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1. Duplication of the SOX3 gene in an sry-negative 46,XX male with associated congenital anomalies of kidneys and the urinary tract: Case report and review of the literature

Author

Tasic V, Mitrotti A, Riepe FG, Kulle AE, Laban N, Polenakovic M, Plaseska-Karanfilska D, Sanna-Cherchi S, Kostovski M, and Gucev Z

Subjects
congenital anomalies of kidneys and the urinary tract (cakut), copy number variations (cnvs), disorders of sex development (dsd), Genetics, QH426-470
Abstract

Disorders of sex development (DSD) are a group of rare conditions characterized by discrepancy between chromosomal sex, gonads and external genitalia. Congenital abnormalities of the kidney and urinary tract are often associated with DSD, mostly in multiple malformation syndromes. We describe the case of an 11-year-old Caucasian boy, with right kidney hypoplasia and hypospadias. Genome-wide copy number variation (CNV) analysis revealed a unique duplication of about 550 kb on chromosome Xq27, and a 46,XX karyotype, consistent with a sex reversal phenotype. This region includes multiple genes, and, among these, SOX3 emerged as the main phenotypic driver. This is the fifth case reporting a genomic imbalance involving the SOX3 gene in a 46,XX SRY-negative male, and the first with associated renal malformations. Our data provide plausible links between SOX3 gene dosage and kidney malformations. It is noteworthy that the current and reported SOX3 gene duplications are below the detection threshold of standard karyotypes and were found only by analyzing CNVs using DNA microarrays. Therefore, all 46,XX SRY-negative males should be screened for SOX3 gene duplications with DNA microarrays.

Published
2019
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3. Natural History and Clinicopathological Associations of TRPC6-Associated Podocytopathy

Author

Wooden, Benjamin, Beenken, Andrew, Martinelli, Elena, Saida, Ken, Knob, Andrea L., Ke, Juntao, Pisani, Isabella, Jin, Gina, Lane, Brandon, Mitrotti, Adele, Colby, Elizabeth, Lim, Tze Y., Guglielmi, Francesca, Osborne, Amy J., Ahram, Dina F., Wang, Chen, Armand, Farid, Zanoni, Francesca, Bomback, Andrew S., Delsante, Marco, Appel, Gerald B., Ferrari, Massimo R.A., Martino, Jeremiah, Sahdeo, Sunil, Breckenridge, David, Petrovski, Slavé, Paul, Dirk S., Hall, Gentzon, Magistroni, Riccardo, Murtas, Corrado, Feriozzi, Sandro, Rampino, Teresa, Esposito, Pasquale, Helmuth, Margaret E., Sampson, Matthew G., Kretzler, Matthias, Kiryluk, Krzysztof, Shril, Shirlee, Gesualdo, Loreto, Maggiore, Umberto, Fiaccadori, Enrico, Gbadegesin, Rasheed, Santoriello, Dominick, DʼAgati, Vivette D., Saleem, Moin A., Gharavi, Ali G., Hildebrandt, Friedhelm, Pollak, Martin R., Goldstein, David B., and Sanna-Cherchi, Simone

Published
2024
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5. Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy

Author

Kiryluk, Krzysztof, Sanchez-Rodriguez, Elena, Zhou, Xu-Jie, Zanoni, Francesca, Liu, Lili, Mladkova, Nikol, Khan, Atlas, Marasa, Maddalena, Zhang, Jun Y., Balderes, Olivia, Sanna-Cherchi, Simone, Bomback, Andrew S., Canetta, Pietro A., Appel, Gerald B., Radhakrishnan, Jai, Trimarchi, Hernan, Sprangers, Ben, Cattran, Daniel C., Reich, Heather, Pei, York, Ravani, Pietro, Galesic, Kresimir, Maixnerova, Dita, Tesar, Vladimir, Stengel, Benedicte, Metzger, Marie, Canaud, Guillaume, Maillard, Nicolas, Berthoux, Francois, Berthelot, Laureline, Pillebout, Evangeline, Monteiro, Renato, Nelson, Raoul, Wyatt, Robert J., Smoyer, William, Mahan, John, Samhar, Al-Akash, Hidalgo, Guillermo, Quiroga, Alejandro, Weng, Patricia, Sreedharan, Raji, Selewski, David, Davis, Keefe, Kallash, Mahmoud, Vasylyeva, Tetyana L., Rheault, Michelle, Chishti, Aftab, Ranch, Daniel, Wenderfer, Scott E., Samsonov, Dmitry, Claes, Donna J., Akchurin, Oleh, Goumenos, Dimitrios, Stangou, Maria, Nagy, Judit, Kovacs, Tibor, Fiaccadori, Enrico, Amoroso, Antonio, Barlassina, Cristina, Cusi, Daniele, Del Vecchio, Lucia, Battaglia, Giovanni Giorgio, Bodria, Monica, Boer, Emanuela, Bono, Luisa, Boscutti, Giuliano, Caridi, Gianluca, Lugani, Francesca, Ghiggeri, GianMarco, Coppo, Rosanna, Peruzzi, Licia, Esposito, Vittoria, Esposito, Ciro, Feriozzi, Sandro, Polci, Rosaria, Frasca, Giovanni, Galliani, Marco, Garozzo, Maurizio, Mitrotti, Adele, Gesualdo, Loreto, Granata, Simona, Zaza, Gianluigi, Londrino, Francesco, Magistroni, Riccardo, Pisani, Isabella, Magnano, Andrea, Marcantoni, Carmelita, Messa, Piergiorgio, Mignani, Renzo, Pani, Antonello, Ponticelli, Claudio, Roccatello, Dario, Salvadori, Maurizio, Salvi, Erica, Santoro, Domenico, Gembillo, Guido, Savoldi, Silvana, Spotti, Donatella, Zamboli, Pasquale, Izzi, Claudia, Alberici, Federico, Delbarba, Elisa, Florczak, Michał, Krata, Natalia, Mucha, Krzysztof, Pączek, Leszek, Niemczyk, Stanisław, Moszczuk, Barbara, Pańczyk-Tomaszewska, Malgorzata, Mizerska-Wasiak, Malgorzata, Perkowska-Ptasińska, Agnieszka, Bączkowska, Teresa, Durlik, Magdalena, Pawlaczyk, Krzysztof, Sikora, Przemyslaw, Zaniew, Marcin, Kaminska, Dorota, Krajewska, Magdalena, Kuzmiuk-Glembin, Izabella, Heleniak, Zbigniew, Bullo-Piontecka, Barbara, Liberek, Tomasz, Dębska-Slizien, Alicja, Hryszko, Tomasz, Materna-Kiryluk, Anna, Miklaszewska, Monika, Szczepańska, Maria, Dyga, Katarzyna, Machura, Edyta, Siniewicz-Luzeńczyk, Katarzyna, Pawlak-Bratkowska, Monika, Tkaczyk, Marcin, Runowski, Dariusz, Kwella, Norbert, Drożdż, Dorota, Habura, Ireneusz, Kronenberg, Florian, Prikhodina, Larisa, van Heel, David, Fontaine, Bertrand, Cotsapas, Chris, Wijmenga, Cisca, Franke, Andre, Annese, Vito, Gregersen, Peter K., Parameswaran, Sreeja, Weirauch, Matthew, Kottyan, Leah, Harley, John B., Suzuki, Hitoshi, Narita, Ichiei, Goto, Shin, Lee, Hajeong, Kim, Dong Ki, Kim, Yon Su, Park, Jin-Ho, Cho, BeLong, Choi, Murim, Van Wijk, Ans, Huerta, Ana, Ars, Elisabet, Ballarin, Jose, Lundberg, Sigrid, Vogt, Bruno, Mani, Laila-Yasmin, Caliskan, Yasar, Barratt, Jonathan, Abeygunaratne, Thilini, Kalra, Philip A., Gale, Daniel P., Panzer, Ulf, Rauen, Thomas, Floege, Jürgen, Schlosser, Pascal, Ekici, Arif B., Eckardt, Kai-Uwe, Chen, Nan, Xie, Jingyuan, Lifton, Richard P., Loos, Ruth J. F., Kenny, Eimear E., Ionita-Laza, Iuliana, Köttgen, Anna, Julian, Bruce A., Novak, Jan, Scolari, Francesco, Zhang, Hong, and Gharavi, Ali G.

Published
2023
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6. Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease

Author

Yask Gupta, David J. Friedman, Michelle T. McNulty, Atlas Khan, Brandon Lane, Chen Wang, Juntao Ke, Gina Jin, Benjamin Wooden, Andrea L. Knob, Tze Y. Lim, Gerald B. Appel, Kinsie Huggins, Lili Liu, Adele Mitrotti, Megan C. Stangl, Andrew Bomback, Rik Westland, Monica Bodria, Maddalena Marasa, Ning Shang, David J. Cohen, Russell J. Crew, William Morello, Pietro Canetta, Jai Radhakrishnan, Jeremiah Martino, Qingxue Liu, Wendy K. Chung, Angelica Espinoza, Yuan Luo, Wei-Qi Wei, Qiping Feng, Chunhua Weng, Yilu Fang, Iftikhar J. Kullo, Mohammadreza Naderian, Nita Limdi, Marguerite R. Irvin, Hemant Tiwari, Sumit Mohan, Maya Rao, Geoffrey K. Dube, Ninad S. Chaudhary, Orlando M. Gutiérrez, Suzanne E. Judd, Mary Cushman, Leslie A. Lange, Ethan M. Lange, Daniel L. Bivona, Miguel Verbitsky, Cheryl A. Winkler, Jeffrey B. Kopp, Dominick Santoriello, Ibrahim Batal, Sérgio Veloso Brant Pinheiro, Eduardo Araújo Oliveira, Ana Cristina Simoes e Silva, Isabella Pisani, Enrico Fiaccadori, Fangming Lin, Loreto Gesualdo, Antonio Amoroso, Gian Marco Ghiggeri, Vivette D. D’Agati, Riccardo Magistroni, Eimear E. Kenny, Ruth J. F. Loos, Giovanni Montini, Friedhelm Hildebrandt, Dirk S. Paul, Slavé Petrovski, David B. Goldstein, Matthias Kretzler, Rasheed Gbadegesin, Ali G. Gharavi, Krzysztof Kiryluk, Matthew G. Sampson, Martin R. Pollak, and Simone Sanna-Cherchi

Subjects
Science
Abstract

Abstract African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.

Published
2023
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7. Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome

Author

Barry, Alexandra, McNulty, Michelle T., Jia, Xiaoyuan, Gupta, Yask, Debiec, Hanna, Luo, Yang, Nagano, China, Horinouchi, Tomoko, Jung, Seulgi, Colucci, Manuela, Ahram, Dina F., Mitrotti, Adele, Sinha, Aditi, Teeninga, Nynke, Jin, Gina, Shril, Shirlee, Caridi, Gianluca, Bodria, Monica, Lim, Tze Y., Westland, Rik, Zanoni, Francesca, Marasa, Maddalena, Turudic, Daniel, Giordano, Mario, Gesualdo, Loreto, Magistroni, Riccardo, Pisani, Isabella, Fiaccadori, Enrico, Reiterova, Jana, Maringhini, Silvio, Morello, William, Montini, Giovanni, Weng, Patricia L., Scolari, Francesco, Saraga, Marijan, Tasic, Velibor, Santoro, Domenica, van Wijk, Joanna A. E., Milošević, Danko, Kawai, Yosuke, Kiryluk, Krzysztof, Pollak, Martin R., Gharavi, Ali, Lin, Fangmin, Simœs e Silva, Ana Cristina, Loos, Ruth J. F., Kenny, Eimear E., Schreuder, Michiel F., Zurowska, Aleksandra, Dossier, Claire, Ariceta, Gema, Drozynska-Duklas, Magdalena, Hogan, Julien, Jankauskiene, Augustina, Hildebrandt, Friedhelm, Prikhodina, Larisa, Song, Kyuyoung, Bagga, Arvind, Cheong, II, Hae, Ghiggeri, Gian Marco, Vachvanichsanong, Prayong, Nozu, Kandai, Lee, Dongwon, Vivarelli, Marina, Raychaudhuri, Soumya, Tokunaga, Katsushi, Sanna-Cherchi, Simone, Ronco, Pierre, Iijima, Kazumoto, and Sampson, Matthew G.

Published
2023
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8. De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.

Author

Weng, Patricia, Majmundar, Amar, Khan, Kamal, Lim, Tze, Shril, Shirlee, Jin, Gina, Musgrove, John, Wang, Minxian, Ahram, Dina, Aggarwal, Vimla, Bier, Louise, Heinzen, Erin, Onuchic-Whitford, Ana, Mann, Nina, Buerger, Florian, Schneider, Ronen, Deutsch, Konstantin, Kitzler, Thomas, Klämbt, Verena, Kolb, Amy, Mao, Youying, Moufawad El Achkar, Christelle, Mitrotti, Adele, Martino, Jeremiah, Beck, Bodo, Altmüller, Janine, Benz, Marcus, Yano, Shoji, Mikati, Mohamad, Gunduz, Talha, Cope, Heidi, Shashi, Vandana, Trachtman, Howard, Bodria, Monica, Caridi, Gianluca, Pisani, Isabella, Fiaccadori, Enrico, AbuMaziad, Asmaa, Martinez-Agosto, Julian, Yadin, Ora, Zuckerman, Jonathan, Kim, Arang, John-Kroegel, Ulrike, Tyndall, Amanda, Parboosingh, Jillian, Innes, A, Bierzynska, Agnieszka, Koziell, Ania, Muorah, Mordi, Saleem, Moin, Hoefele, Julia, Riedhammer, Korbinian, Gharavi, Ali, Jobanputra, Vaidehi, Pierce-Hoffman, Emma, Seaby, Eleanor, ODonnell-Luria, Anne, Rehm, Heidi, Mane, Shrikant, DAgati, Vivette, Pollak, Martin, Ghiggeri, Gian, Lifton, Richard, Goldstein, David, Davis, Erica, Hildebrandt, Friedhelm, and Sanna-Cherchi, Simone

Subjects
FSGS, SRNS, TRIM8, epilepsy, genomics, monogenic, nuclear body, Adult, Animals, Carrier Proteins, Cell Line, Child, Child, Preschool, Codon, Nonsense, Developmental Disabilities, Epilepsy, Female, Glomerulosclerosis, Focal Segmental, Humans, Intranuclear Space, Kidney, Male, Mice, Mutation, Nephrotic Syndrome, Nerve Tissue Proteins, Phenotype, Podocytes, Exome Sequencing
Abstract

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10-15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

Published
2021

9. Implementation and Feasibility of Clinical Genome Sequencing Embedded Into the Outpatient Nephrology Care for Patients With Proteinuric Kidney Disease

Author

Marasa, Maddalena, Ahram, Dina F., Rehman, Atteeq U., Mitrotti, Adele, Abhyankar, Avinash, Jain, Namrata G., Weng, Patricia L., Piva, Stacy E., Fernandez, Hilda E., Uy, Natalie S., Chatterjee, Debanjana, Kil, Byum H., Nestor, Jordan G., Felice, Vanessa, Robinson, Dino, Whyte, Dilys, Gharavi, Ali G., Appel, Gerald B., Radhakrishnan, Jai, Santoriello, Dominick, Bomback, Andrew, Lin, Fangming, D’Agati, Vivette D., Jobanputra, Vaidehi, and Sanna-Cherchi, Simone

Published
2023
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10. Ambroxol as a disease-modifying treatment to reduce the risk of cognitive impairment in GBA-associated Parkinson’s disease: a multicentre, randomised, double-blind, placebo-controlled, phase II trial. The AMBITIOUS study protocol

Author

Matteo Gastaldi, Diego Franciotta, Mario Cirillo, Sara Prioni, Micol Avenali, Fabrizio Esposito, Chiara Reale, Valentina Leta, Enza Maria Valente, Anna Pichiecchio, Barbara Garavaglia, Roberto Eleopra, Marina Grisoli, Roberto Cilia, Luigi Romito, Maria Grazia Bruzzone, Alessandro Tessitore, Ilaria Palmieri, Giada Cuconato, Fabiana Colucci, Pierfrancesco Mitrotti, Rosita De Micco, Marco Fusar Poli, Silvia Cerri, Mario Stanziano, Ana Bacila, Valentina Franco, Cristina Ghezzi, Antonio Emanuele Elia, Grazia Devigili, Nico Golfrè Andreasi, Federico Cazzaniga, Caterina Galandra, Giancarlo Germani, Gerardo Ongari, Marta Picascia, Mattia Verri, Federica Di Nardo, Simone Aloisio, Mattia Siciliano, Paolo Amami, Sylvie Piacentini, and Fabio Moda

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Background Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme β-glucocerebrosidase (GCase), are the most frequent genetic risk factor for Parkinson’s disease (PD). GBA-related PD (GBA-PD) patients have higher risk of dementia and reduced survival than non-carriers. Preclinical studies and one open-label trial in humans demonstrated that the chaperone ambroxol (ABX) increases GCase levels and modulates α-synuclein levels in the blood and cerebrospinal fluid (CSF).Methods and analysis In this multicentre, double-blind, placebo-controlled, phase II clinical trial, we randomise patients with GBA-PD in a 1:1 ratio to either oral ABX 1.2 g/day or placebo. The duration of treatment is 52 weeks. Each participant is assessed at baseline and weeks 12, 26, 38, 52 and 78. Changes in the Montreal Cognitive Assessment score and the frequency of mild cognitive impairment and dementia between baseline and weeks 52 are the primary outcome measures. Secondary outcome measures include changes in validated scales/questionnaires assessing motor and non-motor symptoms. Neuroimaging features and CSF neurodegeneration markers are used as surrogate markers of disease progression. GCase activity, ABX and α-synuclein levels are also analysed in blood and CSF. A repeated-measures analysis of variance will be used for elaborating results. The primary analysis will be by intention to treat.Ethics and dissemination The study and protocols have been approved by the ethics committee of centres. The study is conducted according to good clinical practice and the Declaration of Helsinki. The trial findings will be published in peer-reviewed journals and presented at conferences.Trial registration numbers NCT05287503, EudraCT 2021-004565-13.

Published
2023
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12. Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis

Author

Ahram, Dina F., Lim, Tze Y., Ke, Juntao, Jin, Gina, Verbitsky, Miguel, Bodria, Monica, Kil, Byum Hee, Chatterjee, Debanjana, Piva, Stacy E., Marasa, Maddalena, Zhang, Jun Y., Cocchi, Enrico, Caridi, Gianluca, Gucev, Zoran, Lozanovski, Vladimir J., Pisani, Isabella, Izzi, Claudia, Savoldi, Gianfranco, Gnutti, Barbara, Capone, Valentina P., Morello, William, Guarino, Stefano, Esposito, Pasquale, Lambert, Sarah, Radhakrishnan, Jai, Appel, Gerald B., Uy, Natalie S., Rao, Maya K., Canetta, Pietro A., Bomback, Andrew S., Nestor, Jordan G., Hays, Thomas, Cohen, David J., Finale, Carolina, Wijk, Joanna A.E. van, La Scola, Claudio, Baraldi, Olga, Tondolo, Francesco, Di Renzo, Dacia, Jamry-Dziurla, Anna, Pezzutto, Alessandro, Manca, Valeria, Mitrotti, Adele, Santoro, Domenico, Conti, Giovanni, Martino, Marida, Giordano, Mario, Gesualdo, Loreto, Zibar, Lada, Masnata, Giuseppe, Bonomini, Mario, Alberti, Daniele, La Manna, Gaetano, Caliskan, Yasar, Ranghino, Andrea, Marzuillo, Pierluigi, Kiryluk, Krzysztof, Krzemień, Grażyna, Miklaszewska, Monika, Lin, Fangming, Montini, Giovanni, Scolari, Francesco, Fiaccadori, Enrico, Arapović, Adela, Saraga, Marijan, McKiernan, James, Alam, Shumyle, Zaniew, Marcin, Szczepańska, Maria, Szmigielska, Agnieszka, Sikora, Przemysław, Drożdż, Dorota, Mizerska-Wasiak, Malgorzata, Mane, Shrikant, Lifton, Richard P., Tasic, Velibor, Latos-Bielenska, Anna, Gharavi, Ali G., Ghiggeri, Gian Marco, Materna-Kiryluk, Anna, Westland, Rik, and Sanna-Cherchi, Simone

Published
2023
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13. The copy number variation landscape of congenital anomalies of the kidney and urinary tract.

Author

Verbitsky, Miguel, Westland, Rik, Perez, Alejandra, Kiryluk, Krzysztof, Liu, Qingxue, Krithivasan, Priya, Mitrotti, Adele, Fasel, David, Batourina, Ekaterina, Sampson, Matthew, Bodria, Monica, Werth, Max, Kao, Charlly, Martino, Jeremiah, Capone, Valentina, Vivante, Asaf, Shril, Shirlee, Kil, Byum, Marasà, Maddalena, Zhang, Jun, Na, Young-Ji, Lim, Tze, Ahram, Dina, Weng, Patricia, Heinzen, Erin, Carrea, Alba, Piaggio, Giorgio, Gesualdo, Loreto, Manca, Valeria, Masnata, Giuseppe, Gigante, Maddalena, Cusi, Daniele, Izzi, Claudia, Scolari, Francesco, van Wijk, Joanna, Saraga, Marijan, Santoro, Domenico, Conti, Giovanni, Zamboli, Pasquale, White, Hope, Drozdz, Dorota, Zachwieja, Katarzyna, Miklaszewska, Monika, Tkaczyk, Marcin, Tomczyk, Daria, Krakowska, Anna, Sikora, Przemyslaw, Jarmoliński, Tomasz, Borszewska-Kornacka, Maria, Pawluch, Robert, Szczepanska, Maria, Adamczyk, Piotr, Mizerska-Wasiak, Malgorzata, Krzemien, Grazyna, Szmigielska, Agnieszka, Zaniew, Marcin, Dobson, Mark, Darlow, John, Puri, Prem, Barton, David, Furth, Susan, Warady, Bradley, Gucev, Zoran, Lozanovski, Vladimir, Tasic, Velibor, Pisani, Isabella, Allegri, Landino, Rodas, Lida, Campistol, Josep, Jeanpierre, Cécile, Alam, Shumyle, Casale, Pasquale, Wong, Craig, Lin, Fangming, Miranda, Débora, Oliveira, Eduardo, Simões-E-Silva, Ana, Barasch, Jonathan, Levy, Brynn, Wu, Nan, Hildebrandt, Friedhelm, Ghiggeri, Gian, Latos-Bielenska, Anna, Materna-Kiryluk, Anna, Zhang, Feng, Hakonarson, Hakon, Papaioannou, Virginia, Mendelsohn, Cathy, Gharavi, Ali, and Sanna-Cherchi, Simone

Subjects
Chromosome Deletion, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney, Male, Urinary Tract, Urogenital Abnormalities, Vesico-Ureteral Reflux
Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

Published
2019

14. Introduzione al dossier - Il terzo settore e la sua trascendentale settorialità: per una amministrazione condivisa

Author

Antonio Mitrotti

Subjects
Law, Social Sciences
Abstract

Il Terzo Settore è terzo rispetto a chi? Oppure a che cosa? Ad onor del vero è del tutto intuibile come questi termini alludano (con più o meno consapevolezza) ad una cronica convenzione tacita - seppur cogente - per l’opinione pubblica, secondo cui il Terzo Settore è tale, fenomenologicamente, in quanto esistente rispetto ad altri due settori: ossia il settore pubblico e quello privato, lasciando (per altro) irresolutamente sullo sfondo l’importante nodo concettuale su a chi spetti, in quest’ottica, la posizione di primarietà e/o di secondarietà. A ben riflettere, calandosi in questa cronica dimensione prospettica il Terzo Settore verrebbe a basarsi su di un’idea di alterità soggettiva rispetto ad altri settori (o materie). Ed invece, se ci ragionassimo, la ratio existendi del Terzo Settore nell’ordinamento della Repubblica italiana è tutt’altra: nascendo dal presupposto di un’idea del netto superamento dell’alterità soggettiva e settoriale, per svilupparsi - cioè - sui binari di una sostanziale condivisione, fino al punto di una (fitta) integrazione e di un effettivo superamento delle soggettività, in ragione dell’oggettivo interesse generale

Published
2023
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15. The frequency of rare and monogenic diseases in pediatric organ transplant recipients in Italy

Author

Tiziana Vaisitti, Daniela Peritore, Paola Magistroni, Andrea Ricci, Letizia Lombardini, Enrico Gringeri, Silvia Catalano, Marco Spada, Marco Sciveres, Angelo Di Giorgio, Giuseppe Limongelli, Marisa Varrenti, Gino Gerosa, Amedeo Terzi, Carlo Pace Napoleone, Antonio Amodeo, Luca Ragni, Luca dello Strologo, Elisa Benetti, Iris Fontana, Sara Testa, Licia Peruzzi, Adele Mitrotti, Serena Abbate, Giorgia Comai, Eliana Gotti, Marco Schiavon, Massimo Boffini, Daniele De Angelis, Alessandro Bertani, Domenico Pinelli, Massimo Torre, Camilla Poggi, Silvia Deaglio, Massimo Cardillo, Antonio Amoroso, and Italian Pediatric Transplant Centers

Subjects
Rare diseases, Monogenic diseases, Organ transplantation, Transplant outcome, Medicine
Abstract

Abstract Background Rare diseases are chronic and life-threatening disorders affecting

Published
2021
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16. Territorio, interessi in contesa e modifiche agli articoli 9 e 41 Cost.

Author

Antonio Mitrotti

Subjects
territory - balancing - interests - environment - authorizing powers - constitutional changes., Law, Social Sciences
Abstract

Riassunto Da tempi ancestrali lo spazio territoriale è un campo di contesa tra interessi umani contrastanti e non soltanto tra differenti clan o tribù dell’uomo e, in un secondo momento, tra diversi soggetti statali della Comunità internazionale, ma persino all’interno dei condivisi confini di uno stesso Stato: tanto che ci si è qui interrogati sulle essenziali cause "giuridiche" di questo atavico fenomeno, sforzandosi specialmente di cogliere qualche "piccola" sfida vinta dal costituzionalismo moderno. A tal proposito possono proprio essere lette le recenti modifiche agli articoli 9 e 41 del testo costituzionale della Repubblica italiana, che in relazione al territorio, alla sua endemica storia conflittuale, sembrerebbero foriere di potenziali novità anche circa il regime del così detto "permitting" ambientale.

Published
2022
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17. Autoantibodies Targeting Nephrin in Podocytopathies

Author

Hengel, Felicitas E., primary, Dehde, Silke, additional, Lassé, Morit, additional, Zahner, Gunther, additional, Seifert, Larissa, additional, Schnarre, Annabel, additional, Kretz, Oliver, additional, Demir, Fatih, additional, Pinnschmidt, Hans O., additional, Grahammer, Florian, additional, Lucas, Renke, additional, Mehner, Lea Maxima, additional, Zimmermann, Tom, additional, Billing, Anja M., additional, Oh, Jun, additional, Mitrotti, Adele, additional, Pontrelli, Paola, additional, Debiec, Hanna, additional, Dossier, Claire, additional, Colucci, Manuela, additional, Emma, Francesco, additional, Smoyer, William E., additional, Weins, Astrid, additional, Schaefer, Franz, additional, Alachkar, Nada, additional, Diemert, Anke, additional, Hogan, Julien, additional, Hoxha, Elion, additional, Wiech, Thorsten, additional, Rinschen, Markus M., additional, Ronco, Pierre, additional, Vivarelli, Marina, additional, Gesualdo, Loreto, additional, Tomas, Nicola M., additional, and Huber, Tobias B., additional

Published
2024
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18. Interaction between sex and GBA mutations influences clinical phenotype in Parkinson disease

Author

Gallo, L., primary, Avenali, M., additional, Caminiti, S., additional, Mitrotti, P., additional, Pocora, M., additional, Cuconato, G., additional, Palmieri, I., additional, Pasquini, C., additional, Galandra, C., additional, Calabrese, R., additional, Zangaglia, R., additional, Tassorelli, C., additional, Schapira, A.V.H., additional, Valente, E.M., additional, and Blandini, F., additional

Published
2024
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19. Determination of Ambroxol Levels in Plasma and Cerebrospinal Fluid by Online Solid-Phase Extraction Coupled with Liquid Chromatography-Tandem Mass Spectrometry in GBA-Parkinson Disease Patients

Author

Franco, V., primary, Palmisani, M., additional, Colucci, F., additional, De Micco, R., additional, Aloisio, S., additional, Cazzaniga, F., additional, Cerri, S., additional, Cuconato, G., additional, Devigili, G., additional, Franciotta, D., additional, Eleopra, R., additional, Elia, A., additional, Garavaglia, B., additional, Andreasi, N. Golfrè, additional, Invernizzi, F., additional, Leta, V., additional, Moda, F., additional, Mitrotti, P., additional, Picascia, M., additional, Reale, C., additional, Romito, L., additional, Siciliano, M., additional, Stiuso, R., additional, Tessitore, A., additional, Valente, E.M., additional, Avenali, M., additional, and Cilia, R., additional

Published
2024
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21. What Is Hidden in Patients with Unknown Nephropathy? Genetic Screening Could Be the Missing Link in Kidney Transplantation Diagnosis and Management

Author

Mitrotti, Adele, primary, Di Bari, Ighli, additional, Giliberti, Marica, additional, Franzin, Rossana, additional, Conserva, Francesca, additional, Chiusolo, Anna, additional, Gigante, Maddalena, additional, Accetturo, Matteo, additional, Cafiero, Cesira, additional, Ricciato, Luisa, additional, Stea, Emma Diletta, additional, Forleo, Cinzia, additional, Gallone, Anna, additional, Rossini, Michele, additional, Fiorentino, Marco, additional, Castellano, Giuseppe, additional, Pontrelli, Paola, additional, and Gesualdo, Loreto, additional

Published
2024
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22. Ambroxol as a disease-modifying treatment to reduce the risk of cognitive impairment inGBA-associated Parkinson’s disease: a multicentre, randomised, double-blind, placebo-controlled, phase II trial. The AMBITIOUS study protocol

Author

Colucci, Fabiana, primary, Avenali, Micol, additional, De Micco, Rosita, additional, Fusar Poli, Marco, additional, Cerri, Silvia, additional, Stanziano, Mario, additional, Bacila, Ana, additional, Cuconato, Giada, additional, Franco, Valentina, additional, Franciotta, Diego, additional, Ghezzi, Cristina, additional, Gastaldi, Matteo, additional, Elia, Antonio Emanuele, additional, Romito, Luigi, additional, Devigili, Grazia, additional, Leta, Valentina, additional, Garavaglia, Barbara, additional, Golfrè Andreasi, Nico, additional, Cazzaniga, Federico, additional, Reale, Chiara, additional, Galandra, Caterina, additional, Germani, Giancarlo, additional, Mitrotti, Pierfrancesco, additional, Ongari, Gerardo, additional, Palmieri, Ilaria, additional, Picascia, Marta, additional, Pichiecchio, Anna, additional, Verri, Mattia, additional, Esposito, Fabrizio, additional, Cirillo, Mario, additional, Di Nardo, Federica, additional, Aloisio, Simone, additional, Siciliano, Mattia, additional, Prioni, Sara, additional, Amami, Paolo, additional, Piacentini, Sylvie, additional, Bruzzone, Maria Grazia, additional, Grisoli, Marina, additional, Moda, Fabio, additional, Eleopra, Roberto, additional, Tessitore, Alessandro, additional, Valente, Enza Maria, additional, and Cilia, Roberto, additional

Published
2023
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24. Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations

Author

Sanna-Cherchi, Simone, Khan, Kamal, Westland, Rik, Krithivasan, Priya, Fievet, Lorraine, Rasouly, Hila Milo, Ionita-Laza, Iuliana, Capone, Valentina P., Fasel, David A., Kiryluk, Krzysztof, Kamalakaran, Sitharthan, Bodria, Monica, Otto, Edgar A., Sampson, Matthew G., Gillies, Christopher E., Vega-Warner, Virginia, Vukojevic, Katarina, Pediaditakis, Igor, Makar, Gabriel S., Mitrotti, Adele, Verbitsky, Miguel, Martino, Jeremiah, Liu, Qingxue, Na, Young-Ji, Goj, Vinicio, Ardissino, Gianluigi, Gigante, Maddalena, Gesualdo, Loreto, Janezcko, Magdalena, Zaniew, Marcin, Mendelsohn, Cathy Lee, Shril, Shirlee, Hildebrandt, Friedhelm, van Wijk, Joanna A.E., Arapovic, Adela, Saraga, Marijan, Allegri, Landino, Izzi, Claudia, Scolari, Francesco, Tasic, Velibor, Ghiggeri, Gian Marco, Latos-Bielenska, Anna, Materna-Kiryluk, Anna, Mane, Shrikant, Goldstein, David B., Lifton, Richard P., Katsanis, Nicholas, Davis, Erica E., and Gharavi, Ali G.

Published
2017
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25. Strong protective effect of theAPOL1p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease

Author

Gupta, Yask, primary, Friedman, David J., additional, McNulty, Michelle, additional, Khan, Atlas, additional, Lane, Brandon, additional, Wang, Chen, additional, Ke, Juntao, additional, Jin, Gina, additional, Wooden, Benjamin, additional, Knob, Andrea L., additional, Lim, Tze Y., additional, Appel, Gerald B., additional, Huggins, Kinsie, additional, Liu, Lili, additional, Mitrotti, Adele, additional, Stangl, Megan C., additional, Bomback, Andrew, additional, Westland, Rik, additional, Bodria, Monica, additional, Marasa, Maddalena, additional, Shang, Ning, additional, Cohen, David J., additional, Crew, Russell J., additional, Morello, William, additional, Canetta, Pietro, additional, Radhakrishnan, Jai, additional, Martino, Jeremiah, additional, Liu, Qingxue, additional, Chung, Wendy K., additional, Espinoza, Angelica, additional, Luo, Yuan, additional, Wei, Wei-Qi, additional, Feng, Qiping, additional, Weng, Chunhua, additional, Fang, Yilu, additional, Kullo, Iftikhar J., additional, Naderian, Mohammadreza, additional, Limdi, Nita, additional, Irvin, Marguerite R., additional, Tiwari, Hemant, additional, Mohan, Sumit, additional, Rao, Maya, additional, Dube, Geoffrey, additional, Chaudhary, Ninad S., additional, Gutiérrez, Orlando M., additional, Judd, Suzanne E., additional, Cushman, Mary, additional, Lange, Leslie A., additional, Lange, Ethan M., additional, Bivona, Daniel L., additional, Verbitsky, Miguel, additional, Winkler, Cheryl A., additional, Kopp, Jeffrey B., additional, Santoriello, Dominick, additional, Batal, Ibrahim, additional, Brant Pinheiro, Sérgio Veloso, additional, Araújo Oliveira, Eduardo, additional, e Silva, Ana Cristina Simoes, additional, Pisani, Isabella, additional, Fiaccadori, Enrico, additional, Lin, Fangming, additional, Gesualdo, Loreto, additional, Amoroso, Antonio, additional, Ghiggeri, Gian Marco, additional, D’Agati, Vivette D., additional, Magistroni, Riccardo, additional, Kenny, Eimear E., additional, Loos, Ruth J.F., additional, Montini, Giovanni, additional, Hildebrandt, Friedhelm, additional, Paul, Dirk S., additional, Petrovski, Slavé, additional, Goldstein, David B., additional, Kretzler, Matthias, additional, Gbadegesin, Rasheed, additional, Gharavi, Ali G., additional, Kiryluk, Krzysztof, additional, Sampson, Matthew G., additional, Pollak, Martin R., additional, and Sanna-Cherchi, Simone, additional

Published
2023
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27. The frequency of rare and monogenic diseases in pediatric organ transplant recipients in Italy

Author

Vaisitti T., Peritore D., Magistroni P., Ricci A., Lombardini L., Gringeri E., Catalano S., Spada M., Sciveres M., Di Giorgio A., Limongelli G., Varrenti M., Gerosa G., Terzi A., Napoleone C. P., Amodeo A., Ragni L., Strologo L., Benetti E., Fontana I., Testa S., Peruzzi L., Mitrotti A., Abbate S., Comai G., Gotti E., Schiavon M., Boffini M., De Angelis D., Bertani A., Pinelli D., Torre M., Poggi C., Deaglio S., Cardillo M., Amoroso A., Serena A., Giorgia C., Vaisitti, T., Peritore, D., Magistroni, P., Ricci, A., Lombardini, L., Gringeri, E., Catalano, S., Spada, M., Sciveres, M., Di Giorgio, A., Limongelli, G., Varrenti, M., Gerosa, G., Terzi, A., Napoleone, C. P., Amodeo, A., Ragni, L., Strologo, L., Benetti, E., Fontana, I., Testa, S., Peruzzi, L., Mitrotti, A., Abbate, S., Comai, G., Gotti, E., Schiavon, M., Boffini, M., De Angelis, D., Bertani, A., Pinelli, D., Torre, M., Poggi, C., Deaglio, S., Cardillo, M., Amoroso, A., Serena, A., and Giorgia, C.

Subjects
Registrie, Pediatrics, medicine.medical_specialty, Transplant outcome, Transplant Recipient, Monogenic diseases, Organ transplantation, Rare diseases, Child, Humans, Italy, Quality of Life, Registries, Transplant Recipients, Kidney Transplantation, Organ Transplantation, Disease, Quality of life, medicine, Pharmacology (medical), Monogenic disease, Genetics (clinical), Lung, business.industry, Research, Liver and kidney, General Medicine, Transplantation, medicine.anatomical_structure, Cohort, Medicine, business, Rare disease, Human
Abstract

Background Rare diseases are chronic and life-threatening disorders affecting Results To the purpose of our analysis, we considered heart, lung, liver and kidney transplants included in the Transplant Registry (TR) of the Italian National Transplantation Center in the 2002–2019 timeframe. Overall, 49,404 recipients were enrolled in the cohort, 5.1% of whom in the pediatric age. For 40,909 (82.8%) transplant recipients, a disease diagnosis was available, of which 38,615 in the adult cohort, while 8,495 patients (17.2%) were undiagnosed. There were 128 disease categories, and of these, 117 were listed in the main rare disease databases. In the pediatric cohort, 2,294 (5.6%) patients had a disease diagnosis: of the 2,126 (92.7%) patients affected by a rare disease, 1,402 (61.1%) presented with a monogenic condition. As expected, the frequencies of pathologies leading to organ failure were different between the pediatric and the adult cohort. Moreover, the pediatric group was characterized, compared to the adult one, by an overall better survival of the graft at ten years after transplant, with the only exception of lung transplants. When comparing survival considering rare vs non-rare diseases or rare and monogenic vs rare non-monogenic conditions, no differences were highlighted for kidney and lung transplants, while rare diseases had a better survival in liver as opposed to heart transplants. Conclusions This work represents the first national survey analyzing the main genetic causes and frequencies of rare and/or monogenic diseases leading to organ failure and requiring transplantation both in adults and children.

Published
2021

28. The Via Francigena Salentina as an Opportunity for Experiential Tourism and a Territorial Enhancement Tool

Author

Anna Trono, Francesca Ruppi, Fabio Mitrotti, and Stefano Cortese

Subjects
Via Francigena Salentina, Pilgrim Routes, Responsible Tourim, Territorial Development, Recreation. Leisure, GV1-1860, Economic history and conditions, HC10-1085
Abstract

The essay presents the results of a 10-year archival and on-field study, carried out by a research group (bringing together archaeologists, geographers, medieval historians and art historians) of the Department of Cultural Heritage of the Salento University, who have rebuilt the Via Francigena Salentina following ancient pilgrim routes heading to the Holy Land. The researchers have mapped and catalogued natural and cultural highlights along the route, also analysing tourism services on a local scale and the environmental impact of human activities. After presenting a short assessment of the adequacy of cultural routes in meeting the new requirements imposed by the tourism demand the research analyses the Via Francigena Salentina’s main features, also taking into account goods and services provided by the territory and the capability of local professionals and administrators to drive and boost effective relationships among stakeholders, also activating enhancement processes and organic and unitary promotional initiatives and always respecting both visitors’ needs and the environment.

Published
2017
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29. Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome.

Author

Barry, A., McNulty, M.T., Jia, X., Gupta, Y., Debiec, H., Luo, Y, Nagano, C., Horinouchi, T., Jung, S., Colucci, M., Ahram, D.F., Mitrotti, A., Sinha, A., Teeninga, N., Jin, G., Shril, S., Caridi, G., Bodria, M., Lim, T.Y., Westland, R., Zanoni, F., Marasa, M., Turudic, D., Giordano, M., Gesualdo, L., Magistroni, R., Pisani, I., Fiaccadori, E., Reiterova, J., Maringhini, S., Morello, W., Montini, G., Weng, P.L., Scolari, F., Saraga, M., Tasic, V., Santoro, D., Wijk, J.A. van, Milošević, D., Kawai, Y., Kiryluk, K., Pollak, M.R., Gharavi, A., Lin, F., Simœs E Silva, A.C., Loos, R.J., Kenny, E.E., Schreuder, M.F., Zurowska, A., Dossier, C., Ariceta, G., Drozynska-Duklas, M., Hogan, J., Jankauskiene, A., Hildebrandt, F., Prikhodina, L., Song, K., Bagga, A., Cheong H, 2.n.d., Ghiggeri, G.M., Vachvanichsanong, P., Nozu, K., Lee, D., Vivarelli, M., Raychaudhuri, S., Tokunaga, K., Sanna-Cherchi, S., Ronco, P., Iijima, K., Sampson, M.G., Barry, A., McNulty, M.T., Jia, X., Gupta, Y., Debiec, H., Luo, Y, Nagano, C., Horinouchi, T., Jung, S., Colucci, M., Ahram, D.F., Mitrotti, A., Sinha, A., Teeninga, N., Jin, G., Shril, S., Caridi, G., Bodria, M., Lim, T.Y., Westland, R., Zanoni, F., Marasa, M., Turudic, D., Giordano, M., Gesualdo, L., Magistroni, R., Pisani, I., Fiaccadori, E., Reiterova, J., Maringhini, S., Morello, W., Montini, G., Weng, P.L., Scolari, F., Saraga, M., Tasic, V., Santoro, D., Wijk, J.A. van, Milošević, D., Kawai, Y., Kiryluk, K., Pollak, M.R., Gharavi, A., Lin, F., Simœs E Silva, A.C., Loos, R.J., Kenny, E.E., Schreuder, M.F., Zurowska, A., Dossier, C., Ariceta, G., Drozynska-Duklas, M., Hogan, J., Jankauskiene, A., Hildebrandt, F., Prikhodina, L., Song, K., Bagga, A., Cheong H, 2.n.d., Ghiggeri, G.M., Vachvanichsanong, P., Nozu, K., Lee, D., Vivarelli, M., Raychaudhuri, S., Tokunaga, K., Sanna-Cherchi, S., Ronco, P., Iijima, K., and Sampson, M.G.

Abstract

Item does not contain fulltext, Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.

Published
2023

30. Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease

Author

Gupta, Yask, Friedman, David J., McNulty, Michelle T., Khan, Atlas, Lane, Brandon, Wang, Chen, Ke, Juntao, Jin, Gina, Wooden, Benjamin, Knob, Andrea L., Lim, Tze Y., Appel, Gerald B., Huggins, Kinsie, Liu, Lili, Mitrotti, Adele, Stangl, Megan C., Bomback, Andrew, Westland, Rik, Bodria, Monica, Marasa, Maddalena, Shang, Ning, Cohen, David J., Crew, Russell J., Morello, William, Canetta, Pietro, Radhakrishnan, Jai, Martino, Jeremiah, Liu, Qingxue, Chung, Wendy K., Espinoza, Angelica, Luo, Yuan, Wei, Wei-Qi, Feng, Qiping, Weng, Chunhua, Fang, Yilu, Kullo, Iftikhar J., Naderian, Mohammadreza, Limdi, Nita, Irvin, Marguerite R., Tiwari, Hemant, Mohan, Sumit, Rao, Maya, Dube, Geoffrey K., Chaudhary, Ninad S., Gutiérrez, Orlando M., Judd, Suzanne E., Cushman, Mary, Lange, Leslie A., Lange, Ethan M., Bivona, Daniel L., Verbitsky, Miguel, Winkler, Cheryl A., Kopp, Jeffrey B., Santoriello, Dominick, Batal, Ibrahim, Pinheiro, Sérgio Veloso Brant, Oliveira, Eduardo Araújo, Simoes e Silva, Ana Cristina, Pisani, Isabella, Fiaccadori, Enrico, Lin, Fangming, Gesualdo, Loreto, Amoroso, Antonio, Ghiggeri, Gian Marco, D’Agati, Vivette D., Magistroni, Riccardo, Kenny, Eimear E., Loos, Ruth J.F., Montini, Giovanni, Hildebrandt, Friedhelm, Paul, Dirk S., Petrovski, Slavé, Goldstein, David B., Kretzler, Matthias, Gbadegesin, Rasheed, Gharavi, Ali G., Kiryluk, Krzysztof, Sampson, Matthew G., Pollak, Martin R., Sanna-Cherchi, Simone, Gupta, Yask, Friedman, David J., McNulty, Michelle T., Khan, Atlas, Lane, Brandon, Wang, Chen, Ke, Juntao, Jin, Gina, Wooden, Benjamin, Knob, Andrea L., Lim, Tze Y., Appel, Gerald B., Huggins, Kinsie, Liu, Lili, Mitrotti, Adele, Stangl, Megan C., Bomback, Andrew, Westland, Rik, Bodria, Monica, Marasa, Maddalena, Shang, Ning, Cohen, David J., Crew, Russell J., Morello, William, Canetta, Pietro, Radhakrishnan, Jai, Martino, Jeremiah, Liu, Qingxue, Chung, Wendy K., Espinoza, Angelica, Luo, Yuan, Wei, Wei-Qi, Feng, Qiping, Weng, Chunhua, Fang, Yilu, Kullo, Iftikhar J., Naderian, Mohammadreza, Limdi, Nita, Irvin, Marguerite R., Tiwari, Hemant, Mohan, Sumit, Rao, Maya, Dube, Geoffrey K., Chaudhary, Ninad S., Gutiérrez, Orlando M., Judd, Suzanne E., Cushman, Mary, Lange, Leslie A., Lange, Ethan M., Bivona, Daniel L., Verbitsky, Miguel, Winkler, Cheryl A., Kopp, Jeffrey B., Santoriello, Dominick, Batal, Ibrahim, Pinheiro, Sérgio Veloso Brant, Oliveira, Eduardo Araújo, Simoes e Silva, Ana Cristina, Pisani, Isabella, Fiaccadori, Enrico, Lin, Fangming, Gesualdo, Loreto, Amoroso, Antonio, Ghiggeri, Gian Marco, D’Agati, Vivette D., Magistroni, Riccardo, Kenny, Eimear E., Loos, Ruth J.F., Montini, Giovanni, Hildebrandt, Friedhelm, Paul, Dirk S., Petrovski, Slavé, Goldstein, David B., Kretzler, Matthias, Gbadegesin, Rasheed, Gharavi, Ali G., Kiryluk, Krzysztof, Sampson, Matthew G., Pollak, Martin R., and Sanna-Cherchi, Simone

Abstract

African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.

Published
2023

31. Effect of music therapy intervention on anxiety and pain during percutaneous renal biopsy: a randomized controlled trial.

Author

Giordano, Filippo, Mitrotti, Adele, Losurdo, Antonia, Esposito, Flavia, Granata, Antonio, Pesino, Alessandra, Rossini, Michele, Natale, Patrizia, Dileo, Vincenzo, Fiorentino, Marco, and Gesualdo, Loreto

Subjects
*MUSIC therapy, *RENAL biopsy, *RANDOMIZED controlled trials, *PAIN management, *HEART beat
Abstract

Background Percutaneous renal biopsy (PRB) may subject patients to emotional distress and pain before and during the biopsy. The aim of this study was to evaluate the effects of complementary/non-pharmacological interventions such as music therapy (MT) on anxiety, pain and satisfaction in renal patients undergoing PRB. Methods A prospective, single-centre, single-blind, randomized controlled two-arm trial was conducted. Patients ≥18 years of age, hospitalized at the Nephrology, Dialysis and Transplantation Unit (Bari, Italy) and scheduled for PRB were screened. Participants were assigned to standard treatment (CG) or to the music therapy (MT) intervention group. Participants in the MT group received standard care and an MT intervention by a certified music therapist qualified in guided imagery and music. The CG patients received the standard of care. MT and CG patients were subjected to identical measurements (pre/post) of the parameters in the State Trait Anxiety Inventory Y1 (STAI-Y1), visual analogue scale for pain (VAS-P) and satisfaction (VAS-S) and heart rate variability. Results A statistically significant difference in the anxiety scores after PRB between MT and CG patients (STAI-Y1 35.4 ± 6.2 versus 42.9 ± 9.0) was observed. MT also had strong and significant effects on VAS-P compared with CG (5.0 ± 1.4 versus 6.3 ± 1.3, respectively; P  < .001) and VAS-S (7.8 ± 1.0 versus 6.0 ± 0.9, respectively; P  < .001). Decreased activity of the sympathetic nervous system and increased activity of the parasympathetic nervous system was observed after PRB in the MT group. Conclusion Our study supports the use of MT to mitigate the psychological anxiety, pain and sympathetic activation associated with PRB. [ABSTRACT FROM AUTHOR]

Published
2023
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32. Convalescent plasma therapy in aHUS patient with SARS-CoV-2 infection

Author

Stea Emma Diletta, Pronzo Virginia, Pesce Francesco, Fiorentino Marco, Mitrotti Adele, Di Leo Vincenzo, Cortese Cosma, Casanova Annalisa, Nestola Sebastiano, Capaccio Flavia, and Gesualdo Loreto

Abstract

Endotheliosis, thrombotic microangiopathy and complement system over activation have been described as pathologic features of tissue damage in the setting of coronavirus disease. Interestingly, complement-mediated cell injury is also a typical feature of atypical Hemolytic Uremic Syndrome. Indeed, a growing body of literature has described a higher risk of microangiopathy recurrence, in aHUS patients who test positive for SARS-CoV-2. The correct clinical and therapeutic management patients with a history of HUS and SARS-CoV-2 infection is not well established. We report a case of SARS-CoV-2 infection in an aHUS patient who did not develop a recurrence of the disease and that was successfully treated with convalescent immune plasma therapy.

Published
2022
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36. Are patients with GBA–Parkinson disease good candidates for deep brain stimulation? A longitudinal multicentric study on a large Italian cohort

Author

Avenali, Micol, Zangaglia, Roberta, Cuconato, Giada, Palmieri, Ilaria, Albanese, Alberto, Artusi, Carlo Alberto, Bozzali, Marco, Calandra-Buonaura, Giovanna, Cavallieri, Francesco, Cilia, Roberto, Cocco, Antoniangela, Cogiamanian, Filippo, Colucci, Fabiana, Cortelli, Pietro, Di Fonzo, Alessio, Eleopra, Roberto, Giannini, Giulia, Imarisio, Alberto, Imbalzano, Gabriele, Ledda, Claudia, Lopiano, Leonardo, Malaguti, Maria Chiara, Mameli, Francesca, Minardi, Raffaella, Mitrotti, Pierfrancesco, Monfrini, Edoardo, Spagnolo, Francesca, Tassorelli, Cristina, Valentino, Francesca, Valzania, Franco, Pacchetti, Claudio, and Valente, Enza Maria

Abstract

BackgroundGBAvariants increase the risk of developing Parkinson disease (PD) and influence its outcome. Deep brain stimulation (DBS) is a recognised therapeutic option for advanced PD. Data on DBS long-term outcome in GBAcarriers are scarce.ObjectiveTo elucidate the impact of GBAvariants on long-term DBS outcome in a large Italian cohort.MethodsWe retrospectively recruited a multicentric Italian DBS-PD cohort and assessed: (1) GBAprevalence; (2) pre-DBS clinical features; and (3) outcomes of motor, cognitive and other non-motor features up to 5 years post-DBS.ResultsWe included 365 patients with PD, of whom 73 (20%) carried GBAvariants. 5-year follow-up data were available for 173 PD, including 32 mutated subjects. GBA-PD had an earlier onset and were younger at DBS than non-GBA-PD. They also had shorter disease duration, higher occurrence of dyskinesias and orthostatic hypotension symptoms.At post-DBS, both groups showed marked motor improvement, a significant reduction of fluctuations, dyskinesias and impulsive-compulsive disorders (ICD) and low occurrence of most complications. Only cognitive scores worsened significantly faster in GBA-PD after 3 years. Overt dementia was diagnosed in 11% non-GBA-PD and 25% GBA-PD at 5-year follow-up.ConclusionsEvaluation of long-term impact of GBAvariants in a large Italian DBS-PD cohort supported the role of DBS surgery as a valid therapeutic strategy in GBA-PD, with long-term benefit on motor performance and ICD. Despite the selective worsening of cognitive scores since 3 years post-DBS, the majority of GBA-PD had not developed dementia at 5-year follow-up.

Published
2024
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37. Multi-population genome-wide association study implicates both immune and non-immune factors in the etiology of pediatric steroid sensitive nephrotic syndrome

Author

Alexandra Barry, Michelle T. McNulty, Xiaoyuan Jia, Yask Gupta, Hanna Debiec, Yang Luo, China Nagano, Tomoko Horinouchi, Seulgi Jung, Manuela Colucci, Dina F. Ahram, Adele Mitrotti, Aditi Sinha, Nynke Teeninga, Gina Jin, Shirlee Shril, Gianluca Caridi, Monica Bodria, Tze Y Lim, Rik Westland, Francesca Zanoni, Maddalena Marasa, Daniel Turudic, Mario Giordano, Loreto Gesualdo, Riccardo Magistroni, Isabella Pisani, Enrico Fiaccadori, Jana Reiterova, Silvio Maringhini, William Morello, Giovanni Montini, Patricia L. Weng, Francesco Scolari, Marijan Saraga, Velibor Tasic, Domenica Santoro, Joanna A.E. van Wijk, Danko Milošević, Yosuke Kawai, Krzysztof Kiryluk, Martin R. Pollak, Ali Gharavi, Fangmin Lin, Ana Cristina Simœs e Silva, Ruth J.F. Loos, Eimear E. Kenny, Michiel F. Schreuder, Aleksandra Zurowska, Claire Dossier, Gema Ariceta, Magdalena Drozynska-Duklas, Julien Hogan, Augustina Jankauskiene, Friedhelm Hildebrandt, Larisa Prikhodina, Kyuyoung Song, Arvind Bagga, Hae Il Cheong, Gian Marco Ghiggeri, Prayong Vachvanichsanong, Kandai Nozu, Marina Vivarelli, Soumya Raychaudhuri, Katsushi Tokunaga, Simone Sanna-Cherchi, Pierre Ronco, Kazumoto Iijima, and Matthew G. Sampson

Abstract

Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional signals. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. We conducted a multi-population GWAS meta-analysis in 38,463 participants (2,440 cases) and population specific GWAS, discovering twelve significant associations (eight novel). Fine-mapping implicated specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk signal. Non-HLA loci colocalized with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs was lacking, but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associated with earlier disease onset in two independent cohorts. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cellspecific insights into its molecular drivers.

Published
2022
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38. CHIOSE SULLA RATIO DEL DUP DI UN ENTE LOCALE E SPUNTI DI SNODO CON L'AUTONOMIA COMUNALE FALCIDIATA DALLE VARIANTI EX LEGE AGLI STRUMENTI URBANISTICI

Author

MITROTTI ANTONIO and Mitrotti, Antonio

Subjects
DUP - PROGRAMMAZIONE - AUTONOMIA COMUNALE - VARIANTI URBANISTICHE - GOVERNO DEL TERRITORIO
Abstract

Che cos’è il DUP di un ente locale? Non è affatto semplice (in tutta onestà) cogliere l’intima natura giuridica di un istituto dispiegatosi lungo l’ambiguo crinale tra politica e diritto, sviluppatosi a cavallo delle (sensibili) esigenze tra diritto ed economia e, concretamente, maturato nell’alveo di una costante dialettica (creatrice) tra il diritto positivo ed il diritto vivente. Ebbene, il “Documento Unico di Programmazione” che è anche noto - ai più - con l’acronimo di DUP viene a manifestarsi proprio come un istituto di questo tipo. Perciò, con queste pagine ci si offre di approfondire alcuni ragionamenti di analisi e di “inquadramento” giuridico del DUP. Anche perché lo scopo (più) “pragmatico” è quello di calare la (ricercata) natura del DUP all’interno del materiale contesto di funzionamento dell’autonomia comunale: rapportandolo in particolare con una fondamentale funzione degli enti comunali, qual è la - nevralgica - pianificazione territoriale di un Comune. Ciò viene ad assumere un pregnante rilievo sistematico, specialmente, alla luce delle recenti - e peculiari - fattispecie legislative produttrici di automatiche forme provvedimentali di varianti agli strumenti urbanistici comunali. Analisi senz’altro utile - se non preziosa - per farsi un’idea sullo stato di salute effettiva dell’autonomia dell’ente “Comune”. Cosa non scontata in un cronico periodo di convulse misure emergenziali a contrasto dello scoppio del Virus da Covid-19.

Published
2022

39. Annotazioni su origini ed evoluzioni del Permitting Ambientale

Author

Mitrotti, Antonio and Mitrotti, Antonio

Subjects
Permitting ambientale – Ambiente – Governo del territorio – Sviluppo sostenibile
Abstract

Da tempo è invalso un uso stereotipato negli studi della dottrina, come pure nelle decisioni della giurisprudenza italiana, dei termini di “permitting ambientale”. Ma che cosa è esattamente il permitting ambientale? Quali sono le concrete origini istituzionali e giuridiche di queste parole? Per il vero, tanto usate (se non abusate) nel diritto pubblico italiano. E qual è l’attuale evoluzione del permitting ambientale nell'alveo dell’ordinamento in cui è nato? Il presente contributo intende, in tale prospettiva, offrire alcune essenziali annotazioni analitiche sulle origini del noto permitting ambientale, congiuntamente ad una sintesi del suo effettivo percorso evolutivo, nonché del suo contemporaneo assetto amministrativo sorto nell’ordinamento britannico.

Published
2022

40. Con le lenti del giurista. Sintetiche annotazioni sull'esistenza degli accantonamenti nel bilancio di previsione degli enti locali

Author

Antonio Mitrotti and Mitrotti, Antonio

Subjects
bilancio - prudenza - sana amministrazione - autonomia finanziaria - equilibri di bilancio
Abstract

Cosa sono gli accantonamenti nel bilancio di previsione degli esercizi di un ente locale? La domanda, come pure la sua coerente risposta, incontrerebbe un forte disorientamento tra i giuristi, poco avvezzi alle materie contabili. Eppure l'esistenza degli accantonamenti nei bilanci di previsione rinviene la propria ratio in principi giuridici essenziali per l'azione di qualsiasi Amministrazione Pubblica: come è spontaneamente palpabile (per mano di qualsiasi giurista) se dall'inevitabile tecnicismo contabile delle disposizioni disciplinanti gli accantonamenti si scendesse a comprenderne gli effetti nonché (soprattutto) le pertinenti finalità, teleologicamente, sottese alla costituzione dei "fondi" di un ente locale.

Published
2022

42. Territorio, interessi in contesa e modifiche agli articoli 9 e 41 Cost. Prime riflessioni sul 'permitting' ambientale

Author

Mitrotti and Mitrotti, Antonio

Subjects
territorio - bilanciamento - interessi - ambiente - poteri autorizzatori - modifiche costituzionali
Abstract

Da tempi ancestrali lo spazio territoriale è un campo di contesa tra interessi umani contrastanti e non soltanto tra differenti clan o tribù dell’uomo e, in un secondo momento, tra diversi soggetti statali della Comunità internazionale, ma persino all’interno dei condivisi confini di uno stesso Stato: tanto che ci si è qui interrogati sulle essenziali cause "giuridiche" di questo atavico fenomeno, sforzandosi specialmente di cogliere qualche "piccola" sfida vinta dal costituzionalismo moderno. A tal proposito possono proprio essere lette le recenti modifiche agli articoli 9 e 41 del testo costituzionale della Repubblica italiana, che in relazione al territorio, alla sua endemica storia conflittuale, sembrerebbero foriere di potenziali novità anche circa il regime del così detto "permitting" ambientale.

Published
2022

43. Multi-population genome-wide association study implicates both immune and non-immune factors in the etiology of pediatric steroid sensitive nephrotic syndrome

Author

Barry, Alexandra, primary, McNulty, Michelle T., additional, Jia, Xiaoyuan, additional, Gupta, Yask, additional, Debiec, Hanna, additional, Luo, Yang, additional, Nagano, China, additional, Horinouchi, Tomoko, additional, Jung, Seulgi, additional, Colucci, Manuela, additional, Ahram, Dina F., additional, Mitrotti, Adele, additional, Sinha, Aditi, additional, Teeninga, Nynke, additional, Jin, Gina, additional, Shril, Shirlee, additional, Caridi, Gianluca, additional, Bodria, Monica, additional, Lim, Tze Y, additional, Westland, Rik, additional, Zanoni, Francesca, additional, Marasa, Maddalena, additional, Turudic, Daniel, additional, Giordano, Mario, additional, Gesualdo, Loreto, additional, Magistroni, Riccardo, additional, Pisani, Isabella, additional, Fiaccadori, Enrico, additional, Reiterova, Jana, additional, Maringhini, Silvio, additional, Morello, William, additional, Montini, Giovanni, additional, Weng, Patricia L., additional, Scolari, Francesco, additional, Saraga, Marijan, additional, Tasic, Velibor, additional, Santoro, Domenica, additional, van Wijk, Joanna A.E., additional, Milošević, Danko, additional, Kawai, Yosuke, additional, Kiryluk, Krzysztof, additional, Pollak, Martin R., additional, Gharavi, Ali, additional, Lin, Fangmin, additional, Simœs e Silva, Ana Cristina, additional, Loos, Ruth J.F., additional, Kenny, Eimear E., additional, Schreuder, Michiel F., additional, Zurowska, Aleksandra, additional, Dossier, Claire, additional, Ariceta, Gema, additional, Drozynska-Duklas, Magdalena, additional, Hogan, Julien, additional, Jankauskiene, Augustina, additional, Hildebrandt, Friedhelm, additional, Prikhodina, Larisa, additional, Song, Kyuyoung, additional, Bagga, Arvind, additional, Cheong, Hae Il, additional, Ghiggeri, Gian Marco, additional, Vachvanichsanong, Prayong, additional, Nozu, Kandai, additional, Vivarelli, Marina, additional, Raychaudhuri, Soumya, additional, Tokunaga, Katsushi, additional, Sanna-Cherchi, Simone, additional, Ronco, Pierre, additional, Iijima, Kazumoto, additional, and Sampson, Matthew G., additional

Published
2022
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44. Supplement to: Genetic drivers of kidney defects in the DiGeorge syndrome.

Author

Lopez-Rivera, Esther, Liu, Yangfan P., Verbitsky, Miguel, Anderson, Blair R., Capone, Valentina P., Otto, Edgar A., Yan, Zhonghai, Mitrotti, Adele, Martino, Jeremiah, Steers, Nicholas J., Fasel, David A., Vukojevic, Katarina, Deng, Rong, Racedo, Silvia E., Liu, Qingxue, Werth, Max, Westland, Rik, Vivante, Asaf, Makar, Gabriel S., Bodria, Monica, Sampson, Matthew G., Gillies, Christopher E., Vega-Warner, Virginia, Maiorana, Mariarosa, Petrey, Donald S., Honig, Barry, Lozanovski, Vladimir J., Salomon, Rémi, Heidet, Laurence, Carpentier, Wassila, Gaillard, Dominique, Carrea, Alba, Gesualdo, Loreto, Cusi, Daniele, Izzi, Claudia, Scolari, Francesco, van Wijk, Joanna A.E., Arapovic, Adela, Saraga-Babic, Mirna, Saraga, Marijan, Kunac, Nenad, Samii, Ali, McDonald-McGinn, Donna M., Crowley, Terrence B., Zackai, Elaine H., Drosdz, Dorota, Miklaszewska, Monika, Tkaczyk, Marcin, Sikora, Przemyslaw, Szczepanska, Maria, Mizerska-Wasiak, Malgorzata, Krzemien, Grazyna, Szmigielska, Agnieszka, Zaniew, Marcin, Darlow, John M., Puri, Prem, Barton, David, Casolari, Emilio, Furth, Susan L., Warady, Bradley A., Gucev, Zoran, Hakonarson, Hakon, Flogelova, Hana, Tasic, Velibor, Bielenska, Anna Latos, Materna-Kiryluk, Anna, Allegri, Landino, Wong, Craig S., Drummond, Iain A., DʼAgati, Vivette, Imamoto, Akira, Barasch, Jonathan M., Hildebrandt, Friedhelm, Kiryluk, Krzysztof, Lifton, Richard P., Morrow, Bernice E., Jeanpierre, Cecile, Papaioannou, Virginia E., Ghiggeri, Gian Marco, Gharavi, Ali G., Katsanis, Nicholas, and Sanna-Cherchi, Simone

Published
2017

45. Whole-Exome Sequencing in Adults With Chronic Kidney Disease: A Pilot Study

Author

Lata, Sneh, Marasa, Maddalena, Li, Yifu, Fasel, David A., Groopman, Emily, Jobanputra, Vaidehi, Rasouly, Hila, Mitrotti, Adele, Westland, Rik, Verbitsky, Miguel, Nestor, Jordan, Slater, Lindsey M., DʼAgati, Vivette, Zaniew, Marcin, Materna-Kiryluk, Anna, Lugani, Francesca, Caridi, Gianluca, Rampoldi, Luca, Mattoo, Aditya, Newton, Chad A., Rao, Maya K., Radhakrishnan, Jai, Ahn, Wooin, Canetta, Pietro A., Bomback, Andrew S., Appel, Gerald B., Antignac, Corinne, Markowitz, Glen S., Garcia, Christine K., Kiryluk, Krzysztof, Sanna-Cherchi, Simone, and Gharavi, Ali G.

Published
2018
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46. Author Correction: The copy number variation landscape of congenital anomalies of the kidney and urinary tract

Author

Verbitsky, Miguel, Westland, Rik, Perez, Alejandra, Kiryluk, Krzysztof, Liu, Qingxue, Krithivasan, Priya, Mitrotti, Adele, Fasel, David A., Batourina, Ekaterina, Sampson, Matthew G., Bodria, Monica, Werth, Max, Kao, Charlly, Martino, Jeremiah, Capone, Valentina P., Vivante, Asaf, Shril, Shirlee, Kil, Byum Hee, Marasa, Maddalena, Zhang, Jun Y., Na, Young-Ji, Lim, Tze Y., Ahram, Dina, Weng, Patricia L., Heinzen, Erin L., Carrea, Alba, Piaggio, Giorgio, Gesualdo, Loreto, Manca, Valeria, Masnata, Giuseppe, Gigante, Maddalena, Cusi, Daniele, Izzi, Claudia, Scolari, Francesco, van Wijk, Joanna A. E., Saraga, Marijan, Santoro, Domenico, Conti, Giovanni, Zamboli, Pasquale, White, Hope, Drozdz, Dorota, Zachwieja, Katarzyna, Miklaszewska, Monika, Tkaczyk, Marcin, Tomczyk, Daria, Krakowska, Anna, Sikora, Przemyslaw, Jarmoliński, Tomasz, Borszewska-Kornacka, Maria K., Pawluch, Robert, Szczepanska, Maria, Adamczyk, Piotr, Mizerska-Wasiak, Malgorzata, Krzemien, Grazyna, Szmigielska, Agnieszka, Zaniew, Marcin, Dobson, Mark G., Darlow, John M., Puri, Prem, Barton, David E., Furth, Susan L., Warady, Bradley A., Gucev, Zoran, Lozanovski, Vladimir J., Tasic, Velibor, Pisani, Isabella, Allegri, Landino, Rodas, Lida M., Campistol, Josep M., Jeanpierre, Cécile, Alam, Shumyle, Casale, Pasquale, Wong, Craig S., Lin, Fangming, Miranda, Débora M., Oliveira, Eduardo A., Simoes-e-Silva, Ana Cristina, Barasch, Jonathan M., Levy, Brynn, Wu, Nan, Hildebrandt, Friedhelm, Ghiggeri, Gian Marco, Latos-Bielenska, Anna, Materna-Kiryluk, Anna, Zhang, Feng, Hakonarson, Hakon, Papaioannou, Virginia E., Mendelsohn, Cathy L., Gharavi, Ali G., and Sanna-Cherchi, Simone

Published
2019
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47. De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis

Author

Verena Klämbt, Youying Mao, Vimla Aggarwal, Arang Kim, Friedhelm Hildebrandt, Mohamad A. Mikati, Vandana Shashi, Anne H. O’Donnell-Luria, Vaidehi Jobanputra, Jeremiah Martino, Vivette D. D'Agati, Minxian Wang, Marcus R. Benz, Shoji Yano, Janine Altmüller, Ali G. Gharavi, Florian Buerger, Enrico Fiaccadori, Richard P. Lifton, Bodo B. Beck, Amy Kolb, Mordi Muorah, David Goldstein, Nina Mann, Martin R. Pollak, Dina Ahram, Heidi Cope, Gian Marco Ghiggeri, Jillian S. Parboosingh, Asmaa S. AbuMaziad, Kamal Khan, Ana C. Onuchic-Whitford, Louise Bier, Emma Pierce-Hoffman, Jonathan E. Zuckerman, Shrikant Mane, Moin A. Saleem, Amar J. Majmundar, Heidi L. Rehm, Ora Yadin, Erin L. Heinzen, Gina Y. Jin, Christelle Moufawad El Achkar, Konstantin Deutsch, Julia Hoefele, Ania Koziell, Gianluca Caridi, Talha Gunduz, Agnieszka Bierzynska, Korbinian M. Riedhammer, Monica Bodria, Ronen Schneider, Julian A. Martinez-Agosto, Thomas M. Kitzler, Shirlee Shril, Ulrike John-Kroegel, Howard Trachtman, Adele Mitrotti, Eleanor G. Seaby, Amanda V. Tyndall, Isabella Pisani, Patricia L. Weng, Tze Y Lim, A. Micheil Innes, John Musgrove, Simone Sanna-Cherchi, and Erica E. Davis

Subjects
Adult, Male, 0301 basic medicine, Proband, medicine.medical_specialty, Nephrotic Syndrome, Developmental Disabilities, 030232 urology & nephrology, Neurogenetics, Nerve Tissue Proteins, Biology, Kidney, Cell Line, Mice, 03 medical and health sciences, Exon, 0302 clinical medicine, Focal segmental glomerulosclerosis, Report, Exome Sequencing, Genetics, medicine, Animals, Humans, Child, Exome, Genetics (clinical), Exome sequencing, Epilepsy, Glomerulosclerosis, Focal Segmental, Podocytes, medicine.disease, 3. Good health, Phenotype, 030104 developmental biology, Codon, Nonsense, Child, Preschool, Mutation, Medical genetics, Female, Intranuclear Space, Carrier Proteins, Nephrotic syndrome
Abstract

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10(−11)). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10(−15)). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

Published
2021
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49. MO1056: Music Therapy Reduces Anxiety and Pain and Improves Satisfaction in Patients Undergoing Percutaneous Renal Biopsy

Author

Filippo Giordano, Alessandra Pesino, Cosma Cortese, Flavia Esposito, Nicla Campobasso, Nicola Grandolfo, Michele Rossini, Adele Mitrotti, and Loreto Gesualdo

Subjects
Transplantation, Nephrology
Abstract

BACKGROUND AND AIMS Percutaneous kidney biopsy (PRB) is an invasive procedure performed under local anaesthesia that often creates anxiety, stress and pain in the patient before, during and after the procedure. Music therapy (MT), defined as the clinical- and evidence-based use of music, is administered by a trained professional to achieve individualized goals within a therapeutic relationship between patient, music and music therapist. MT can be used as a complementary non-drug intervention to prevent and treat emotional distress and pain. The main objectives of the study were 1. evaluate the effectiveness of MT in managing anxiety, pain and satisfaction in patients undergoing PRB. 2. investigate the effect of MTI on heart rate variability (HRV). METHOD This study was a two-arm, single-centre, parallel-group and pre–post PRB randomized controlled trial. Patients programmed for PRB were enrolled (n = 80) and assigned to the MT intervention group (MG, n = 40) or standard treatment [control group (CG), n = 40]. MG received, from a FAMI-certified music therapist, a personalized playlist administered during the PRB, adapted to the individual patient. Patient anxiety was assessed before and after PRB using the State Y-1 Trait Anxiety Inventory (STAI-Y1). A visual analog scale (VAS) was used for self-assessment of pain (VAS-P) and satisfaction (VAS-S). Physiological stress parameters (PRE–POST) were assessed using HRV (SDNN, RMSSD, LH/HF, SD1, SD2) from E4 wristbands—Empatica Inc.1. The bracelet was placed 5 min before the patient entered the operating room for the procedure and removed after the completion of the PRB. The data of each session were divided into two segments: (1) pre, before the administration of the local anesthetic and (2) post, after the conclusion of the biopsy. RESULTS A statistically significant difference in anxiety levels was observed between the MG and CG groups (35.35 ± 6.208 versus 42.83 ± 9.027; P CONCLUSION This study supports the efficacy of MT in reducing anxiety and pain and improving satisfaction in patients undergoing PRB. MT modulates the autonomic nervous system, reducing sympathetic activity, increasing parasympathetic activity and inducing physiological relaxation.

Published
2022
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