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1. Identification and functional characterization of three NoLS (nucleolar localisation signals) mutations of the CDC73 gene.

Author

Valerio Pazienza, Annamaria la Torre, Filomena Baorda, Michela Alfarano, Massimiliano Chetta, Lucia Anna Muscarella, Claudia Battista, Massimiliano Copetti, Dieter Kotzot, Klaus Kapelari, Dalia Al-Abdulrazzaq, Kusiel Perlman, Etienne Sochett, David E C Cole, Fabio Pellegrini, Lucie Canaff, Geoffrey N Hendy, Leonardo D'Agruma, Leopoldo Zelante, Massimo Carella, Alfredo Scillitani, and Vito Guarnieri

Subjects
Medicine, Science
Abstract

Hyperparathyroidism Jaw-Tumour Syndrome (HPT-JT) is characterized by primary hyperparathyroidism (PHPT), maxillary/mandible ossifying fibromas and by parathyroid carcinoma in 15% of cases. Inactivating mutations of the tumour suppressor CDC73/HRPT2 gene have been found in HPT-JT patients and also as genetic determinants of sporadic parathyroid carcinoma/atypical adenomas and, rarely, typical adenomas, in familial PHPT. Here we report the genetic and molecular analysis of the CDC73/HRPT2 gene in three patients affected by PHPT due to atypical and typical parathyroid adenomas, in one case belonging to familial PHPT. Flag-tagged WT and mutant CDC73/HRPT2 proteins were transiently transfected in HEK293 cells and functional assays were performed in order to investigate the effect of the variants on the whole protein expression, nuclear localization and cell overgrowth induction. We identified four CDC73/HRPT2 gene mutations, three germline (c.679_680delAG, p.Val85_Val86del and p.Glu81_Pro84del), one somatic (p.Arg77Pro). In three cases the mutation was located within the Nucleolar Localisation Signals (NoLS). The three NoLS variants led to instability either of the corresponding mutated protein or mRNA or both. When transfected in HEK293 cells, NoLS mutated proteins mislocalized with a predeliction for cytoplasmic or nucleo-cytoplasmic localization and, finally, they resulted in overgrowth, consistent with a dominant negative interfering effect in the presence of the endogenous protein.

Published
2013
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2. DNA methylation age calculators reveal association with diabetic neuropathy in type 1 diabetes

Author

Thomas Donner, P. Rezaeian, John I. Malone, Sharon B. Schwartz, Xiaoyu Gao, Szilard Kiss, Matthew J. Budoff, David R. Sell, A. Dwoskin, Ronald J. Prineas, C. Pittman, M. Reid, C. McDonald, S. Caulder, M. Szpiech, Oscar B. Crofford, Rachel G. Miller, Louis A. Lobes, M. Patronas, C. Canny, M. E. Lackaye, Sandra R. Montezuma, Richard M. Bergenstal, Patricia Gatcomb, Julie A. Stoner, H. Pan, James L. Kinyoun, J. Mortenson, Osama Hamdy, Connie Fountain, David D. Moore, Kusiel Perlman, R. Trail, David A. Lee, J. Sheindlin, Samuel Dagogo-Jack, Jeffrey L. Mahon, Jill P. Crandall, L. Gill, T. Thompson, Lee M. Jampol, K. Koushan, David S. Schade, J. Brown-Friday, M. Basco, S. Dunnigan, J. Bylsma, R. Birk, L. H. Ketai, J. Hotaling, Stephen W. Scherer, W. Mestrezat, Stephan Villavicencio, R. Lyon, M. Carney, John Kramer, Sunder Mudaliar, David M. Nathan, M. Moran, F. Leandre, James W. Albers, L. Survant, Joseph F. Polak, Manjot K. Gill, Anton Orlin, M. Prince, Pamela A. Silver, Amy K. Saenger, John D. Brunzell, Kathleen E. Bainbridge, L. Babbione, Amisha Wallia, J. Vaccaro-Kish, Bradley D. Jones, M. Hebdon, L. McKenzie, Richard M. Hoffman, S. Chang, C. Siebert, George S. Sharuk, D. Counts, A. Lucas, P. Ramos, N. Burkhart, N. Bakshi, N. Flaherty, D. Kenny, M. Driscoll, Harjit Chahal, Ronald K. Mayfield, S. Hensley, E. Weimann, M. Franz, Martin J. Stevens, N. S. Gregory, Christopher J. O'Donnell, J. Laechelt, Pamela Ossorio, Jerry P. Palmer, Rama Natarajan, G. Ziegler, K. Martin, R. Beaser, C. Beck, L. Zhang, T. J. Declue, David M. Kendall, H. Solc, A. Vella, H. Martinez, Cormac T. Taylor, S. Neill, Douglas A. Greene, P. Lee, D. Norman, Andrew J. Barkmeier, Dean P. Hainsworth, Alka Jain, Sapna Gangaputra, N. Thangthaeng, Lorraine Thomas, Michael H. Brent, M. Bracey, Philip Raskin, Q. Clemens, Barbara H. Braffett, Mark S. Mandelcorn, Lloyd Paul Aiello, John E. Godine, T. Speigelberg, R. Chan, R. Hanna, Shelley B. Bull, William I. Sivitz, R. Sussman, C. Kwong, S. Cercone, P. Hollander, N. Leloudes, Joseph M. Terry, J. Wesche, E. A. Tanaka, D. Rosenberg, Wanjie Sun, L. Sun, Tom Clark, Deborah K. Schlossman, Louis M. Luttrell, R. Dunn, A. Farr, K. McVary, Gayle M. Lorenzi, A. Joseph, Catherine C. Cowie, M. Barr, D. Zimbler, S. Mendley, S. Schussler, N. Grove, Matthew D. Davis, Jong Mu Sun, Sophie Rogers, John P. Bantle, Brandy N. Rutledge, Senda Ajroud-Driss, Vincent M. Monnier, Cladd E. Stevens, Y. G. He, M. Phillips, C. Williams, J. MacIndoe, Kaleigh Farrell, Helen Lambeth, Ayad A. Jaffa, J. Quin, Morey W. Haymond, R. Kirby, D. Steinberg, William H. Herman, M. Mech, Arup Das, Robert Detrano, J. Brown, D. McMillan, Linda Snetselaar, Mark W. Johnson, R. Zeitler, T. Taylor, Peter R. Pavan, Michael H. Goldbaum, Bruce A. Perkins, R. G. Campbell, David A. Nicolle, R. J. van der Geest, Irene Hramiak, D. Freking, Lucy A. Levandoski, S. Colson, Charles Campbell, Victoria R. Trapani, Lawrence J. Singerman, D. Meyer, W. Tang, J. Soule, Anita Harrington, Julie A. Nelson, John A. Colwell, Naji Younes, P. Salemi, K. Hansen, Trevor J. Orchard, S. Huddleston, L. Steranchak, C. Sommer, G. Castle, J. Ginsberg, Paula McGee, V. Gama, John Dupre, Z. Strugula, M. Swenson, N. Wong, David A. Bluemke, M. Nutaitis, Anita Agarwal, M. Lin, K. Nickander, Elsayed Z. Soliman, Joao A. Lima, M. L. Schluter, Fred W. Whitehouse, Lisa Diminick, C. Cornish, M. Spencer, Daniel T. Lackland, Ionut Bebu, Hunter Wessells, S. Yacoub-Wasef, A. Determan, L. Van Ottingham, Howard Wolpert, R. Ehrlich, A. Blevins, L. Jovanovic, D. Finegold, Davida F. Kruger, Jye-Yu C. Backlund, K. Chan, Timothy J. Murtha, R. K. Mayfield, Robert W. Cavicchi, Maria F. Lopes-Virella, Thomas A. Weingeist, K. Lee, Mary E. Larkin, B. Blodi, J. Gott, Timothy J. Lyons, J. Selby, Chris Ryan, J. Harth, P. Pugsley, L. Keasler, John D. Maynard, Paul G. Arrigg, Amy B. Karger, P. Colby, J. Farquhar, Mark H. Schutta, Murk-Hein Heinemann, Kathie L. Hermayer, B. Bosco, C. Lovell, A. Bhan, A. Galprin, M. Cayford, M. Schumer, John E. Chapin, D. Rubinstein, F. Miao, V. Asuquo, Catherine L. Martin, Rodney A. Lorenz, Samuel S. Engel, L. Funk, Cyndi F. Liu, Barbara J. Maschak-Carey, Stephen S. Feman, P. Lindsey, M. Giotta, Philip A. Low, S. Kwon, R. Fahlstrom, A. Iannacone, B. French, H. Remtema, L. Cimino, S. Barron, J. McConnell, Jane L. Lynch, L. Kim, T. Williams, A. Degillio, Blanche M. Chavers, M. Novak, Julio V. Santiago, Ronald P. Danis, P. Gaston, Tae Sup Lee, T. Woodfill, R. Cuddihy, Scott M. Steidl, Alanna C. Morrison, E. Ryan, D. Lawrence, D. Cros, T. Adkins, D. Adelman, L. Dews, Patricia A. Cleary, J. Parker, L. Olmos De Koo, C. Kim, Mark R. Palmert, P. Astelford, Stefan Fritz, B. Olson, Kelvin C. Fong, Alan M. Jacobson, Stanley L. Hazen, D. Hornbeck, K. Folino, M. L. Bernal, Gabriel Virella, William V. Tamborlane, Neil H. White, Daniel L. McGee, Denis Daneman, H. Shamoon, William Dahms, S. Elsing, S. Brink, J. Ahern, Delnaz Roshandel, John M. Pach, N. W. Rodger, E. Cupelli, Dara D. Koozekanani, Abbas E. Kitabchi, K. Stoessel, B. Petty, Jamie R. Wood, J. Seegmiller, T. Strand, Y. Li, Eva L. Feldman, Larry Rand, Robert C. Colligan, T. Smith, A. Carlson, David J. Brillon, Margaret L. Bayless, M. Ong, S. Darabian, W. Hsu, Janet E. Olson, B. Rogness, N. Silvers, M. Pfiefer, B. Schaefer, E. Mendelson, S. Braunstein, Maren Nowicki, R. Reed, James S. Floyd, Z. M. Zhang, T. Sandford, R. B. Avery, A. Pratt, Paolo S. Silva, H. Bode, Alexander J. Brucker, Nikhil D. Patel, Alexander R. Lyon, M. Jenner, N. Wimmergren, L. Tuason, J. Rosenzwieg, D. J. Becker, C. Gauthier-Kelly, M. Richardson, Richard S. Crow, Andrew D. Paterson, Mark E. Molitch, Suzanne M. Strowig, S. Pendegast, M. Burger, Ramzi K. Hemady, J. Dingledine, I. H. de Boer, L. Mayer, F. Perdikaris, Om P. Ganda, F. Thoma, Karen J. Cruickshanks, Abraham Thomas, K. Klumpp, Jerry D. Cavallerano, D. Zheng, Annette Barnie, J. L. Canady, C. Wigley, David G. Miller, Sheila Smith-Brewer, D. Ostrowski, P. Crawford, K. Kelly, Robert G. Devenyi, B. Zimmerman, Susan M. Hitt, C. Johnson, L. Gurry, R. Jarboe, E. Angus, David E. Goldstein, A. Killeen, H. Schrott, Orville G. Kolterman, Mark R. Burge, Michael Rubin, J. Lipps Hagan, Alicia J. Jenkins, Hugh D. Wabers, R. Warhol, Edward Chaum, Karen L. Jones, L. Spillers, C. Miao, J. K. Jones, Angelo J. Canty, Rickey E. Carter, Evrim B. Turkbey, B. Burzuk, R. Woodwick, Evica Simjanoski, Michael W. Steffes, S. Crowell, Suresh D. Shah, H. Ricks, J. D. Carey, Paul A. Edwards, S. Holt, W. F. Schwenk, Ronald J. Oudiz, E. Brown, J. Heier, R. L. Ufret-Vincenty, L. M. Aiello, Robert A. Rizza, Karen L. Anderson, Valerie L. Arends, J. Giangiacomo, R. Liss, Aruna V. Sarma, B. Levy, Ellen J. Anderson, S. Catton, P. Callahan, Rodica Pop-Busui, S. Debrabandere, S. Moser, Bernard H. Doft, A. Malayeri, C. Johannes, R. Ramker, J. Rich, M. Fox, Rukhsana G. Mirza, Katherine A. Morgan, Thomas J. Songer, C. Shah, H. Engel, Saul M. Genuth, S. Ferguson, Anushka Patel, C. Haggan, P. Lou, J. Gordon, M. B. Murphy, D. Sandstrom, Dawn M. Ryan, Daniel H. O'Leary, B. Gloeb, Lois E. Schmidt, H. Zegarra, D. Dalton, W. Brown, Tom G. Sheidow, Margaret E. Stockman, Shyam M. Thomas, Charles McKitrick, Jyotika K. Fernandes, P. A. Bourne, L. Baker, G. Friedenberg, Allan Gordon, Allan L. Drash, S. Yoser, D. Wood, S. Johnsonbaugh, A. De Manbey, L. Kaminski, M. May, L. Bestourous, A. Kowarski, M. Geckle, M. Hartmuller, Michael Bryer-Ash, S. List, F. Goetz, V. Reppucci, D. Etzwiler, Rose A. Gubitosi-Klug, M. Brabham, E. Golden, A. Nayate, J. Hu, M. McLellan, Ronald Klein, N. Rude, B. Vittetoe, John M. Lachin, M. Christofi, Zhuo Chen, Isaac Boniuk, C. Strauch, K. Gunyou, L. Delahanty, W. T. Garvey, Andrew P. Boright, Larry D. Hubbard, D. Weiss, Igor Grant, Jonathan Q. Purnell, Jean M. Bucksa, N. Olson, and B. Zinman

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Diabetic neuropathy, Adolescent, 030209 endocrinology & metabolism, Gastroenterology, Nephropathy, Epigenesis, Genetic, Diabetic complications, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Diabetic Neuropathies, Internal medicine, Diabetes mellitus, Albumins, Genetics, Medicine, Humans, Molecular Biology, Genetics (clinical), Whole blood, Oligonucleotide Array Sequence Analysis, Type 1 diabetes, business.industry, Research, dNaM, DNA methylation age, DNA Methylation, medicine.disease, 030104 developmental biology, Blood pressure, Peripheral neuropathy, Diabetes Mellitus, Type 1, CpG Islands, Female, business, Developmental Biology, Genome-Wide Association Study
Abstract

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

Published
2020

3. Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

Author

Jose M. Rial, Lorna W. Harries, Sian Ellard, Kusiel Perlman, Adnan Alshaikh, Khalid Hussain, Zdenek Sumnik, Thiruvengadam Vasanthi, Ildem Akerman, Rüveyde Bundak, Juan M. Fernandez, Guiomar Perez de Nanclares, Dorothee Deiss, Emma L. Edghill, Karen A. Johnstone, Gabriel del Castillo, Jonathan M. Locke, Eduardo Fernandez-Rebollo, Noel G. Morgan, Miguel A. Maestro, Estibaliz Ugarte, Thomasz Klupa, Sarah E. Flanagan, Oscar Rubio-Cabezas, Fauzia Mohsin, Stanislava Kolouskova, Michele O’Connell, Itxaso Rica, Luis Castaño, Asma Deeb, Jorge Ferrer, Carlos Castaño, Klemens Raile, Rosa de Diego Martínez, Intza Garin, Ann-Marie Patch, Koumudi Godbole, and Andrew T. Hattersley

Subjects
Male, Preproinsulin, medicine.medical_treatment, DNA Mutational Analysis, Gene Dosage, Genes, Recessive, 030209 endocrinology & metabolism, Biology, Gene dosage, 03 medical and health sciences, Diabetes mellitus genetics, 0302 clinical medicine, Diabetes mellitus, Diabetes Mellitus, medicine, Humans, Insulin, Protein Precursors, Gene, DNA Primers, 030304 developmental biology, Proinsulin, Regulation of gene expression, Genetics, 0303 health sciences, Multidisciplinary, Infant, Newborn, Biological Sciences, medicine.disease, Mutation, Oligonucleotide Probes
Abstract

Heterozygous coding mutations in the INS gene that encodes preproinsulin were recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal folding of proinsulin, which leads to beta-cell death through endoplasmic reticulum stress and apoptosis. We now report 10 different recessive INS mutations in 15 probands with neonatal diabetes. Functional studies showed that recessive mutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylation signal. A subset of recessive mutations caused abnormal INS transcription, including the deletion of the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-cell defect, patients with recessive INS mutations had a lower birth weight (−3.2 SD score vs. −2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant INS mutations. Mutations in the insulin gene can therefore result in neonatal diabetes as a result of two contrasting pathogenic mechanisms. Moreover, the recessively inherited mutations provide a genetic demonstration of the essential role of multiple sequence elements that regulate the biosynthesis of insulin in man.

Published
2010
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4. Quality Control Measures over 30 Years in a Multicenter Clinical Study: Results from the Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study

Author

M. Bracey, B. French, Brandy N. Rutledge, Sharon B. Schwartz, D. Steinberg, Peter R. Pavan, Xiaoyu Gao, Alan M. Jacobson, David A. Nicolle, C. Canny, Maria F. Lopes-Virella, A. Kitabchi, K. Hansen, M. E. Lackaye, Denis Daneman, Kandace A. Klumpp, David A. Lee, H. Engel, L. Survant, C. Haggan, K. Lee, G. Ziegler, Dawn M. Ryan, Lloyd Paul Aiello, Tom G. Sheidow, Allan Gordon, Allan L. Drash, S. Johnsonbaugh, L. Kaminski, S. Yoser, David J. Brillon, Osama Hamdy, Connie Fountain, N. Silvers, Kusiel Perlman, S. Caulder, M. Szpiech, D. Freking, Paula McGee, George S. Sharuk, D. Counts, H. Solc, David E. Goldstein, L. Bestourous, W. F. Schwenk, E. Brown, S. Cercone, M. Patronas, James L. Kinyoun, G. Castle, Mark H. Schutta, M. L. Schluter, Anton Orlin, E. Chaum, Daniel P. Joseph, F. Goetz, V. Reppucci, D. Etzwiler, E. Golden, A. Iannacone, R. Kirby, Lucy A. Levandoski, Lawrence J. Singerman, P. Salemi, A. Morrison, G. Vagstad, J. Laechelt, Pamela Ossorio, Tae Sup Lee, R. Cuddihy, S. Hitt, Fred W. Whitehouse, Michael H. Brent, Gayle M. Lorenzi, Anthony D. Morrison, B. Zinman, Szilard Kiss, D. Norman, N. Olson, Thomas Donner, John Dupre, M. Swenson, M. Spencer, Jerry P. Palmer, Scott M. Steidl, M. Franz, R. Beaser, H. Martinez, Samuel S. Engel, L. Diminick, J. Mortenson, David S. Schade, S. Yacoub-Wasef, Misty Good, John E. Chapin, Paolo S. Silva, J. Ginsberg, A. Dwoskin, John P. Bantle, J. D. Carey, D. McMillan, R. G. Campbell, Lisa Diminick, C. Cornish, Ramzi K. Hemady, P. Hollander, A. Farr, D. Zimbler, M. Mech, A. Lucas, Jye-Yu C. Backlund, K. Chan, Timothy J. Murtha, V. Asuquo, A. Bhan, A. Galprin, F. Perdikaris, Michael D. Larsen, L. Gill, Pamela A. Silver, S. Brink, Louis M. Luttrell, Sheila Smith-Brewer, D. Ostrowski, M. Bratkowksi, P. Crawford, M. Bryer-Ash, E. Angus, S. Braunstein, John I. Malone, R. Conwit, C. Pittman, Louis A. Lobes, Rodney A. Lorenz, J. Rosenzwieg, Neil H. White, William I. Sivitz, D. J. Becker, Stephen S. Feman, M. Zaucha, M. Reid, M. Jenner, L. Tuason, C. Gauthier-Kelly, C. McDonald, William H. Herman, John Kramer, Jeffrey L. Mahon, A. Campbell, J. L. Canady, A. Degillio, T. Adkins, P. W. Conrad, Senda Ajroud-Driss, L. Dews, Stephan Villavicencio, David G. Miller, Manjot K. Gill, D. Curtin, J. Brown-Friday, M. Basco, Elsayed Z. Soliman, J. Selby, Bradley D. Jones, M. Hebdon, B. Olson, John M. Pach, N. W. Rodger, K. Stoessel, N. Leloudes, J. Floyd, H. Lambeth, G. Lorenzi, Richard M. Hoffman, S. Chang, M. Guiliani, H. Zegarra, N. Bakshi, Dean P. Hainsworth, Murk-Hein Heinemann, S. Dagogo-Jack, Wanjie Sun, J. Warnicki, Dean B. Burgess, D. Kenny, L. McKenzie, B. Rogness, Martin J. Stevens, M. Nutaitis, William V. Tamborlane, L. Schmidt, Deborah K. Schlossman, J. Giangiacomo, C. Williams, R. Liss, Barbara J. Maschak-Carey, Barbara H. Braffett, Stefan Fritz, J. MacIndoe, Tom Clark, M. Novak, Michael H. Goldbaum, A. DeManbey, J. Ahern, L. Jovanovic, D. Finegold, Davida F. Kruger, Mary E. Larkin, M. Johnson, S. Shah, M. Ong, Catherine L. Martin, M. Giotta, R. Reed, B. Levy, Evica Simjanoski, L. Cimino, P. Callahan, S. Crowell, Rodica Pop-Busui, Howard Wolpert, Bernard H. Doft, J. Arch, C. Shipe, Mark R. Palmert, Philip Raskin, B. Schaefer, P. Astelford, Dara D. Koozekanani, R. B. Avery, Michael W. Steffes, Robert A. Rizza, Karen L. Anderson, Charles McKitrick, P. A. Bourne, L. Baker, G. Friedenberg, D. Wood, J. Wesche, M. Phillips, Gaurav K. Shah, John M. Lachin, M. Christofi, Kevin J. Blinder, R. Ehrlich, J. Rinkoff, Morey W. Haymond, Irene Hramiak, Z. Strugula, A. Blevins, R. Hyre, M. Richardson, Mark E. Molitch, I. H. de Boer, Annette Barnie, Mark R. Burge, M. Prince, P. Ramos, R. Chan, R. Hanna, Jong Mu Sun, Suzanne M. Strowig, C. Wigley, Om P. Ganda, R. Harris, Abraham Thomas, K. Klumpp, K. Kelly, David D. Moore, J. Sheindlin, T. J. Declue, Cormac T. Taylor, C. Kwong, Rose Gubitosi-Klug, T. Sandford, Isaac Boniuk, B. Zimmerman, R. Zeitler, S. Rogers, Joseph M. Terry, C. Johnson, Linda Snetselaar, Naji Younes, Ionut Bebu, N. Wimmergren, Rukhsana G. Mirza, K. Gunyou, Karl R. Olsen, H. Bode, J. Fruit, Michael Rubin, G. Grand, Trevor J. Orchard, Douglas A. Greene, J. Quin, R. Birk, W. Mestrezat, P. Pugsley, Anupam Agarwal, L. Mayer, C. Palmer, Timothy J. Lyons, C. Johannes, A. Determan, L. Van Ottingham, J. Gott, Jerry D. Cavallerano, D. Cros, J. Parker, M. May, Robert Bergren, A. Kowarski, L. Delahanty, Katherine A. Morgan, E. A. Tanaka, Robert W. Cavicchi, Thomas J. Songer, Robert G. Devenyi, J. Harth, Jill P. Crandall, T. Thompson, Lee M. Jampol, H. Schrott, Paul G. Arrigg, Orville G. Kolterman, R. Warhol, L. Thomas, S. Kwon, Jane L. Lynch, Arup Das, Theresa M. Williams, Thomas A. Weingeist, Patricia A. Cleary, Matthew A. Thomas, L. Babbione, Amisha Wallia, J. Lipps Hagan, D. Meyer, D. Rubinstein, P. Lindsey, Mark S. Mandelcorn, R. Fahlstrom, John E. Godine, Kathie L. Hermayer, B. Bosco, J. Rich, K. Folino, M. L. Bernal, S. Yalamanchi, S. Barron, J. McConnell, J. K. Jones, J. Vaccaro-Kish, R. Woodwick, P. Colby, Kelvin C. Fong, Ronald K. Mayfield, L. H. Ketai, Julio V. Santiago, M. B. Murphy, S. Schussler, N. Grove, Larry Rand, Robert C. Colligan, Ronald P. Danis, Valerie L. Arends, S. Ferguson, B. Petty, Christine Stevens, P. Ostrosaka, Margaret L. Bayless, S. Moser, Paul A. Edwards, R. Lyon, M. Carney, Katrina Jones, T. Strand, W. Hsu, Alexander J. Brucker, H. Shamoon, Alice T. Lyon, T. Smith, David M. Nathan, P. Lou, Bruce A. Perkins, Janet E. Olson, D. Rosenberg, H. Ricks, J. Gordon, D. Hornbeck, Nikhil D. Patel, Shelly Olson, Ellen J. Anderson, William Dahms, P. Paczan Rath, S. Elsing, L. Steranchak, L. M. Aiello, Saul Genuth, S. Catton, Sandra R. Montezuma, S. Pendegast, Richard M. Bergenstal, Patricia Gatcomb, Igor Grant, B. Braffett, W. Brown, Margaret E. Stockman, N. Burkhart, David M. Kendall, Jyotika K. Fernandes, S. List, J. Soule, Julie A. Nelson, John A. Colwell, M. McLellan, Silva A. Arslanian, N. Rude, B. Vittetoe, M. Driscoll, and E. Weimann

Subjects
Adult, Male, 030213 general clinical medicine, medicine.medical_specialty, Adolescent, Quality Assurance, Health Care, Psychological intervention, lcsh:Medicine, law.invention, Diabetes Complications, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Health care, medicine, Humans, Medical physics, lcsh:Science, Multidisciplinary, Data collection, business.industry, lcsh:R, Quality control, 3. Good health, Surgery, Data quality, Cohort, 030221 ophthalmology & optometry, Female, lcsh:Q, business, Quality assurance, Follow-Up Studies, Research Article
Abstract

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.

Published
2015

5. Relationship of Etiology to Treatment in Congenital Hypothyroidism

Author

Lori Brnjac, Kusiel Perlman, Denis Daneman, Igor Shamis, Aaron Hanukoglu, and Joanne Rovet

Subjects
Male, Thyroid Hormones, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Thyroid Gland, Thyrotropin, Biochemistry, Cohort Studies, Dysgenesis, Endocrinology, Hypothyroidism, Thyroid-stimulating hormone, Internal medicine, Blood plasma, Congenital Hypothyroidism, medicine, Humans, Dose-Response Relationship, Drug, business.industry, Biochemistry (medical), Thyroid, Infant, Newborn, Infant, Gestational age, medicine.disease, Congenital hypothyroidism, Thyroxine, medicine.anatomical_structure, Child, Preschool, Etiology, Female, business, Follow-Up Studies, Cohort study
Abstract

We examined the patterns of TSH, T(4), and treatment schedules from diagnosis to 4 yr of age in 125 children (50 males anf 75 females) with congenital hypothyroidism (CH). Subjects were divided into 3 groups based on their thyroid scans: 1) athyreosis (n = 31), 2) dysgenesis (n = 54; 49 lingual and 5 hypoplastic), and 3) dyshormonogenesis (n = 40). Follow-up evaluation was carried out at 2-4 wk and 3, 6, 9, 12, 24, 36, and 48 months of age. Median gestational age, age at onset of therapy, and starting L-T(4) dose were similar in the three groups. In infants with athyreosis median screening TSH levels were higher (P < 0.02) and confirmatory T(4) levels were lower than in the other two groups (P < 0.01 vs. dysgenetic; P < 0.05 vs. dyshormonogenetic CH). During the first 6 months of therapy, mean TSH levels were highest in the athyrotic group, intermediate in the dysgenetic group, and lowest in the dyshormonogenetic group. In children with athyreosis, TSH levels normalized by 12 months of age. At 12 months dysgenetic patients had the highest TSH levels (P < 0.05). During the entire study period, TSH levels were lowest in patients with dyshormonogenesis (except at 48 months) and normalized earlier. Mean T(4) levels normalized by 2-4 weeks in all groups. At 3 and 6 months, the percentage of patients who required dose changes was highest in the athyrotic group, and at 12 months it was highest in the dysgenetic group. The athyrotic group received the highest dose of L-T(4), and dyshormonogenetic group received the lowest dose. We conclude that treatment and follow-up schedules for CH may differ in the three etiological categories based on the different hormonal patterns and responses to therapy. Children with athyreosis need close monitoring particularly early in life, whereas those with dysgenesis and dyshormonogenesis require more attention later in life.

Published
2001
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6. The infant and toddler with diabetes: Challenges of diagnosis and management

Author

Denis Daneman, Jean Wittenberg, Marcia Frank, and Kusiel Perlman

Subjects
Type 1 diabetes, medicine.medical_specialty, Pediatrics, Continuing Medical Education, business.industry, Child care personnel, Hypoglycemia, medicine.disease, Diabetes mellitus, Pediatrics, Perinatology and Child Health, Health care, medicine, Early childhood, Toddler, business, Intensive care medicine, Psychosocial
Abstract

Infants and toddlers comprise a small minority of individuals with type 1 diabetes. However, epidemiological data provide evidence of a trend towards diagnosis at a younger age. These very young children pose significant challenges to both the health care professionals involved in their care as well as to their families. At diagnosis, younger children often do not present with classical symptoms of diabetes. Unless health professionals remain alert to the possibility of diabetes being the underlying cause of a child’s illness, the diagnosis may be missed. Once the diabetes has been diagnosed, the major challenge is to set up a treatment regimen that is both reasonable and realistic; in the youngest children, the goal of very tight metabolic control may expose them to episodes of severe hypoglycemia which may lead to subtle cognitive impairments later in life. The therapeutic regimen must balance the naturally erratic eating and exercise patterns of very young children with the need to maintain adequate metabolic control. Setting a blood glucose target range of 6 to 12 mmol/L usually allows this to be accomplished. Diabetes during early childhood creates a psychosocial challenge to the families of these children. Successful management of infants and toddlers with diabetes depends on a well functioning and educated family, the availability of diabetes health care team experienced in the treatment of these youngsters, and the involvement of the extended family, child care personnel and others who play a role in their daily care.

Published
1999
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7. From diarrhea to obesity in prohormone convertase 1/3 deficiency: age-dependent clinical, pathologic, and enteroendocrine characteristics

Author

Rose Chami, Stanley Zlotkin, Martin G. Martin, Christiane Sokollik, Kusiel Perlman, Robert H. J. Bandsma, Patricia L. Brubaker, Jill K. Hamilton, Yaron Avitzur, Philip M. Sherman, David L. Sigalet, and Ernest Cutz

Subjects
Male, obesity, Malabsorption, malabsorption, medicine.medical_treatment, Enteroendocrine cell, Severity of Illness Index, Glucagon-Like Peptide 1, Insulin Secretion, Glucagon-Like Peptide 2, Medicine, Insulin, 2.1 Biological and endogenous factors, Aetiology, Child, Proinsulin, Pediatric, Glucose tolerance test, Microscopy, biology, medicine.diagnostic_test, Gastroenterology, Age Factors, Chromogranin A, Hospitals, Pediatric, Immunohistochemistry, Pathophysiology, Hospitals, Diarrhea, prohormone convertase deficiency, Proprotein Convertase 2, Proprotein Convertase 1, Child, Preschool, congenital diarrhea, medicine.symptom, endocrine system, medicine.medical_specialty, insulin, Enteroendocrine Cells, Clinical Sciences, Endocrine System Diseases, Electron, Article, children, Clinical Research, Internal medicine, Humans, Obesity, Preschool, Metabolic and endocrine, Retrospective Studies, Nutrition, Gastroenterology & Hepatology, business.industry, Infant, Glucose Tolerance Test, medicine.disease, Microscopy, Electron, Endocrinology, biology.protein, business, Digestive Diseases
Abstract

GOALS The aim of this report is to delineate the clinical, pathologic, and enteroendocrine (EE) features of prohormone convertase 1/3 (PC1/3) deficiency in children. BACKGROUND Prohormone convertases play a pivotal role in the activation of biologically inactive hormones. Congenital defects in the EE axis, such as PC1/3 deficiency, have been rarely reported and their pathophysiological mechanisms are largely unknown. STUDY EE function and pathology was evaluated in 4 males (1, 2, 7, and 10 y old) from 2 families with PC1/3 deficiency at a university children's hospital. Clinical course, pathology analysis including immunohistochemistry for PC1/3, PC2, and glucagon-like peptide 1 (GLP-1) and electron microscopy, as well as EE function tests (GLP-1, GLP-2, oral glucose tolerance test) were performed. RESULTS All (n=4) suffered from congenital severe diarrhea associated with malabsorption. The diarrhea improved during the first year of life and hyperphagia with excessive weight gain (BMI>97th percentile) became the predominant phenotype at an older age. Analysis of the enteroendocrine axis revealed high proinsulin levels (57 to 1116 pmol/L) in all patients, low serum GLP-2 levels, and impaired insulin and GLP-1 secretion after an oral glucose tolerance test at a young age, with improvement in 1 older child tested. Electron microscopy showed normal ultrastructure of enterocytes and EE cells. Immunohistochemistry revealed normal expression of chromogranin A, a marker of EE cells but markedly reduced immunostaining for PC1/3 and PC2 in all patients. CONCLUSIONS PC1/3 deficiency is associated with an age dependent, variable clinical phenotype caused by severe abnormalities in intestinal and EE functions. Serum level of proinsulin can be used as an effective screening tool.

Published
2013

8. Identification and functional characterization of three NoLS (nucleolar localisation signals) mutations of the CDC73 gene

Author

Massimo Carella, Massimiliano Copetti, Valerio Pazienza, Dalia Al-Abdulrazzaq, Dieter Kotzot, Michela Alfarano, Massimiliano Chetta, Lucia Anna Muscarella, Alfredo Scillitani, Claudia Battista, Klaus Kapelari, Leopoldo Zelante, David E. C. Cole, Geoffrey N. Hendy, Etienne Sochett, Annamaria la Torre, Kusiel Perlman, Leonardo D'Agruma, Vito Guarnieri, Fabio Pellegrini, Filomena Baorda, and Lucie Canaff

Subjects
Male, Pathology, medicine.medical_specialty, Cytoplasm, endocrine system diseases, Adolescent, Nuclear Localization Signals, lcsh:Medicine, Gene mutation, Biology, medicine.disease_cause, Germline, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, medicine, Humans, lcsh:Science, Child, Germ-Line Mutation, 030304 developmental biology, 0303 health sciences, Hyperparathyroidism, Mutation, Multidisciplinary, Tumor Suppressor Proteins, lcsh:R, Middle Aged, medicine.disease, Hyperparathyroidism, Primary, Molecular biology, Jaw Neoplasms, 3. Good health, Neoplasm Proteins, Protein Transport, HEK293 Cells, Parathyroid carcinoma, 030220 oncology & carcinogenesis, Fibroma, Ossifying, lcsh:Q, Female, Primary hyperparathyroidism, Research Article
Abstract

Hyperparathyroidism Jaw-Tumour Syndrome (HPT-JT) is characterized by primary hyperparathyroidism (PHPT), maxillary/mandible ossifying fibromas and by parathyroid carcinoma in 15% of cases. Inactivating mutations of the tumour suppressor CDC73/HRPT2 gene have been found in HPT-JT patients and also as genetic determinants of sporadic parathyroid carcinoma/atypical adenomas and, rarely, typical adenomas, in familial PHPT. Here we report the genetic and molecular analysis of the CDC73/HRPT2 gene in three patients affected by PHPT due to atypical and typical parathyroid adenomas, in one case belonging to familial PHPT. Flag-tagged WT and mutant CDC73/HRPT2 proteins were transiently transfected in HEK293 cells and functional assays were performed in order to investigate the effect of the variants on the whole protein expression, nuclear localization and cell overgrowth induction. We identified four CDC73/HRPT2 gene mutations, three germline (c.679_680delAG, p.Val85_Val86del and p.Glu81_Pro84del), one somatic (p.Arg77Pro). In three cases the mutation was located within the Nucleolar Localisation Signals (NoLS). The three NoLS variants led to instability either of the corresponding mutated protein or mRNA or both. When transfected in HEK293 cells, NoLS mutated proteins mislocalized with a predeliction for cytoplasmic or nucleo-cytoplasmic localization and, finally, they resulted in overgrowth, consistent with a dominant negative interfering effect in the presence of the endogenous protein.

Published
2013

9. 1171 CONTINUOUS INTRAVENOUS INSULIN DELIVERY IN AMBULATORY ADOLESCENT DIABETICS

Author

R M Filler, A M Albisser, Kusiel Perlman, D Carver, and R M Ehrlich

Subjects
Meal, medicine.medical_specialty, Basal rate, Evening, business.industry, Insulin, medicine.medical_treatment, Excretion, Catheter, Endocrinology, Internal medicine, Anesthesia, Pediatrics, Perinatology and Child Health, Ambulatory, medicine, Local anesthesia, business
Abstract

Devices and methods for long term intravenous insulin infusion in ambulatory patients have recently been developed. With informed consent we studied 7 non-obese uncomplicated Type I diabetics (aged 15-17y) who received insulin for 14-23 days by central venous infusion (CVII). All subjects were studied in hospital with otherwise unrestricted activity and received 3 daily meals and an evening snack of constant caloric content. Under local anesthesia, a thin silicone rubber catheter was inserted into a branch of the external jugular vein, advanced to the SVC and tunnelled subcutaneously to exit in the supramammary region, where it was connected to the portable system consisting of a small peristaltic pump, a flow rate controller and a reservoir of soluble insulin. Insulin was infused at a constant basal rate of 17±3 mU/min. The rate was increased 15 minutes from the start of a meal 4-5 fold for 60-120 min then returned to the basal rate in a 2 step fashion over 40-120 min. Fasting plasma glucose (mean±SEM) was 262±40 prior to infusion and fell to 92±9 mg/dl on CVII with increases during mealtimes from 80±3 to 115±3 mg/dl at 41±3 min pc. Mean urinary glucose excretion of 55 g/day fell to 1.9 during CVII and fasting serum cholesterol of 220±28 and triglycerides of 281±94 fell to 138±13 and 115±24 mg/dl respectively. Mean HgbAl (N:6.5 - 8.5%) fell from 14.8 to 10.7% by the end of the study period. All indices of control showed improvement with p

Published
1981
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