7 results on '"Andrew L. Schwaderer"'
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2. Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis
- Author
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Deborah R. Stein, Weizhen Tan, Amar J. Majmundar, Richard P. Lifton, David Schapiro, Daniela A. Braun, Jan Halbritter, Christian Hanna, John A. Sayer, Margarita Halty, Avram Z. Traum, Sherif M. El-Desoky, Velibor Tasic, Shrikant Mane, Friedhelm Hildebrandt, Asaf Vivante, Michelle A. Baum, Shirlee Shril, Seema Hashmi, Michael A. J. Ferguson, Zoran Gucev, Caleb P. Nelson, Avi Katz, Ghaleb Daouk, Heon Yung Gee, Neveen A. Soliman, Tilman Jobst-Schwan, Michael J. Somers, Eugen Widmeier, Danko Milosevic, Ari J. Wassner, Jameela A. Kari, Hanan M. Fathy, Ankana Daga, Andrew L. Schwaderer, Jennifer A. Lawson, Jillian K. Warejko, and Nancy Rodig
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Genetic Markers ,Male ,0301 basic medicine ,Heredity ,Adolescent ,030232 urology & nephrology ,Disease ,Consanguinity ,Biology ,Nephrolithiasis ,Bioinformatics ,Article ,Young Adult ,Kidney Calculi ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Risk Factors ,Exome Sequencing ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Age of Onset ,Child ,Gene ,Genetic Association Studies ,Exome sequencing ,Ultrasonography ,Genetics ,Phenocopy ,Incidence (epidemiology) ,Infant ,Prognosis ,medicine.disease ,Pedigree ,Nephrocalcinosis ,Phenotype ,030104 developmental biology ,Nephrology ,Child, Preschool ,Mutation ,Mutation (genetic algorithm) ,Disease Progression ,Female ,nephrolithiasis ,nephrocalcinosis, monogenic cause ,whole exome sequencing ,Tomography, X-Ray Computed - Abstract
The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes ( AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1 ), in one dominant gene ( SLC9A3R1 ), and in one gene ( SLC34A1 ) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.
- Published
- 2018
3. An endogenous ribonuclease inhibitor regulates the antimicrobial activity of ribonuclease 7 in the human urinary tract
- Author
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Jennifer Kline, David S. Hains, Sheryl S. Justice, Huanyu Wang, Andrew L. Schwaderer, Daniel M. Cohen, John David Spencer, and Tad Eichler
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Male ,Time Factors ,Kidney ,0302 clinical medicine ,Cell Wall ,Enterococcus faecalis ,Child ,0303 health sciences ,Pyelonephritis ,medicine.diagnostic_test ,Antimicrobial Peptide ,Middle Aged ,Antimicrobial ,Recombinant Proteins ,Innate Immunity ,3. Good health ,Intercalated Cells ,medicine.anatomical_structure ,Nephrology ,Child, Preschool ,030220 oncology & carcinogenesis ,Host-Pathogen Interactions ,Female ,Protein Binding ,Adult ,Adolescent ,RNase P ,Proteolysis ,Ribonuclease inhibitor ,Urinary Bladder ,Antimicrobial peptides ,Biology ,Gene Expression Regulation, Enzymologic ,Article ,03 medical and health sciences ,Ribonucleases ,Escherichia coli ,Ribonuclease 7 ,medicine ,Humans ,RNA, Messenger ,Urothelium ,Aged ,030304 developmental biology ,Ribonuclease Inhibitor ,RNA ,Molecular biology ,Urinary Tract Infection ,Case-Control Studies ,Carrier Proteins ,Leukocyte Elastase - Abstract
Recent studies stress the importance of antimicrobial peptides in protecting the urinary tract from infection. Previously, we have shown that ribonuclease 7 (RNase 7) is a potent antimicrobial peptide that has a broad-spectrum antimicrobial activity against uropathogenic bacteria. The urothelium of the lower urinary tract and intercalated cells of the kidney produce RNase 7, but regulation of its antimicrobial activity has not been well defined. Here, we characterize the expression of an endogenous inhibitor, ribonuclease inhibitor (RI), in the urinary tract and evaluate its effect on the antimicrobial activity of RNase 7. Using RNA isolated from non-infected human bladder and kidney tissue, quantitative real-time polymerase chain reaction showed that RNH1, the gene encoding RI, is constitutively expressed throughout the urinary tract. With pyelonephritis, RNH1 expression and RI peptide production significantly decrease. Immunostaining localized RI production to the umbrella cells of the bladder and intercalated cells of the renal collecting tubule. In vitro assays showed that RI bound to RNase 7 and suppressed its antimicrobial activity by blocking its ability to bind the cell wall of uropathogenic bacteria. Thus, these results demonstrate a new immunomodulatory role for RI and identified a unique regulatory pathway that may affect how RNase 7 maintains urinary tract sterility.
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- 2014
4. Ribonuclease 7, an antimicrobial peptide upregulated during infection, contributes to microbial defense of the human urinary tract
- Author
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Peter B. Baker, Sunder Sims-Lucas, Andrew L. Schwaderer, Julianne Bartz, Tad Eichler, David S. Hains, Jennifer Kline, John David Spencer, Kristin R. DeSouza, and Huanyu Wang
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Sterility ,RNase P ,Urinary system ,Antimicrobial peptides ,030232 urology & nephrology ,Enzyme-Linked Immunosorbent Assay ,Nephron ,Biology ,Kidney ,Microscopy, Atomic Force ,Real-Time Polymerase Chain Reaction ,Microbiology ,03 medical and health sciences ,0302 clinical medicine ,Ribonucleases ,medicine ,Humans ,RNA, Messenger ,030304 developmental biology ,0303 health sciences ,Innate immune system ,Microbial Viability ,Bacteria ,Pyelonephritis ,Cell Membrane ,Antimicrobial ,Molecular biology ,3. Good health ,Up-Regulation ,Kinetics ,medicine.anatomical_structure ,Nephrology ,Case-Control Studies ,Host-Pathogen Interactions ,Urinary Tract Infections - Abstract
The mechanisms that maintain sterility in the urinary tract are incompletely understood; however, recent studies stress the importance of antimicrobial peptides in protecting the urinary tract from infection. Ribonuclease 7 (RNase 7), a potent antimicrobial peptide contributing to urinary tract sterility, is expressed by intercalated cells in the renal collecting tubules and is present in the urine at levels sufficient to kill bacteria at baseline. Here, we characterize the expression and function of RNase 7 in the human urinary tract during infection. Both quantitative real-time PCR and enzyme-linked immunosorbant assays demonstrated increases in RNASE7 expression in the kidney along with kidney and urinary RNase 7 peptide concentrations with infection. While immunostaining localized RNase 7 production to the intercalated cells of the collecting tubule during sterility, its expression during pyelonephritis was found to increase throughout the nephron but not in glomeruli or the interstitium. Recombinant RNase 7 exhibited antimicrobial activity against uropathogens at low micromolar concentrations by disrupting the microbial membrane as determined by atomic force microscopy. Thus, RNase 7 expression is increased in the urinary tract with infection and has antibacterial activity against uropathogens at micromolar concentrations.
- Published
- 2013
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5. Insulin and the phosphatidylinositol 3-kinase signaling pathway regulate Ribonuclease 7 expression in the human urinary tract
- Author
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Ariel Cohen, Robert S. Easterling, Daniel M. Cohen, John David Spencer, David S. Hains, Brian Becknell, Andrew L. Schwaderer, Birong Li, Susan E. Ingraham, Jackie Metheny, Tad Eichler, and Susheela Tridandapani
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0301 basic medicine ,Male ,medicine.medical_specialty ,Cell signaling ,Adolescent ,RNase P ,medicine.medical_treatment ,Primary Cell Culture ,Biology ,Article ,03 medical and health sciences ,Phosphatidylinositol 3-Kinases ,Ribonucleases ,Antigens, CD ,Internal medicine ,Diabetes mellitus ,Cell Line, Tumor ,medicine ,Escherichia coli ,Humans ,Insulin ,Child ,Urinary Tract ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Escherichia coli Infections ,Middle Aged ,medicine.disease ,Receptor, Insulin ,030104 developmental biology ,Endocrinology ,Diabetes Mellitus, Type 1 ,Nephrology ,Child, Preschool ,Urinary Tract Infections ,Phosphatidylinositol 3-kinase signaling ,Female ,Signal transduction ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Diabetes mellitus is a systemic disease associated with a deficiency of insulin production or action. Diabetic patients have an increased susceptibility to infection with the urinary tract being the most common site of infection. Recent studies suggest that Ribonuclease 7 (RNase 7) is a potent antimicrobial peptide that plays an important role in protecting the urinary tract from bacterial insult. The impact of diabetes on RNase 7 expression and function are unknown. Here, we investigate the effects of insulin on RNase 7. Using human urine specimens, we measured urinary RNase 7 concentrations in healthy control patients and insulin-deficient type 1 diabetics before and after starting insulin therapy. Compared to controls, diabetic patients had suppressed urinary RNase 7 concentrations, which increased with insulin. Using primary human urothelial cells, we explored the mechanisms by which insulin induces RNase 7. Insulin induces RNase 7 production via the phosphatidylinositide 3-kinase signaling pathway (PI3K/AKT) to shield urothelial cells from uropathogenic E. coli. In contrast, we show that uropathogenic E. coli suppresses PI3K/AKT and RNase 7. Together, these results indicate that insulin and PI3K/AKT signaling are essential for RNase 7 expression. They also suggest that increased infection risks in diabetic patients may be secondary to suppressed RNase 7 production. These data may provide unique insight into novel UTI therapeutic strategies in at risk populations.
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- 2016
6. Urine risk factors in children with calcium kidney stones and their siblings
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Andrew L. Schwaderer, Fredric L. Coe, Michael Erhard, William DeFoor, John D. Mahan, Kristin J. Bergsland, Mark D. White, and John R. Asplin
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Calcium Phosphates ,Male ,medicine.medical_specialty ,Adolescent ,030232 urology & nephrology ,Calcium oxalate ,Physiology ,chemistry.chemical_element ,Urine ,030204 cardiovascular system & hematology ,Calcium ,Risk Assessment ,Article ,Excretion ,03 medical and health sciences ,chemistry.chemical_compound ,kidney calculi ,0302 clinical medicine ,Risk Factors ,Internal medicine ,calcium oxalate ,Humans ,Medicine ,Genetic Predisposition to Disease ,Hypercalciuria ,Risk factor ,Child ,hypercalciuria ,business.industry ,Siblings ,Age Factors ,medicine.disease ,United States ,3. Good health ,Endocrinology ,chemistry ,Nephrology ,Case-Control Studies ,Linear Models ,Female ,Kidney stones ,Crystallization ,business ,Hypocitraturia ,Biomarkers - Abstract
Calcium nephrolithiasis in children is increasing in prevalence and tends to be recurrent. Although children have a lower incidence of nephrolithiasis than adults, its etiology in children is less well understood; hence treatments targeted for adults may not be optimal in children. To better understand metabolic abnormalities in stone forming children, we compared chemical measurements and the crystallization properties of 24-hour urine collections from 129 stone formers matched to 105 non-stone forming siblings and 183 normal, healthy children with no family history of stones; all aged 6 to 17 years. The principal risk factor for calcium stone formation was hypercalciuria. Stone formers have strikingly higher calcium excretion along with high supersaturation for calcium oxalate and calcium phosphate, and a reduced distance between the upper limit of metastability and supersaturation for calcium phosphate, indicating increased risk of calcium phosphate crystallization. Other differences in urine chemistry that exist between adult stone formers and normal individuals such as hyperoxaluria, hypocitraturia, abnormal urine pH and low urine volume were not found in these children. Hence, hypercalciuria and a reduction in the gap between calcium phosphate upper limit of metastability and supersaturation are crucial determinants of stone risk. This highlights the importance of managing hypercalciuria in children with calcium stones.
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- 2012
7. Ribonuclease 7 is a potent antimicrobial peptide within the human urinary tract
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Glen McGillivary, Jürgen Harder, Kirk M. McHugh, Sheryl S. Justice, John David Spencer, Julianne DiRosario, Andrew L. Schwaderer, Peter B. Baker, David S. Hains, and Ashley R. Carpenter
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medicine.medical_specialty ,antimicrobial peptide ,RNase P ,Urinary system ,Urinary Bladder ,Antimicrobial peptides ,030232 urology & nephrology ,Biology ,Kidney ,Real-Time Polymerase Chain Reaction ,Microbiology ,immunology ,03 medical and health sciences ,Ribonucleases ,0302 clinical medicine ,Ureter ,Internal medicine ,medicine ,Humans ,Tissue Distribution ,Urothelium ,Urinary Tract ,innate immunity ,030304 developmental biology ,0303 health sciences ,Urinary bladder ,Bacteria ,Antimicrobial ,3. Good health ,medicine.anatomical_structure ,Endocrinology ,Nephrology ,urinary tract infection ,Antimicrobial Cationic Peptides - Abstract
Although the urinary tract is constantly challenged by microbial invasion, it remains free from colonization. Although little is known about how the urinary tract maintains sterility, the presence of antimicrobial peptides (AMPs) in the urine suggests that they may play a role in its protection from infection. Ribonuclease 7 (RNase 7) is a potent AMP that was first identified in the skin. Here, we characterize the expression and relevance of RNase 7 in the human kidney and urinary tract. Using RNA isolated from healthy human tissue, we performed quantitative real-time PCR and found basal RNASE7 expression in kidney and bladder tissue. Immunohistochemical and immunofluorescent analysis localized RNase 7 to the urothelium of the bladder, ureter, and the intercalated cells of the collecting tubules. In control urine samples from healthy individuals, the concentration of RNase 7 was found to be in the low micromolar range; very abundant for an AMP. Antibacterial neutralization assays showed that urinary RNase 7 has potent antimicrobial properties against Gram-negative and Gram-positive uropathogenic bacteria. Thus, RNase 7 is expressed in the human kidney and urinary tract and it may have an important antimicrobial role in maintaining tract sterility.
- Published
- 2011
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