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1. Investigating the genotype-phenotype correlations in paediatric steroid resistant nephrotic syndrome patients

Author

Bierzynska, Agnieszka

Subjects
616.6
Abstract

Steroid Resistant Nephrotic Syndrome (SRNS) is characterised by either primary or late onset resistance to immunosuppression. Prognosis is poor and often results in rapid progression to end stage renal failure (ESRF). Generally, the incidence of disease-causing mutations in paediatric SRNS is 20-30%. 50 genes are currently associated with SRNS and since the advent of next generation sequencing, new genes are being linked each year. This study aimed to discover the true extent and spectrum of genetic variation in a comprehensive national NS population, selected by clinically relevant inclusion criteria. Patients were collected via a comprehensive national UK Renal Registry (RaDaR), which filtered recruits according to actual or presumed steroid resistance, and exclusion of secondary causes. Exome sequencing together with a stringent filtering algorithm was used to screen 187 paediatric SRNS and/or FSGS patients for the 50 genes associated with NS and to look for novel SRNS gene candidates. 25.7% of the sequenced patients had either, a previously described mutation or variant likely to be disease-causing. Detailed analysis revealed both known and novel disease-associated variations in the most common Nephrotic causing genes: NPH51, NPH52 and WTl and other more rarely associated genes such as LMX1B, MY01E, ADCK4 and the recently identified CRB2 and NUP107. Unexpected phenotypes were found in patients with mutations in genes usually associated with a different renal presentation, such as OCRL and DGKE. Genetic SRNS had no recurrence risk post-transplantation, whereas non-genetic SRNS had a 50% risk. Novel SRNS gene candidates e.g. MAGI2, along with potential risk factors were also found. This study demonstrates: 1. A broader genetic heterogeneity causing SRNS than previously realised and 2. A novel clinical and genetic stratification algorithm yielding a high rate of monogenic disease discovery and prognostic utility. Exome sequencing of this paediatric cohort also enabled novel SRNS genes discovery

Published
2016

2. Correction: Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria(European Journal of Human Genetics, (2021), 29, 8, (1186-1197), 10.1038/s41431-021-00858-1)

Author

Genetica Klinische Genetica, Cancer, Child Health, Savige, Judy, Storey, Helen, Watson, Elizabeth, Hertz, Jens Michael, Deltas, Constantinos, Renieri, Alessandra, Mari, Francesca, Hilbert, Pascale, Plevova, Pavlina, Byers, Peter, Cerkauskaite, Agne, Gregory, Martin, Cerkauskiene, Rimante, Ljubanovic, Danica Galesic, Becherucci, Francesca, Errichiello, Carmela, Massella, Laura, Aiello, Valeria, Lennon, Rachel, Hopkinson, Louise, Koziell, Ania, Lungu, Adrian, Rothe, Hansjorg Martin, Hoefele, Julia, Zacchia, Miriam, Martic, Tamara Nikuseva, Gupta, Asheeta, van Eerde, Albertien, Gear, Susie, Landini, Samuela, Palazzo, Viviana, al-Rabadi, Laith, Claes, Kathleen, Corveleyn, Anniek, Van Hoof, Evelien, van Geel, Micheel, Williams, Maggie, Ashton, Emma, Belge, Hendica, Ars, Elisabeth, Bierzynska, Agnieszka, Gangemi, Concetta, Lipska-Ziętkiewicz, Beata S., Genetica Klinische Genetica, Cancer, Child Health, Savige, Judy, Storey, Helen, Watson, Elizabeth, Hertz, Jens Michael, Deltas, Constantinos, Renieri, Alessandra, Mari, Francesca, Hilbert, Pascale, Plevova, Pavlina, Byers, Peter, Cerkauskaite, Agne, Gregory, Martin, Cerkauskiene, Rimante, Ljubanovic, Danica Galesic, Becherucci, Francesca, Errichiello, Carmela, Massella, Laura, Aiello, Valeria, Lennon, Rachel, Hopkinson, Louise, Koziell, Ania, Lungu, Adrian, Rothe, Hansjorg Martin, Hoefele, Julia, Zacchia, Miriam, Martic, Tamara Nikuseva, Gupta, Asheeta, van Eerde, Albertien, Gear, Susie, Landini, Samuela, Palazzo, Viviana, al-Rabadi, Laith, Claes, Kathleen, Corveleyn, Anniek, Van Hoof, Evelien, van Geel, Micheel, Williams, Maggie, Ashton, Emma, Belge, Hendica, Ars, Elisabeth, Bierzynska, Agnieszka, Gangemi, Concetta, and Lipska-Ziętkiewicz, Beata S.

Published
2024

3. Guidelines for Genetic Testing and Management of Alport Syndrome

Author

Genetica Klinische Genetica, Child Health, Cancer, Savige, Judy, Lipska-Zietkiewicz, Beata S, Watson, Elizabeth, Hertz, Jens Michael, Deltas, Constantinos, Mari, Francesca, Hilbert, Pascale, Plevova, Pavlina, Byers, Peter, Cerkauskaite, Agne, Gregory, Martin, Cerkauskiene, Rimante, Ljubanovic, Danica Galesic, Becherucci, Francesca, Errichiello, Carmela, Massella, Laura, Aiello, Valeria, Lennon, Rachel, Hopkinson, Louise, Koziell, Ania, Lungu, Adrian, Rothe, Hansjorg Martin, Hoefele, Julia, Zacchia, Miriam, Martic, Tamara Nikuseva, Gupta, Asheeta, van Eerde, Albertien, Gear, Susie, Landini, Samuela, Palazzo, Viviana, Al-Rabadi, Laith, Claes, Kathleen, Corveleyn, Anniek, Van Hoof, Evelien, van Geel, Micheel, Williams, Maggie, Ashton, Emma, Belge, Hendica, Ars, Elisabet, Bierzynska, Agnieszka, Gangemi, Concetta, Renieri, Alessandra, Storey, Helen, Flinter, Frances, Genetica Klinische Genetica, Child Health, Cancer, Savige, Judy, Lipska-Zietkiewicz, Beata S, Watson, Elizabeth, Hertz, Jens Michael, Deltas, Constantinos, Mari, Francesca, Hilbert, Pascale, Plevova, Pavlina, Byers, Peter, Cerkauskaite, Agne, Gregory, Martin, Cerkauskiene, Rimante, Ljubanovic, Danica Galesic, Becherucci, Francesca, Errichiello, Carmela, Massella, Laura, Aiello, Valeria, Lennon, Rachel, Hopkinson, Louise, Koziell, Ania, Lungu, Adrian, Rothe, Hansjorg Martin, Hoefele, Julia, Zacchia, Miriam, Martic, Tamara Nikuseva, Gupta, Asheeta, van Eerde, Albertien, Gear, Susie, Landini, Samuela, Palazzo, Viviana, Al-Rabadi, Laith, Claes, Kathleen, Corveleyn, Anniek, Van Hoof, Evelien, van Geel, Micheel, Williams, Maggie, Ashton, Emma, Belge, Hendica, Ars, Elisabet, Bierzynska, Agnieszka, Gangemi, Concetta, Renieri, Alessandra, Storey, Helen, and Flinter, Frances

Published
2022

4. Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria

Author

Genetica Klinische Genetica, Cancer, Child Health, Savige, Judy, Storey, Helen, Watson, Elizabeth, Hertz, Jens Michael, Deltas, Constantinos, Renieri, Alessandra, Mari, Francesca, Hilbert, Pascale, Plevova, Pavlina, Byers, Peter, Cerkauskaite, Agne, Gregory, Martin, Cerkauskiene, Rimante, Ljubanovic, Danica Galesic, Becherucci, Francesca, Errichiello, Carmela, Massella, Laura, Aiello, Valeria, Lennon, Rachel, Hopkinson, Louise, Koziell, Ania, Lungu, Adrian, Rothe, Hansjorg Martin, Hoefele, Julia, Zacchia, Miriam, Martic, Tamara Nikuseva, Gupta, Asheeta, van Eerde, Albertien, Gear, Susie, Landini, Samuela, Palazzo, Viviana, al-Rabadi, Laith, Claes, Kathleen, Corveleyn, Anniek, Van Hoof, Evelien, van Geel, Micheel, Williams, Maggie, Ashton, Emma, Belge, Hendica, Ars, Elisabeth, Bierzynska, Agnieszka, Gangemi, Concetta, Lipska-Ziętkiewicz, Beata S., Genetica Klinische Genetica, Cancer, Child Health, Savige, Judy, Storey, Helen, Watson, Elizabeth, Hertz, Jens Michael, Deltas, Constantinos, Renieri, Alessandra, Mari, Francesca, Hilbert, Pascale, Plevova, Pavlina, Byers, Peter, Cerkauskaite, Agne, Gregory, Martin, Cerkauskiene, Rimante, Ljubanovic, Danica Galesic, Becherucci, Francesca, Errichiello, Carmela, Massella, Laura, Aiello, Valeria, Lennon, Rachel, Hopkinson, Louise, Koziell, Ania, Lungu, Adrian, Rothe, Hansjorg Martin, Hoefele, Julia, Zacchia, Miriam, Martic, Tamara Nikuseva, Gupta, Asheeta, van Eerde, Albertien, Gear, Susie, Landini, Samuela, Palazzo, Viviana, al-Rabadi, Laith, Claes, Kathleen, Corveleyn, Anniek, Van Hoof, Evelien, van Geel, Micheel, Williams, Maggie, Ashton, Emma, Belge, Hendica, Ars, Elisabeth, Bierzynska, Agnieszka, Gangemi, Concetta, and Lipska-Ziętkiewicz, Beata S.

Published
2021

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

Author

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

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 3 10(-11)). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 3 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

6. FAT1 mutations cause a glomerulotubular nephropathy

Author

Gee, Heon Yung, Sadowski, Carolin E, Aggarwal, Pardeep K, Porath, Jonathan D, Yakulov, Toma A, Schueler, Markus, Lovric, Svjetlana, Ashraf, Shazia, Braun, Daniela A, Halbritter, Jan, Fang, Humphrey, Airik, Rannar, Vega-Warner, Virginia, Jee Cho, Kyeong, Chan, Timothy A, Morris, Luc G T, Ffrench-Constant, Charles, Allen, Nicholas, McNeill, Helen, Büscher, Rainer, Kyrieleis, Henriette, Wallot, Michael, Gaspert, Ariana, Kistler, Thomas, Milford, David V, Saleem, Moin A, Keng, Wee Teik, Alexander, Stephen I, Valentini, Rudolph P, Licht, Christoph, Teh, Jun C, Bogdanovic, Radovan, Koziell, Ania, Bierzynska, Agnieszka, Soliman, Neveen A, Otto, Edgar A, Lifton, Richard P, Holzman, Lawrence B, Sibinga, Nicholas E S, Walz, Gerd, Tufro, Alda, Hildebrandt, Friedhelm, Gee, Heon Yung, Sadowski, Carolin E, Aggarwal, Pardeep K, Porath, Jonathan D, Yakulov, Toma A, Schueler, Markus, Lovric, Svjetlana, Ashraf, Shazia, Braun, Daniela A, Halbritter, Jan, Fang, Humphrey, Airik, Rannar, Vega-Warner, Virginia, Jee Cho, Kyeong, Chan, Timothy A, Morris, Luc G T, Ffrench-Constant, Charles, Allen, Nicholas, McNeill, Helen, Büscher, Rainer, Kyrieleis, Henriette, Wallot, Michael, Gaspert, Ariana, Kistler, Thomas, Milford, David V, Saleem, Moin A, Keng, Wee Teik, Alexander, Stephen I, Valentini, Rudolph P, Licht, Christoph, Teh, Jun C, Bogdanovic, Radovan, Koziell, Ania, Bierzynska, Agnieszka, Soliman, Neveen A, Otto, Edgar A, Lifton, Richard P, Holzman, Lawrence B, Sibinga, Nicholas E S, Walz, Gerd, Tufro, Alda, and Hildebrandt, Friedhelm

Abstract

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function.

Published
2016

7. Defects of CRB2 Cause Steroid-Resistant Nephrotic Syndrome

Author

Ebarasi, Lwaki, Ashraf, Shazia, Bierzynska, Agnieszka, Gee, Heon Yung, McCarthy, Hugh J., Lovric, Svjetlana, Sadowski, Carolin E., Pabst, Werner, Vega-Warner, Virginia, Fang, Humphrey, Koziell, Ania, Simpson, Michael A., Dursun, Ismail, Serdaroglu, Erkin, Levy, Shawn, Saleem, Moin A., Hildebrandt, Friedhelm, Majumdar, Arindam, Ebarasi, Lwaki, Ashraf, Shazia, Bierzynska, Agnieszka, Gee, Heon Yung, McCarthy, Hugh J., Lovric, Svjetlana, Sadowski, Carolin E., Pabst, Werner, Vega-Warner, Virginia, Fang, Humphrey, Koziell, Ania, Simpson, Michael A., Dursun, Ismail, Serdaroglu, Erkin, Levy, Shawn, Saleem, Moin A., Hildebrandt, Friedhelm, and Majumdar, Arindam

Abstract

Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.

Published
2015
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8. ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption.

Author

Ashraf, Shazia, Ashraf, Shazia, Gee, Heon Yung, Woerner, Stephanie, Xie, Letian X, Vega-Warner, Virginia, Lovric, Svjetlana, Fang, Humphrey, Song, Xuewen, Cattran, Daniel C, Avila-Casado, Carmen, Paterson, Andrew D, Nitschké, Patrick, Bole-Feysot, Christine, Cochat, Pierre, Esteve-Rudd, Julian, Haberberger, Birgit, Allen, Susan J, Zhou, Weibin, Airik, Rannar, Otto, Edgar A, Barua, Moumita, Al-Hamed, Mohamed H, Kari, Jameela A, Evans, Jonathan, Bierzynska, Agnieszka, Saleem, Moin A, Böckenhauer, Detlef, Kleta, Robert, El Desoky, Sherif, Hacihamdioglu, Duygu O, Gok, Faysal, Washburn, Joseph, Wiggins, Roger C, Choi, Murim, Lifton, Richard P, Levy, Shawn, Han, Zhe, Salviati, Leonardo, Prokisch, Holger, Williams, David S, Pollak, Martin, Clarke, Catherine F, Pei, York, Antignac, Corinne, Hildebrandt, Friedhelm, Ashraf, Shazia, Ashraf, Shazia, Gee, Heon Yung, Woerner, Stephanie, Xie, Letian X, Vega-Warner, Virginia, Lovric, Svjetlana, Fang, Humphrey, Song, Xuewen, Cattran, Daniel C, Avila-Casado, Carmen, Paterson, Andrew D, Nitschké, Patrick, Bole-Feysot, Christine, Cochat, Pierre, Esteve-Rudd, Julian, Haberberger, Birgit, Allen, Susan J, Zhou, Weibin, Airik, Rannar, Otto, Edgar A, Barua, Moumita, Al-Hamed, Mohamed H, Kari, Jameela A, Evans, Jonathan, Bierzynska, Agnieszka, Saleem, Moin A, Böckenhauer, Detlef, Kleta, Robert, El Desoky, Sherif, Hacihamdioglu, Duygu O, Gok, Faysal, Washburn, Joseph, Wiggins, Roger C, Choi, Murim, Lifton, Richard P, Levy, Shawn, Han, Zhe, Salviati, Leonardo, Prokisch, Holger, Williams, David S, Pollak, Martin, Clarke, Catherine F, Pei, York, Antignac, Corinne, and Hildebrandt, Friedhelm

Abstract

Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.

Published
2013

9. Exploring the relevance of NUP93 variants in steroid-resistant nephrotic syndrome using next generation sequencing and a fly kidney model.

Author

Bierzynska, A., Bull, K., Miellet, S., Dean, P., Neal, C., Colby, E., McCarthy, H. J., Hegde, S., Sinha, M. D., Bugarin Diz, C., Stirrups, K., Megy, K., Mapeta, R., Penkett, C., Marsh, S., Forrester, N., Afzal, M., Stark, H., BioResource, N., Williams, M., Welsh, G. I., Koziell, A. B., Hartley, Paul S., Saleem, M. A., Bierzynska, A., Bull, K., Miellet, S., Dean, P., Neal, C., Colby, E., McCarthy, H. J., Hegde, S., Sinha, M. D., Bugarin Diz, C., Stirrups, K., Megy, K., Mapeta, R., Penkett, C., Marsh, S., Forrester, N., Afzal, M., Stark, H., BioResource, N., Williams, M., Welsh, G. I., Koziell, A. B., Hartley, Paul S., and Saleem, M. A.

Abstract

BACKGROUND: Variants in genes encoding nuclear pore complex (NPC) proteins are a newly identified cause of paediatric steroid-resistant nephrotic syndrome (SRNS). Recent reports describing NUP93 variants suggest these could be a significant cause of paediatric onset SRNS. We report NUP93 cases in the UK and demonstrate in vivo functional effects of Nup93 depletion in a fly (Drosophila melanogaster) nephrocyte model. METHODS: Three hundred thirty-seven paediatric SRNS patients from the National cohort of patients with Nephrotic Syndrome (NephroS) were whole exome and/or whole genome sequenced. Patients were screened for over 70 genes known to be associated with Nephrotic Syndrome (NS). D. melanogaster Nup93 knockdown was achieved by RNA interference using nephrocyte-restricted drivers. RESULTS: Six novel homozygous and compound heterozygous NUP93 variants were detected in 3 sporadic and 2 familial paediatric onset SRNS characterised histologically by focal segmental glomerulosclerosis (FSGS) and progressing to kidney failure by 12 months from clinical diagnosis. Silencing of the two orthologs of human NUP93 expressed in D. melanogaster, Nup93-1, and Nup93-2 resulted in significant signal reduction of up to 82% in adult pericardial nephrocytes with concomitant disruption of NPC protein expression. Additionally, nephrocyte morphology was highly abnormal in Nup93-1 and Nup93-2 silenced flies surviving to adulthood. CONCLUSION: We expand the spectrum of NUP93 variants detected in paediatric onset SRNS and demonstrate its incidence within a national cohort. Silencing of either D. melanogaster Nup93 ortholog caused a severe nephrocyte phenotype, signaling an important role for the nucleoporin complex in podocyte biology. A higher resolution version of the Graphical abstract is available as Supplementary information.

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