
    Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels
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    IMPAIRED FUNCTION OF FANCONI ANEMIA TYPE C DEFICIENT MACROPHAGES
    (2012-03-16) Liu, Ying; Haneline, Laura S.; Dent, Alexander L.; He, Johnny J.; Srour, Edward F.; Yoder, Mervin C.
    Fanconi anemia (FA) is a genetic disorder characterized by bone marrow (BM) failure. Previous studies suggest that FA patients exhibit alterations in immunologic function. However, it is unclear whether the immune defects are immune cell autonomous or secondary to leucopenia from evolving BM failure. The aim of the current study was to determine whether FA type C deficient (Fancc-/-) macrophages exhibit impaired function and contribute to an altered inflammatory response. In this study, primary peritoneal macrophage function and the inflammatory response of Fancc-/- immune cells after in vivo intraperitoneal (IP) administration of lipopolysaccharide (LPS) were assessed. Fancc-/- peritoneum exhibit normal macrophage distribution at baseline. However, Fancc-/- macrophages exhibit reduced adhesion both on fibronectin and endothelial cells, impaired migration toward monocyte chemotactic protein-1 (MCP-1) and macrophages-colony stimulating factor (M-CSF), and altered phagocytosis of E.coli and ImmunoglobulinG (IgG)-labeled latex beads compared to WT. An altered F-actin reorganization and impaired activation of RhoA were observed in Fancc-/- macrophages. After single LPS injection IP, Fancc-/- mice exhibited decreased macrophage recruitment, reduced peripheral inflammatory monocytes and impaired myeloid colony formation in presence of M-CSF. Upon M-CSF stimulation, Fancc-/- BM derived macrophages (BMDM) showed a decreased phosphorylation of AKT and ERK compared to WT, leading to reduced proliferation. Collectively, these data suggest that Fancc-/- macrophages and subsequent defects in adhesion, migration, phagocytosis, and recruitment in vivo. These data also support a Fancc-/- macrophage cells autonomous defect predisposing to an altered inflammatory response.
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    Investigating Cardiac Class, Extracardiac Anomalies, and Dysmorphology Patterns Predictive of Mendelian Genetic Disorders in Pediatric Congenital Heart Disease
    (2024-05) Helm, Benjamin Michael; Wessel, Jennifer; Han, Jiali; Landis, Benjamin J.; Ware, Stephanie M.; Wetherill, Leah
    Congenital heart disease (CHD) is the most common class of birth defects, accounting for one-third of all congenital anomalies. There is a need to understand risk factors early in the CHD life course, as half of all mortalities affect infants. Approximately 20-30% of CHD is caused by Mendelian genetic diseases, and genetic risk factors strongly influence health outcomes. However, genetics evaluations are underutilized and unstandardized. We leveraged a clinical program standardizing genetics evaluations for pediatric CHD. Using a test-negative case-control design, we investigated novel phenotypic predictors of patients with Mendelian genetic disorders. In the first study of 588 patients (96% ≤1 year, 20.7% with a genetic diagnosis), we found that dysmorphic status was associated with two-fold increased risk of genetic diagnoses being identified, after adjusting for extracardiac anomalies (ECA) status. In the second work, we developed and applied a novel dysmorphology score for quantifying dysmorphology burden in 1,001 patients (95% ≤1 year, 23.4% with a genetic diagnosis). Using multivariable logistic regression models, we quantified associations between dysmorphology score, ECA status, and genetic diagnoses identified later by genetic testing. A clinical prediction model was developed to improve risk-stratification of patients with genetic disorders more objectively and based on quantification of dysmorphology. Last, we developed a novel method of body region dysmorphology (BRD) classification and investigated how BRD patterns were predictive of cytogenetic and monogenic diagnoses. Dysmorphism of the face, forehead, neck, and hands/feet regions were associated with genetic diagnoses, while adjusting for ECA status. Surprisingly, dysmorphism of the forehead was the strongest predictor of genetic diagnoses, including both chromosomal and monogenic disorders. We found 23.4% (n=234/1001) of patients had genetic diagnoses following standardized testing, and our novel phenotypic predictors, i.e., BRDs and dysmorphology score, will improve identification of rare genetic disorders. However, 8.7-13.1% of apparently isolated/non-dysmorphic patients had genetic disorders identified by genetic testing, highlighting the limitation of phenotype-driven prediction of genetic diagnoses. This work builds a foundation for investigating novel phenotypic associations with genetic causes of CHD, and future research will assess how early recognition of dysmorphology, ECA status, and CHD class predicts other long-term outcomes.
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    Metabolism of the covalent phosphate in glycogen
    (2010-07) Tagliabracci, Vincent S.; Roach, Peter J.; DePaoli-Roach, Anna A.; Hurley, Thomas D., 1961-; Morral, Nuria
    Glycogen is a highly branched polymer of glucose that functions to store glucose residues for future metabolic use. Skeletal muscle and liver comprise the largest glycogen reserves and play critical roles in maintaining whole body glucose homeostasis. In addition to glucose, glycogen contains small amounts of covalent phosphate of unknown function, origin and structure. Evidence to support the involvement of glycogen associated phosphate in glycogen metabolism comes from patients with Lafora Disease. Lafora disease is an autosomal recessive, fatal form of progressive myoclonus epilepsy. Approximately 90% of cases of Lafora disease are caused by mutations in either the EPM2A or EPM2B genes that encode, respectively, a dual specificity phosphatase called laforin and an E3 ubiquitin ligase called malin. Lafora patients accumulate intracellular inclusion bodies, known as Lafora bodies that are primarily composed of poorly branched, insoluble glycogen-like polymers. We have shown that laforin is a glycogen phosphatase capable of releasing phosphate from glycogen in vitro and that this activity is dependent on a functional carbohydrate binding domain. In studies of laforin knockout mice, we observed a progressive change in the properties and structure of glycogen that paralleled the formation of Lafora bodies. Glycogen isolated from these mice showed increased glycogen phosphate, up to 6-fold (p< 0.001) compared to WT, providing strong evidence that laforin acts as a glycogen phosphatase in vivo. Furthermore we have demonstrated that glycogen synthase introduces phosphate into glycogen during synthesis by transferring the beta-phosphate of UDP-glucose into the polymer and that laforin is capable of releasing the phosphate incorporated by glycogen synthase. Analysis of mammalian glycogen revealed the presence of covalently linked phosphate at the 2 hydroxyl and the 3 hydroxyl of glucose residues in the polysaccharide, providing the first direct evidence of the chemical nature of the phosphate linkage. We envision a glycogen damage/repair process, analogous to errors during DNA synthesis that are subsequently repaired. We propose that laforin action parallels that of DNA repair enzymes and Lafora disease results from the inability of the phosphatase to repair damaged glycogen, adding another biological polymer to the list of those prone to errors by their respective polymerizing enzymes.
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    Phenotypic and molecular characterization of a novel mouse model of neurofibromatosis type 2
    (2015-05) Gehlhausen, Jeff R.; Clapp, D. Wade; Goebl, Mark G.; Harrington, Maureen A.; Nalepa, Grzegorz J.