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1. Genetics in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Author

Koettgen, A, Cornec-Le Gall, E, Halbritter, J, Kiryluk, K, Mallett, AJ, Parekh, RS, Rasouly, HM, Sampson, MG, Tin, A, Antignac, C, Ars, E, Bergmann, C, Bleyer, AJ, Bockenhauer, D, Devuyst, O, Florez, JC, Fowler, KJ, Franceschini, N, Fukagawa, M, Gale, DP, Gbadegesin, RA, Goldstein, DB, Grams, ME, Greka, A, Gross, O, Guay-Woodford, LM, Harris, PC, Hoefele, J, Hung, AM, Knoers, NVAM, Kopp, JB, Kretzler, M, Lanktree, MB, Lipska-Zietkiewicz, BS, Nicholls, K, Nozu, K, Ojo, A, Parsa, A, Pattaro, C, Pei, Y, Pollak, MR, Rhee, EP, Sanna-Cherchi, S, Savige, J, Sayer, JA, Scolari, F, Sedor, JR, Sim, X, Somlo, S, Susztak, K, Tayo, BO, Torra, R, van Eerde, AM, Weinstock, A, Winkler, CA, Wuttke, M, Zhang, H, King, JM, Cheung, M, Jadoul, M, Winkelmayer, WC, Gharavi, AG, Koettgen, A, Cornec-Le Gall, E, Halbritter, J, Kiryluk, K, Mallett, AJ, Parekh, RS, Rasouly, HM, Sampson, MG, Tin, A, Antignac, C, Ars, E, Bergmann, C, Bleyer, AJ, Bockenhauer, D, Devuyst, O, Florez, JC, Fowler, KJ, Franceschini, N, Fukagawa, M, Gale, DP, Gbadegesin, RA, Goldstein, DB, Grams, ME, Greka, A, Gross, O, Guay-Woodford, LM, Harris, PC, Hoefele, J, Hung, AM, Knoers, NVAM, Kopp, JB, Kretzler, M, Lanktree, MB, Lipska-Zietkiewicz, BS, Nicholls, K, Nozu, K, Ojo, A, Parsa, A, Pattaro, C, Pei, Y, Pollak, MR, Rhee, EP, Sanna-Cherchi, S, Savige, J, Sayer, JA, Scolari, F, Sedor, JR, Sim, X, Somlo, S, Susztak, K, Tayo, BO, Torra, R, van Eerde, AM, Weinstock, A, Winkler, CA, Wuttke, M, Zhang, H, King, JM, Cheung, M, Jadoul, M, Winkelmayer, WC, and Gharavi, AG

Abstract

Numerous genes for monogenic kidney diseases with classical patterns of inheritance, as well as genes for complex kidney diseases that manifest in combination with environmental factors, have been discovered. Genetic findings are increasingly used to inform clinical management of nephropathies, and have led to improved diagnostics, disease surveillance, choice of therapy, and family counseling. All of these steps rely on accurate interpretation of genetic data, which can be outpaced by current rates of data collection. In March of 2021, Kidney Diseases: Improving Global Outcomes (KDIGO) held a Controversies Conference on "Genetics in Chronic Kidney Disease (CKD)" to review the current state of understanding of monogenic and complex (polygenic) kidney diseases, processes for applying genetic findings in clinical medicine, and use of genomics for defining and stratifying CKD. Given the important contribution of genetic variants to CKD, practitioners with CKD patients are advised to "think genetic," which specifically involves obtaining a family history, collecting detailed information on age of CKD onset, performing clinical examination for extrarenal symptoms, and considering genetic testing. To improve the use of genetics in nephrology, meeting participants advised developing an advanced training or subspecialty track for nephrologists, crafting guidelines for testing and treatment, and educating patients, students, and practitioners. Key areas of future research, including clinical interpretation of genome variation, electronic phenotyping, global representation, kidney-specific molecular data, polygenic scores, translational epidemiology, and open data resources, were also identified.

Published
2022

2. Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome

Author

Braun, D.A., Lovric, S., Schapiro, D., Schneider, R., Marquez, J., Asif, M., Hussain, M.S., Daga, A., Widmeier, E., Rao, J., Ashraf, S., Tan, W., Lusk, C.P., Kolb, A., Jobst-Schwan, T., Schmidt, J.M., Hoogstraten, C.A., Eddy, K., Kitzler, T.M., Shril, S., Moawia, A., Schrage, K., Khayyat, A.I.A., Lawson, J.A., Gee, H.Y., Warejko, J.K., Hermle, T., Majmundar, A.J., Hugo, H., Budde, B., Motameny, S., Altmuller, J., Noegel, A.A., Fathy, H.M., Gale, D.P., Waseem, S.S., Khan, A., Kerecuk, L., Hashmi, S., Mohebbi, N., Ettenger, R., Serdaroglu, E., Alhasan, K.A., Hashem, M., Goncalves, S., Ariceta, G., Ubetagoyena, M., Antonin, W., Baig, S.M., Alkuraya, F.S., Shen, Q., Xu, H., Antignac, C., Lifton, R.P., Mane, S., Nurnberg, P., Khokha, M.K., Hildebrandt, F., Braun, D.A., Lovric, S., Schapiro, D., Schneider, R., Marquez, J., Asif, M., Hussain, M.S., Daga, A., Widmeier, E., Rao, J., Ashraf, S., Tan, W., Lusk, C.P., Kolb, A., Jobst-Schwan, T., Schmidt, J.M., Hoogstraten, C.A., Eddy, K., Kitzler, T.M., Shril, S., Moawia, A., Schrage, K., Khayyat, A.I.A., Lawson, J.A., Gee, H.Y., Warejko, J.K., Hermle, T., Majmundar, A.J., Hugo, H., Budde, B., Motameny, S., Altmuller, J., Noegel, A.A., Fathy, H.M., Gale, D.P., Waseem, S.S., Khan, A., Kerecuk, L., Hashmi, S., Mohebbi, N., Ettenger, R., Serdaroglu, E., Alhasan, K.A., Hashem, M., Goncalves, S., Ariceta, G., Ubetagoyena, M., Antonin, W., Baig, S.M., Alkuraya, F.S., Shen, Q., Xu, H., Antignac, C., Lifton, R.P., Mane, S., Nurnberg, P., Khokha, M.K., and Hildebrandt, F.

Abstract

Item does not contain fulltext, Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, an important effector of SRNS pathogenesis. CRISPR/Cas9 knockout of nup107 or nup85 in zebrafish caused developmental anomalies and early lethality. In contrast, an in-frame mutation of nup107 did not affect survival, thus mimicking the allelic effects seen in humans. In conclusion, we discovered here that mutations in 4 genes encoding components of the outer ring subunits of the NPC cause SRNS and thereby provide further evidence that specific hypomorphic mutations in these essential genes cause a distinct, organ-specific phenotype.

Published
2018

3. Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome

Author

Braun, D.A., Lovric, S., Schapiro, D., Schneider, R., Marquez, J., Asif, M., Hussain, M.S., Daga, A., Widmeier, E., Rao, J., Ashraf, S., Tan, W., Lusk, C.P., Kolb, A., Jobst-Schwan, T., Schmidt, J.M., Hoogstraten, C.A., Eddy, K., Kitzler, T.M., Shril, S., Moawia, A., Schrage, K., Khayyat, A.I.A., Lawson, J.A., Gee, H.Y., Warejko, J.K., Hermle, T., Majmundar, A.J., Hugo, H., Budde, B., Motameny, S., Altmuller, J., Noegel, A.A., Fathy, H.M., Gale, D.P., Waseem, S.S., Khan, A., Kerecuk, L., Hashmi, S., Mohebbi, N., Ettenger, R., Serdaroglu, E., Alhasan, K.A., Hashem, M., Goncalves, S., Ariceta, G., Ubetagoyena, M., Antonin, W., Baig, S.M., Alkuraya, F.S., Shen, Q., Xu, H., Antignac, C., Lifton, R.P., Mane, S., Nurnberg, P., Khokha, M.K., Hildebrandt, F., Braun, D.A., Lovric, S., Schapiro, D., Schneider, R., Marquez, J., Asif, M., Hussain, M.S., Daga, A., Widmeier, E., Rao, J., Ashraf, S., Tan, W., Lusk, C.P., Kolb, A., Jobst-Schwan, T., Schmidt, J.M., Hoogstraten, C.A., Eddy, K., Kitzler, T.M., Shril, S., Moawia, A., Schrage, K., Khayyat, A.I.A., Lawson, J.A., Gee, H.Y., Warejko, J.K., Hermle, T., Majmundar, A.J., Hugo, H., Budde, B., Motameny, S., Altmuller, J., Noegel, A.A., Fathy, H.M., Gale, D.P., Waseem, S.S., Khan, A., Kerecuk, L., Hashmi, S., Mohebbi, N., Ettenger, R., Serdaroglu, E., Alhasan, K.A., Hashem, M., Goncalves, S., Ariceta, G., Ubetagoyena, M., Antonin, W., Baig, S.M., Alkuraya, F.S., Shen, Q., Xu, H., Antignac, C., Lifton, R.P., Mane, S., Nurnberg, P., Khokha, M.K., and Hildebrandt, F.

Abstract

Item does not contain fulltext, Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, an important effector of SRNS pathogenesis. CRISPR/Cas9 knockout of nup107 or nup85 in zebrafish caused developmental anomalies and early lethality. In contrast, an in-frame mutation of nup107 did not affect survival, thus mimicking the allelic effects seen in humans. In conclusion, we discovered here that mutations in 4 genes encoding components of the outer ring subunits of the NPC cause SRNS and thereby provide further evidence that specific hypomorphic mutations in these essential genes cause a distinct, organ-specific phenotype.

Published
2018

4. Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome

Author

Braun, D.A., Lovric, S., Schapiro, D., Schneider, R., Marquez, J., Asif, M., Hussain, M.S., Daga, A., Widmeier, E., Rao, J., Ashraf, S., Tan, W., Lusk, C.P., Kolb, A., Jobst-Schwan, T., Schmidt, J.M., Hoogstraten, C.A., Eddy, K., Kitzler, T.M., Shril, S., Moawia, A., Schrage, K., Khayyat, A.I.A., Lawson, J.A., Gee, H.Y., Warejko, J.K., Hermle, T., Majmundar, A.J., Hugo, H., Budde, B., Motameny, S., Altmuller, J., Noegel, A.A., Fathy, H.M., Gale, D.P., Waseem, S.S., Khan, A., Kerecuk, L., Hashmi, S., Mohebbi, N., Ettenger, R., Serdaroglu, E., Alhasan, K.A., Hashem, M., Goncalves, S., Ariceta, G., Ubetagoyena, M., Antonin, W., Baig, S.M., Alkuraya, F.S., Shen, Q., Xu, H., Antignac, C., Lifton, R.P., Mane, S., Nurnberg, P., Khokha, M.K., Hildebrandt, F., Braun, D.A., Lovric, S., Schapiro, D., Schneider, R., Marquez, J., Asif, M., Hussain, M.S., Daga, A., Widmeier, E., Rao, J., Ashraf, S., Tan, W., Lusk, C.P., Kolb, A., Jobst-Schwan, T., Schmidt, J.M., Hoogstraten, C.A., Eddy, K., Kitzler, T.M., Shril, S., Moawia, A., Schrage, K., Khayyat, A.I.A., Lawson, J.A., Gee, H.Y., Warejko, J.K., Hermle, T., Majmundar, A.J., Hugo, H., Budde, B., Motameny, S., Altmuller, J., Noegel, A.A., Fathy, H.M., Gale, D.P., Waseem, S.S., Khan, A., Kerecuk, L., Hashmi, S., Mohebbi, N., Ettenger, R., Serdaroglu, E., Alhasan, K.A., Hashem, M., Goncalves, S., Ariceta, G., Ubetagoyena, M., Antonin, W., Baig, S.M., Alkuraya, F.S., Shen, Q., Xu, H., Antignac, C., Lifton, R.P., Mane, S., Nurnberg, P., Khokha, M.K., and Hildebrandt, F.

Abstract

Item does not contain fulltext, Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, an important effector of SRNS pathogenesis. CRISPR/Cas9 knockout of nup107 or nup85 in zebrafish caused developmental anomalies and early lethality. In contrast, an in-frame mutation of nup107 did not affect survival, thus mimicking the allelic effects seen in humans. In conclusion, we discovered here that mutations in 4 genes encoding components of the outer ring subunits of the NPC cause SRNS and thereby provide further evidence that specific hypomorphic mutations in these essential genes cause a distinct, organ-specific phenotype.

Published
2018

5. A mouse model suggests two mechanisms for thyroid alterations in infantile cystinosis: decreased thyroglobulin synthesis due to endoplasmic reticulum stress/unfolded protein response and impaired lysosomal processing.

Author

Gaide Chevronnay, HP, Gaide Chevronnay, HP, Janssens, V, Van Der Smissen, P, Liao, XH, Abid, Y, Nevo, N, Antignac, C, Refetoff, S, Cherqui, S, Pierreux, CE, Courtoy, PJ, Gaide Chevronnay, HP, Gaide Chevronnay, HP, Janssens, V, Van Der Smissen, P, Liao, XH, Abid, Y, Nevo, N, Antignac, C, Refetoff, S, Cherqui, S, Pierreux, CE, and Courtoy, PJ

Abstract

Thyroid hormones are released from thyroglobulin (Tg) in lysosomes, which are impaired in infantile/nephropathic cystinosis. Cystinosis is a lysosomal cystine storage disease due to defective cystine exporter, cystinosin. Cystinotic children develop subclinical and then overt hypothyroidism. Why hypothyroidism is the most frequent and earliest endocrine complication of cystinosis is unknown. We here defined early alterations in Ctns(-/-) mice thyroid and identified subcellular and molecular mechanisms. At 9 months, T4 and T3 plasma levels were normal and TSH was moderately increased (∼4-fold). By histology, hyperplasia and hypertrophy of most follicles preceded colloid exhaustion. Increased immunolabeling for thyrocyte proliferation and apoptotic shedding indicated accelerated cell turnover. Electron microscopy revealed endoplasmic reticulum (ER) dilation, apical lamellipodia indicating macropinocytic colloid uptake, and lysosomal cystine crystals. Tg accumulation in dilated ER contrasted with mRNA down-regulation. Increased expression of ER chaperones, glucose-regulated protein of 78 kDa and protein disulfide isomerase, associated with alternative X-box binding protein-1 splicing, revealed unfolded protein response (UPR) activation by ER stress. Decreased Tg mRNA and ER stress suggested reduced Tg synthesis. Coordinated increase of UPR markers, activating transcription factor-4 and C/EBP homologous protein, linked ER stress to apoptosis. Hormonogenic cathepsins were not altered, but lysosome-associated membrane protein-1 immunolabeling disclosed enlarged vesicles containing iodo-Tg and impaired lysosomal fusion. Isopycnic fractionation showed iodo-Tg accumulation in denser lysosomes, suggesting defective lysosomal processing and hormone release. In conclusion, Ctns(-/-) mice showed the following alterations: 1) compensated primary hypothyroidism and accelerated thyrocyte turnover; 2) impaired Tg production linked to ER stress/UPR response; and 3) altered endolysoso

Published
2015

6. A mouse model suggests two mechanisms for thyroid alterations in infantile cystinosis: decreased thyroglobulin synthesis due to endoplasmic reticulum stress/unfolded protein response and impaired lysosomal processing.

Author

UCL - SSS/DDUV - Institut de Duve, UCL - (SLuc) Service de biologie hématologique, UCL - SSS/IRSS - Institut de recherche santé et société, UCL - MD/RMED/CAMG - Centre académique de médecine générale, Gaide Chevronnay, Héloïse P., Janssens, Virginie, Van Der Smissen, Patrick, Liao, X H, Abid, Yasmin, Nevo, N, Antignac, C, Refetoff, S, Cherqui, S, Pierreux, Christophe, Courtoy, Pierre J., UCL - SSS/DDUV - Institut de Duve, UCL - (SLuc) Service de biologie hématologique, UCL - SSS/IRSS - Institut de recherche santé et société, UCL - MD/RMED/CAMG - Centre académique de médecine générale, Gaide Chevronnay, Héloïse P., Janssens, Virginie, Van Der Smissen, Patrick, Liao, X H, Abid, Yasmin, Nevo, N, Antignac, C, Refetoff, S, Cherqui, S, Pierreux, Christophe, and Courtoy, Pierre J.

Abstract

Thyroid hormones are released from thyroglobulin (Tg) in lysosomes, which is impaired in infantile/nephropathic cystinosis. Cystinosis is a lysosomal cystine storage disease due to defective cystine exporter, cystinosin (CTNS). Cystinotic children develop subclinical then overt hypothyroidism. Why hypothyroidism is the most frequent and earliest endocrine complication of cystinosis is unknown. We here defined early alterations in Ctns(-/-) mice thyroid and identified subcellular and molecular mechanisms. At 9 months, T4 and T3 plasma levels were normal and TSH was moderately increased (∼4-fold). By histology, hyperplasia and hypertrophy of most follicles preceded colloid exhaustion. Increased immunolabelling for thyrocyte proliferation and apoptotic shedding indicated accelerated cell turnover. Electron microscopy revealed endoplasmic reticulum (ER) dilation, apical lamellipodia indicating macropinocytic colloid uptake, and lysosomal cystine crystals. Tg accumulation in dilated ER contrasted with mRNA down-regulation. Increased expression of ER chaperones, GRP78 and PDI, associated with alternative XBP-1 splicing, revealed unfolded protein response (UPR) activation by ER stress. Decreased Tg mRNA and ER stress suggested reduced Tg synthesis. Coordinated increase of UPR markers, ATF-4 and CHOP, linked ER stress to apoptosis. Hormonogenic cathepsins were not altered, but LAMP-1 immunolabelling disclosed enlarged vesicles containing iodo-Tg and impaired lysosomal fusion. Isopycnic fractionation showed iodo-Tg accumulation in denser lysosomes, suggesting defective lysosomal processing and hormone release. In conclusion, Ctns(-/-) mice show (i) compensated primary hypothyroidism and accelerated thyrocyte turnover; (ii) impaired Tg production linked to ER stress/UPR response; and (iii) altered endolysosomal trafficking and iodo-Tg processing. The Ctns(-/-) thyroid is useful to study disease progression and evaluate novel therapies.

Published
2015

7. A mouse model suggests two mechanisms for thyroid alterations in infantile cystinosis: decreased thyroglobulin synthesis due to endoplasmic reticulum stress/unfolded protein response and impaired lysosomal processing.

Author

Gaide Chevronnay, HP, Gaide Chevronnay, HP, Janssens, V, Van Der Smissen, P, Liao, XH, Abid, Y, Nevo, N, Antignac, C, Refetoff, S, Cherqui, S, Pierreux, CE, Courtoy, PJ, Gaide Chevronnay, HP, Gaide Chevronnay, HP, Janssens, V, Van Der Smissen, P, Liao, XH, Abid, Y, Nevo, N, Antignac, C, Refetoff, S, Cherqui, S, Pierreux, CE, and Courtoy, PJ

Abstract

Thyroid hormones are released from thyroglobulin (Tg) in lysosomes, which are impaired in infantile/nephropathic cystinosis. Cystinosis is a lysosomal cystine storage disease due to defective cystine exporter, cystinosin. Cystinotic children develop subclinical and then overt hypothyroidism. Why hypothyroidism is the most frequent and earliest endocrine complication of cystinosis is unknown. We here defined early alterations in Ctns(-/-) mice thyroid and identified subcellular and molecular mechanisms. At 9 months, T4 and T3 plasma levels were normal and TSH was moderately increased (∼4-fold). By histology, hyperplasia and hypertrophy of most follicles preceded colloid exhaustion. Increased immunolabeling for thyrocyte proliferation and apoptotic shedding indicated accelerated cell turnover. Electron microscopy revealed endoplasmic reticulum (ER) dilation, apical lamellipodia indicating macropinocytic colloid uptake, and lysosomal cystine crystals. Tg accumulation in dilated ER contrasted with mRNA down-regulation. Increased expression of ER chaperones, glucose-regulated protein of 78 kDa and protein disulfide isomerase, associated with alternative X-box binding protein-1 splicing, revealed unfolded protein response (UPR) activation by ER stress. Decreased Tg mRNA and ER stress suggested reduced Tg synthesis. Coordinated increase of UPR markers, activating transcription factor-4 and C/EBP homologous protein, linked ER stress to apoptosis. Hormonogenic cathepsins were not altered, but lysosome-associated membrane protein-1 immunolabeling disclosed enlarged vesicles containing iodo-Tg and impaired lysosomal fusion. Isopycnic fractionation showed iodo-Tg accumulation in denser lysosomes, suggesting defective lysosomal processing and hormone release. In conclusion, Ctns(-/-) mice showed the following alterations: 1) compensated primary hypothyroidism and accelerated thyrocyte turnover; 2) impaired Tg production linked to ER stress/UPR response; and 3) altered endolysoso

Published
2015

8. Nephropathic cystinosis: an international consensus document

Author

Emma, F., Nesterova, G., Langman, C., Labbe, A., Cherqui, S., Goodyer, P., Janssen, M.C., Greco, M., Topaloglu, R., Elenberg, E., Dohil, R., Trauner, D., Antignac, C., Cochat, P., Kaskel, F., Servais, A., Wuhl, E., Niaudet, P., Hoff, W. van 't, Gahl, W., Levtchenko, E.N., Emma, F., Nesterova, G., Langman, C., Labbe, A., Cherqui, S., Goodyer, P., Janssen, M.C., Greco, M., Topaloglu, R., Elenberg, E., Dohil, R., Trauner, D., Antignac, C., Cochat, P., Kaskel, F., Servais, A., Wuhl, E., Niaudet, P., Hoff, W. van 't, Gahl, W., and Levtchenko, E.N.

Abstract

Contains fulltext : 136370.pdf (publisher's version ) (Closed access), Cystinosis is caused by mutations in the CTNS gene (17p13.2), which encodes for a lysosomal cystine/proton symporter termed cystinosin. It is the most common cause of inherited renal Fanconi syndrome in young children. Because of its rarity, the diagnosis and specific treatment of cystinosis are frequently delayed, which has a significant impact on the overall prognosis. In this document, we have summarized expert opinions on several aspects of the disease to improve knowledge and provide guidance for diagnosis and treatment.

Published
2014

9. Clinical utility gene card for: cystinosis

Author

Levtchenko, E.N., Heuvel, L.P.W.J. van den, Emma, F., Antignac, C., Levtchenko, E.N., Heuvel, L.P.W.J. van den, Emma, F., and Antignac, C.

Abstract

Contains fulltext : 137646.pdf (publisher's version ) (Closed access)

Published
2014

10. Nephropathic cystinosis: an international consensus document

Author

Emma, F., Nesterova, G., Langman, C., Labbe, A., Cherqui, S., Goodyer, P., Janssen, M.C., Greco, M., Topaloglu, R., Elenberg, E., Dohil, R., Trauner, D., Antignac, C., Cochat, P., Kaskel, F., Servais, A., Wuhl, E., Niaudet, P., Hoff, W. van 't, Gahl, W., Levtchenko, E.N., Emma, F., Nesterova, G., Langman, C., Labbe, A., Cherqui, S., Goodyer, P., Janssen, M.C., Greco, M., Topaloglu, R., Elenberg, E., Dohil, R., Trauner, D., Antignac, C., Cochat, P., Kaskel, F., Servais, A., Wuhl, E., Niaudet, P., Hoff, W. van 't, Gahl, W., and Levtchenko, E.N.

Abstract

Contains fulltext : 136370.pdf (publisher's version ) (Closed access), Cystinosis is caused by mutations in the CTNS gene (17p13.2), which encodes for a lysosomal cystine/proton symporter termed cystinosin. It is the most common cause of inherited renal Fanconi syndrome in young children. Because of its rarity, the diagnosis and specific treatment of cystinosis are frequently delayed, which has a significant impact on the overall prognosis. In this document, we have summarized expert opinions on several aspects of the disease to improve knowledge and provide guidance for diagnosis and treatment.

Published
2014

11. Clinical utility gene card for: cystinosis

Author

Levtchenko, E.N., Heuvel, L.P.W.J. van den, Emma, F., Antignac, C., Levtchenko, E.N., Heuvel, L.P.W.J. van den, Emma, F., and Antignac, C.

Abstract

Contains fulltext : 137646.pdf (publisher's version ) (Closed access)

Published
2014

12. Nephropathic cystinosis: an international consensus document

Author

Emma, F., Nesterova, G., Langman, C., Labbe, A., Cherqui, S., Goodyer, P., Janssen, M.C., Greco, M., Topaloglu, R., Elenberg, E., Dohil, R., Trauner, D., Antignac, C., Cochat, P., Kaskel, F., Servais, A., Wuhl, E., Niaudet, P., Hoff, W. van 't, Gahl, W., Levtchenko, E.N., Emma, F., Nesterova, G., Langman, C., Labbe, A., Cherqui, S., Goodyer, P., Janssen, M.C., Greco, M., Topaloglu, R., Elenberg, E., Dohil, R., Trauner, D., Antignac, C., Cochat, P., Kaskel, F., Servais, A., Wuhl, E., Niaudet, P., Hoff, W. van 't, Gahl, W., and Levtchenko, E.N.

Abstract

Contains fulltext : 136370.pdf (publisher's version ) (Closed access), Cystinosis is caused by mutations in the CTNS gene (17p13.2), which encodes for a lysosomal cystine/proton symporter termed cystinosin. It is the most common cause of inherited renal Fanconi syndrome in young children. Because of its rarity, the diagnosis and specific treatment of cystinosis are frequently delayed, which has a significant impact on the overall prognosis. In this document, we have summarized expert opinions on several aspects of the disease to improve knowledge and provide guidance for diagnosis and treatment.

Published
2014

13. Clinical utility gene card for: cystinosis

Author

Levtchenko, E.N., Heuvel, L.P.W.J. van den, Emma, F., Antignac, C., Levtchenko, E.N., Heuvel, L.P.W.J. van den, Emma, F., and Antignac, C.

Abstract

Contains fulltext : 137646.pdf (publisher's version ) (Closed access)

Published
2014

14. The ERA-EDTA Working Group on inherited kidney disorders.

Author

Devuyst, O., Antignac, C., Bindels, R.J.M., Chauveau, D., Emma, F., Gansevoort, R., Maxwell, P.H., Ong, A.C., Remuzzi, G., Ronco, P., Schaefer, F., Devuyst, O., Antignac, C., Bindels, R.J.M., Chauveau, D., Emma, F., Gansevoort, R., Maxwell, P.H., Ong, A.C., Remuzzi, G., Ronco, P., and Schaefer, F.

Abstract

1 januari 2012, Item does not contain fulltext

Published
2012

15. Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling

Author

Chaki, M., Airik, R., Ghosh, A.K., Giles, R.H., Chen, R., Slaats, G.G., Wang, H, Hurd, T.W., Zhou, W., Cluckey, A., Gee, H.Y., Ramaswami, G., Hong, C.J., Hamilton, B.A., Cervenka, I., Ganji, R.S., Bryja, V., Arts, H.H., Reeuwijk, J. van, Oud, M.M., Letteboer, S.J., Roepman, R., Husson, H., Ibraghimov-Beskrovnaya, O., Yasunaga, T., Walz, G., Eley, L., Sayer, J.A., Schermer, B., Liebau, M.C., Benzing, T., Le Corre, S., Drummond, I., Janssen, S., Allen, S.J., Natarajan, S., O'Toole, J.F., Attanasio, M., Saunier, S., Antignac, C., Koenekoop, R.K., Ren, H., Lopez, I., Nayir, A., Stoetzel, C., Dollfus, H., Massoudi, R., Gleeson, J.G., Andreoli, S.P., Doherty, D.G., Lindstrad, A., Golzio, C., Katsanis, N., Pape, L., Abboud, E.B., Al-Rajhi, A.A., Lewis, R.A., Omran, H., Lee, E.Y., Wang, S., Sekiguchi, J.M., Saunders, R., Johnson, C.A., Garner, E., Vanselow, K., Andersen, J.S., Shlomai, J., Nurnberg, G., Nurnberg, P., Levy, S., Smogorzewska, A., Otto, E.A., Hildebrandt, F., Chaki, M., Airik, R., Ghosh, A.K., Giles, R.H., Chen, R., Slaats, G.G., Wang, H, Hurd, T.W., Zhou, W., Cluckey, A., Gee, H.Y., Ramaswami, G., Hong, C.J., Hamilton, B.A., Cervenka, I., Ganji, R.S., Bryja, V., Arts, H.H., Reeuwijk, J. van, Oud, M.M., Letteboer, S.J., Roepman, R., Husson, H., Ibraghimov-Beskrovnaya, O., Yasunaga, T., Walz, G., Eley, L., Sayer, J.A., Schermer, B., Liebau, M.C., Benzing, T., Le Corre, S., Drummond, I., Janssen, S., Allen, S.J., Natarajan, S., O'Toole, J.F., Attanasio, M., Saunier, S., Antignac, C., Koenekoop, R.K., Ren, H., Lopez, I., Nayir, A., Stoetzel, C., Dollfus, H., Massoudi, R., Gleeson, J.G., Andreoli, S.P., Doherty, D.G., Lindstrad, A., Golzio, C., Katsanis, N., Pape, L., Abboud, E.B., Al-Rajhi, A.A., Lewis, R.A., Omran, H., Lee, E.Y., Wang, S., Sekiguchi, J.M., Saunders, R., Johnson, C.A., Garner, E., Vanselow, K., Andersen, J.S., Shlomai, J., Nurnberg, G., Nurnberg, P., Levy, S., Smogorzewska, A., Otto, E.A., and Hildebrandt, F.

Abstract

Item does not contain fulltext, Nephronophthisis-related ciliopathies (NPHP-RC) are degenerative recessive diseases that affect kidney, retina, and brain. Genetic defects in NPHP gene products that localize to cilia and centrosomes defined them as "ciliopathies." However, disease mechanisms remain poorly understood. Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway. We demonstrate that, upon induced DNA damage, the NPHP-RC proteins ZNF423, CEP164, and NPHP10 colocalize to nuclear foci positive for TIP60, known to activate ATM at sites of DNA damage. We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents and that cep164 knockdown in zebrafish results in dysregulated DDR and an NPHP-RC phenotype. Our findings link degenerative diseases of the kidney and retina, disorders of increasing prevalence, to mechanisms of DDR.

Published
2012

16. Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations

Author

Perrault, I., Saunier, S., Hanein, S., Filhol, E., Bizet, A.A., Collins, F., Salih, M.A., Gerber, S., Delphin, N., Bigot, K., Orssaud, C., Silva, E., Baudouin, V., Oud, M.M., Shannon, N., Le Merrer, M., Roche, O., Pietrement, C., Goumid, J., Baumann, C., Bole-Feysot, C., Nitschke, P., Zahrate, M., Beales, P., Arts, H.H., Munnich, A., Kaplan, J., Antignac, C., Cormier-Daire, V., Rozet, J.M., Perrault, I., Saunier, S., Hanein, S., Filhol, E., Bizet, A.A., Collins, F., Salih, M.A., Gerber, S., Delphin, N., Bigot, K., Orssaud, C., Silva, E., Baudouin, V., Oud, M.M., Shannon, N., Le Merrer, M., Roche, O., Pietrement, C., Goumid, J., Baumann, C., Bole-Feysot, C., Nitschke, P., Zahrate, M., Beales, P., Arts, H.H., Munnich, A., Kaplan, J., Antignac, C., Cormier-Daire, V., and Rozet, J.M.

Abstract

Item does not contain fulltext, Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal dystrophy. Through a combination of ciliome resequencing and Sanger sequencing, we identified IFT140 mutations in six MSS families and in a family with the clinically overlapping Jeune syndrome. IFT140 is one of the six currently known components of the intraflagellar transport complex A (IFT-A) that regulates retrograde protein transport in ciliated cells. Ciliary abundance and localization of anterograde IFTs were altered in fibroblasts of affected individuals, a result that supports the pivotal role of IFT140 in proper development and function of ciliated cells.

Published
2012

17. Cellular and tissue mechanisms of the spatial and transcriptional heterogeneity of cystinotic lesions in Ctns-/- mice, and their correction by hematopoietic stem cell grafting

Author

UCL - SSS/DDUV - Institut de Duve, Gaide Chevronnay, Héloïse P., Janssens, V., Van Der Smissen, Patrick, Lac, Thanh, Harisson, F., Pierreux, Christophe, Antignac, C., Cherqui, S., Courtoy, Pierre J., 3d Cystinosis Research Foundation Symposium, UCL - SSS/DDUV - Institut de Duve, Gaide Chevronnay, Héloïse P., Janssens, V., Van Der Smissen, Patrick, Lac, Thanh, Harisson, F., Pierreux, Christophe, Antignac, C., Cherqui, S., Courtoy, Pierre J., and 3d Cystinosis Research Foundation Symposium

Published
2012

18. The ERA-EDTA Working Group on inherited kidney disorders.

Author

Devuyst, O., Antignac, C., Bindels, R.J.M., Chauveau, D., Emma, F., Gansevoort, R., Maxwell, P.H., Ong, A.C., Remuzzi, G., Ronco, P., Schaefer, F., Devuyst, O., Antignac, C., Bindels, R.J.M., Chauveau, D., Emma, F., Gansevoort, R., Maxwell, P.H., Ong, A.C., Remuzzi, G., Ronco, P., and Schaefer, F.

Abstract

01 januari 2012, Item does not contain fulltext

Published
2012

19. Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling

Author

Chaki, M., Airik, R., Ghosh, A.K., Giles, R.H., Chen, R., Slaats, G.G., Wang, H, Hurd, T.W., Zhou, W., Cluckey, A., Gee, H.Y., Ramaswami, G., Hong, C.J., Hamilton, B.A., Cervenka, I., Ganji, R.S., Bryja, V., Arts, H.H., Reeuwijk, J. van, Oud, M.M., Letteboer, S.J., Roepman, R., Husson, H., Ibraghimov-Beskrovnaya, O., Yasunaga, T., Walz, G., Eley, L., Sayer, J.A., Schermer, B., Liebau, M.C., Benzing, T., Le Corre, S., Drummond, I., Janssen, S., Allen, S.J., Natarajan, S., O'Toole, J.F., Attanasio, M., Saunier, S., Antignac, C., Koenekoop, R.K., Ren, H., Lopez, I., Nayir, A., Stoetzel, C., Dollfus, H., Massoudi, R., Gleeson, J.G., Andreoli, S.P., Doherty, D.G., Lindstrad, A., Golzio, C., Katsanis, N., Pape, L., Abboud, E.B., Al-Rajhi, A.A., Lewis, R.A., Omran, H., Lee, E.Y., Wang, S., Sekiguchi, J.M., Saunders, R., Johnson, C.A., Garner, E., Vanselow, K., Andersen, J.S., Shlomai, J., Nurnberg, G., Nurnberg, P., Levy, S., Smogorzewska, A., Otto, E.A., Hildebrandt, F., Chaki, M., Airik, R., Ghosh, A.K., Giles, R.H., Chen, R., Slaats, G.G., Wang, H, Hurd, T.W., Zhou, W., Cluckey, A., Gee, H.Y., Ramaswami, G., Hong, C.J., Hamilton, B.A., Cervenka, I., Ganji, R.S., Bryja, V., Arts, H.H., Reeuwijk, J. van, Oud, M.M., Letteboer, S.J., Roepman, R., Husson, H., Ibraghimov-Beskrovnaya, O., Yasunaga, T., Walz, G., Eley, L., Sayer, J.A., Schermer, B., Liebau, M.C., Benzing, T., Le Corre, S., Drummond, I., Janssen, S., Allen, S.J., Natarajan, S., O'Toole, J.F., Attanasio, M., Saunier, S., Antignac, C., Koenekoop, R.K., Ren, H., Lopez, I., Nayir, A., Stoetzel, C., Dollfus, H., Massoudi, R., Gleeson, J.G., Andreoli, S.P., Doherty, D.G., Lindstrad, A., Golzio, C., Katsanis, N., Pape, L., Abboud, E.B., Al-Rajhi, A.A., Lewis, R.A., Omran, H., Lee, E.Y., Wang, S., Sekiguchi, J.M., Saunders, R., Johnson, C.A., Garner, E., Vanselow, K., Andersen, J.S., Shlomai, J., Nurnberg, G., Nurnberg, P., Levy, S., Smogorzewska, A., Otto, E.A., and Hildebrandt, F.

Abstract

Item does not contain fulltext, Nephronophthisis-related ciliopathies (NPHP-RC) are degenerative recessive diseases that affect kidney, retina, and brain. Genetic defects in NPHP gene products that localize to cilia and centrosomes defined them as "ciliopathies." However, disease mechanisms remain poorly understood. Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway. We demonstrate that, upon induced DNA damage, the NPHP-RC proteins ZNF423, CEP164, and NPHP10 colocalize to nuclear foci positive for TIP60, known to activate ATM at sites of DNA damage. We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents and that cep164 knockdown in zebrafish results in dysregulated DDR and an NPHP-RC phenotype. Our findings link degenerative diseases of the kidney and retina, disorders of increasing prevalence, to mechanisms of DDR.

Published
2012

20. Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations

Author

Perrault, I., Saunier, S., Hanein, S., Filhol, E., Bizet, A.A., Collins, F., Salih, M.A., Gerber, S., Delphin, N., Bigot, K., Orssaud, C., Silva, E., Baudouin, V., Oud, M.M., Shannon, N., Le Merrer, M., Roche, O., Pietrement, C., Goumid, J., Baumann, C., Bole-Feysot, C., Nitschke, P., Zahrate, M., Beales, P., Arts, H.H., Munnich, A., Kaplan, J., Antignac, C., Cormier-Daire, V., Rozet, J.M., Perrault, I., Saunier, S., Hanein, S., Filhol, E., Bizet, A.A., Collins, F., Salih, M.A., Gerber, S., Delphin, N., Bigot, K., Orssaud, C., Silva, E., Baudouin, V., Oud, M.M., Shannon, N., Le Merrer, M., Roche, O., Pietrement, C., Goumid, J., Baumann, C., Bole-Feysot, C., Nitschke, P., Zahrate, M., Beales, P., Arts, H.H., Munnich, A., Kaplan, J., Antignac, C., Cormier-Daire, V., and Rozet, J.M.

Abstract

Item does not contain fulltext, Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal dystrophy. Through a combination of ciliome resequencing and Sanger sequencing, we identified IFT140 mutations in six MSS families and in a family with the clinically overlapping Jeune syndrome. IFT140 is one of the six currently known components of the intraflagellar transport complex A (IFT-A) that regulates retrograde protein transport in ciliated cells. Ciliary abundance and localization of anterograde IFTs were altered in fibroblasts of affected individuals, a result that supports the pivotal role of IFT140 in proper development and function of ciliated cells.

Published
2012

21. The ERA-EDTA Working Group on inherited kidney disorders.

Author

Devuyst, O., Antignac, C., Bindels, R.J.M., Chauveau, D., Emma, F., Gansevoort, R., Maxwell, P.H., Ong, A.C., Remuzzi, G., Ronco, P., Schaefer, F., Devuyst, O., Antignac, C., Bindels, R.J.M., Chauveau, D., Emma, F., Gansevoort, R., Maxwell, P.H., Ong, A.C., Remuzzi, G., Ronco, P., and Schaefer, F.

Abstract

01 januari 2012, Item does not contain fulltext

Published
2012

22. Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations

Author

Perrault, I., Saunier, S., Hanein, S., Filhol, E., Bizet, A.A., Collins, F., Salih, M.A., Gerber, S., Delphin, N., Bigot, K., Orssaud, C., Silva, E., Baudouin, V., Oud, M.M., Shannon, N., Le Merrer, M., Roche, O., Pietrement, C., Goumid, J., Baumann, C., Bole-Feysot, C., Nitschke, P., Zahrate, M., Beales, P., Arts, H.H., Munnich, A., Kaplan, J., Antignac, C., Cormier-Daire, V., Rozet, J.M., Perrault, I., Saunier, S., Hanein, S., Filhol, E., Bizet, A.A., Collins, F., Salih, M.A., Gerber, S., Delphin, N., Bigot, K., Orssaud, C., Silva, E., Baudouin, V., Oud, M.M., Shannon, N., Le Merrer, M., Roche, O., Pietrement, C., Goumid, J., Baumann, C., Bole-Feysot, C., Nitschke, P., Zahrate, M., Beales, P., Arts, H.H., Munnich, A., Kaplan, J., Antignac, C., Cormier-Daire, V., and Rozet, J.M.

Abstract

Item does not contain fulltext, Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal dystrophy. Through a combination of ciliome resequencing and Sanger sequencing, we identified IFT140 mutations in six MSS families and in a family with the clinically overlapping Jeune syndrome. IFT140 is one of the six currently known components of the intraflagellar transport complex A (IFT-A) that regulates retrograde protein transport in ciliated cells. Ciliary abundance and localization of anterograde IFTs were altered in fibroblasts of affected individuals, a result that supports the pivotal role of IFT140 in proper development and function of ciliated cells.

Published
2012

23. Novel perspectives for investigating congenital anomalies of the kidney and urinary tract (CAKUT)

Author

Renkema, K.Y., Winyard, P.J., Skovorodkin, I.N., Levtchenko, E.N., Hindryckx, A., Jeanpierre, C., Weber, S., Salomon, R., Antignac, C., Vainio, S., Schedl, A., Schaefer, F., Knoers, N.V.A.M., Bongers, M.H.F., Renkema, K.Y., Winyard, P.J., Skovorodkin, I.N., Levtchenko, E.N., Hindryckx, A., Jeanpierre, C., Weber, S., Salomon, R., Antignac, C., Vainio, S., Schedl, A., Schaefer, F., Knoers, N.V.A.M., and Bongers, M.H.F.

Abstract

Item does not contain fulltext, Congenital anomalies of the kidney and urinary tract (CAKUT) are the commonest cause of chronic kidney disease in children. Structural anomalies within the CAKUT spectrum include renal agenesis, kidney hypo-/dysplasia, multicystic kidney dysplasia, duplex collecting system, posterior urethral valves and ureter abnormalities. While most CAKUT cases are sporadic, familial clustering of CAKUT is common, emphasizing a strong genetic contribution to CAKUT origin. Animal experiments demonstrate that alterations in genes crucial for kidney development can cause experimental CAKUT, while expression studies implicate mislocalization and/or aberrant levels of the encoded proteins in human CAKUT. Further insight into the pathogenesis of CAKUT will improve strategies for early diagnosis, follow-up and treatment. Here, we outline a collaborative approach to identify and characterize novel factors underlying human CAKUT. This European consortium will share the largest collection of CAKUT patients available worldwide and undertake multidisciplinary research into molecular and genetic pathogenesis, with extension into translational studies to improve long-term patient outcomes.

Published
2011

24. Novel perspectives for investigating congenital anomalies of the kidney and urinary tract (CAKUT)

Author

Renkema, K.Y., Winyard, P.J., Skovorodkin, I.N., Levtchenko, E.N., Hindryckx, A., Jeanpierre, C., Weber, S., Salomon, R., Antignac, C., Vainio, S., Schedl, A., Schaefer, F., Knoers, N.V.A.M., Bongers, M.H.F., Renkema, K.Y., Winyard, P.J., Skovorodkin, I.N., Levtchenko, E.N., Hindryckx, A., Jeanpierre, C., Weber, S., Salomon, R., Antignac, C., Vainio, S., Schedl, A., Schaefer, F., Knoers, N.V.A.M., and Bongers, M.H.F.

Abstract

Item does not contain fulltext, Congenital anomalies of the kidney and urinary tract (CAKUT) are the commonest cause of chronic kidney disease in children. Structural anomalies within the CAKUT spectrum include renal agenesis, kidney hypo-/dysplasia, multicystic kidney dysplasia, duplex collecting system, posterior urethral valves and ureter abnormalities. While most CAKUT cases are sporadic, familial clustering of CAKUT is common, emphasizing a strong genetic contribution to CAKUT origin. Animal experiments demonstrate that alterations in genes crucial for kidney development can cause experimental CAKUT, while expression studies implicate mislocalization and/or aberrant levels of the encoded proteins in human CAKUT. Further insight into the pathogenesis of CAKUT will improve strategies for early diagnosis, follow-up and treatment. Here, we outline a collaborative approach to identify and characterize novel factors underlying human CAKUT. This European consortium will share the largest collection of CAKUT patients available worldwide and undertake multidisciplinary research into molecular and genetic pathogenesis, with extension into translational studies to improve long-term patient outcomes.

Published
2011

25. Novel perspectives for investigating congenital anomalies of the kidney and urinary tract (CAKUT)

Author

Renkema, K.Y., Winyard, P.J., Skovorodkin, I.N., Levtchenko, E.N., Hindryckx, A., Jeanpierre, C., Weber, S., Salomon, R., Antignac, C., Vainio, S., Schedl, A., Schaefer, F., Knoers, N.V.A.M., Bongers, M.H.F., Renkema, K.Y., Winyard, P.J., Skovorodkin, I.N., Levtchenko, E.N., Hindryckx, A., Jeanpierre, C., Weber, S., Salomon, R., Antignac, C., Vainio, S., Schedl, A., Schaefer, F., Knoers, N.V.A.M., and Bongers, M.H.F.

Abstract

Item does not contain fulltext, Congenital anomalies of the kidney and urinary tract (CAKUT) are the commonest cause of chronic kidney disease in children. Structural anomalies within the CAKUT spectrum include renal agenesis, kidney hypo-/dysplasia, multicystic kidney dysplasia, duplex collecting system, posterior urethral valves and ureter abnormalities. While most CAKUT cases are sporadic, familial clustering of CAKUT is common, emphasizing a strong genetic contribution to CAKUT origin. Animal experiments demonstrate that alterations in genes crucial for kidney development can cause experimental CAKUT, while expression studies implicate mislocalization and/or aberrant levels of the encoded proteins in human CAKUT. Further insight into the pathogenesis of CAKUT will improve strategies for early diagnosis, follow-up and treatment. Here, we outline a collaborative approach to identify and characterize novel factors underlying human CAKUT. This European consortium will share the largest collection of CAKUT patients available worldwide and undertake multidisciplinary research into molecular and genetic pathogenesis, with extension into translational studies to improve long-term patient outcomes.

Published
2011

26. Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy.

Author

Otto, E.A., Hurd, T.W., Airik, R., Chaki, M., Zhou, W., Stoetzel, C., Patil, S.B., Levy, S., Ghosh, A.K., Murga-Zamalloa, C.A., Reeuwijk, J. van, Letteboer, S.J.F., Sang, L., Giles, R.H., Liu, Q., Coene, K.L.M., Estrada-Cuzcano, A., Collin, R.W.J., McLaughlin, H.M., Held, S., Kasanuki, J.M., Ramaswami, G., Conte, J., Lopez, I., Washburn, J., Macdonald, J., Hu, J., Yamashita, Y., Maher, E.R., Guay-Woodford, L.M., Neumann, H.P., Obermuller, N., Koenekoop, R.K., Bergmann, C., Bei, X., Lewis, R.A., Katsanis, N., Lopes, V., Williams, D.S., Lyons, R.H., Dang, C.V., Brito, D.A., Dias, M.B., Zhang, X., Cavalcoli, J.D., Nurnberg, G., Nurnberg, P., Pierce, E.A., Jackson, P.K., Antignac, C., Saunier, S., Roepman, R., Dollfus, H., Khanna, H., Hildebrandt, F., Otto, E.A., Hurd, T.W., Airik, R., Chaki, M., Zhou, W., Stoetzel, C., Patil, S.B., Levy, S., Ghosh, A.K., Murga-Zamalloa, C.A., Reeuwijk, J. van, Letteboer, S.J.F., Sang, L., Giles, R.H., Liu, Q., Coene, K.L.M., Estrada-Cuzcano, A., Collin, R.W.J., McLaughlin, H.M., Held, S., Kasanuki, J.M., Ramaswami, G., Conte, J., Lopez, I., Washburn, J., Macdonald, J., Hu, J., Yamashita, Y., Maher, E.R., Guay-Woodford, L.M., Neumann, H.P., Obermuller, N., Koenekoop, R.K., Bergmann, C., Bei, X., Lewis, R.A., Katsanis, N., Lopes, V., Williams, D.S., Lyons, R.H., Dang, C.V., Brito, D.A., Dias, M.B., Zhang, X., Cavalcoli, J.D., Nurnberg, G., Nurnberg, P., Pierce, E.A., Jackson, P.K., Antignac, C., Saunier, S., Roepman, R., Dollfus, H., Khanna, H., and Hildebrandt, F.

Abstract

1 oktober 2010, Contains fulltext : 88200.pdf (publisher's version ) (Closed access), Nephronophthisis-related ciliopathies (NPHP-RC) are recessive disorders that feature dysplasia or degeneration occurring preferentially in the kidney, retina and cerebellum. Here we combined homozygosity mapping with candidate gene analysis by performing 'ciliopathy candidate exome capture' followed by massively parallel sequencing. We identified 12 different truncating mutations of SDCCAG8 (serologically defined colon cancer antigen 8, also known as CCCAP) in 10 families affected by NPHP-RC. We show that SDCCAG8 is localized at both centrioles and interacts directly with OFD1 (oral-facial-digital syndrome 1), which is associated with NPHP-RC. Depletion of sdccag8 causes kidney cysts and a body axis defect in zebrafish and induces cell polarity defects in three-dimensional renal cell cultures. This work identifies loss of SDCCAG8 function as a cause of a retinal-renal ciliopathy and validates exome capture analysis for broadly heterogeneous single-gene disorders.

Published
2010

27. More on clinical renal genetics.

Author

Grunfeld, J.P., Hwu, W., Chien, Y., Lee, N., Chiang, S., Dobrovolny, R., Huang, A., Yeh, H., Chao, M., Lin, S., Kitagawa, T., Desnick, R., Hsu, L., Keimpema, L. van, Nevens, F., Vanslembrouck, R., Oijen, G. Van, Hoffmann, A., Dekker, H., Man, R. de, Drenth, J.P.H., Alamovitch, S., Plaisier, E., Favrole, P., Prost, C., Chen, Z., Agrmael, T. Van, Marro, B., Ronco, P., Zivna, M., Hulkova, H., Matignon, M., Hodanova, K., Vylet'al, P., Kalbacova, M., Baresova, V., Sikora, J., Blazkova, H., Zivny, J., Ivanek, R., Stranecky, V., Sovova, J., Claes, K., Lerut, E., Fryns, J.P., Hart, P. t, Hart, T., Adams, J., Pawtowski, A., Clemessy, M., Gasc, J., Gubler, M., Antignac, C., Elleder, M., Kapp, K., Grimbert, P., Bleyer, A., Kmoch, S., Brown, E., Schlondorff, J., Becker, D.J., Tsukaguchi, H., Uschinski, A., Higgs, H., Henderson, J., Pollak, M., Grunfeld, J.P., Hwu, W., Chien, Y., Lee, N., Chiang, S., Dobrovolny, R., Huang, A., Yeh, H., Chao, M., Lin, S., Kitagawa, T., Desnick, R., Hsu, L., Keimpema, L. van, Nevens, F., Vanslembrouck, R., Oijen, G. Van, Hoffmann, A., Dekker, H., Man, R. de, Drenth, J.P.H., Alamovitch, S., Plaisier, E., Favrole, P., Prost, C., Chen, Z., Agrmael, T. Van, Marro, B., Ronco, P., Zivna, M., Hulkova, H., Matignon, M., Hodanova, K., Vylet'al, P., Kalbacova, M., Baresova, V., Sikora, J., Blazkova, H., Zivny, J., Ivanek, R., Stranecky, V., Sovova, J., Claes, K., Lerut, E., Fryns, J.P., Hart, P. t, Hart, T., Adams, J., Pawtowski, A., Clemessy, M., Gasc, J., Gubler, M., Antignac, C., Elleder, M., Kapp, K., Grimbert, P., Bleyer, A., Kmoch, S., Brown, E., Schlondorff, J., Becker, D.J., Tsukaguchi, H., Uschinski, A., Higgs, H., Henderson, J., and Pollak, M.

Abstract

1 april 2010, Contains fulltext : 89212.pdf (publisher's version ) (Closed access)

Published
2010

28. Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy.

Author

Otto, E.A., Hurd, T.W., Airik, R., Chaki, M., Zhou, W., Stoetzel, C., Patil, S.B., Levy, S., Ghosh, A.K., Murga-Zamalloa, C.A., Reeuwijk, J. van, Letteboer, S.J.F., Sang, L., Giles, R.H., Liu, Q., Coene, K.L.M., Estrada-Cuzcano, A., Collin, R.W.J., McLaughlin, H.M., Held, S., Kasanuki, J.M., Ramaswami, G., Conte, J., Lopez, I., Washburn, J., Macdonald, J., Hu, J., Yamashita, Y., Maher, E.R., Guay-Woodford, L.M., Neumann, H.P., Obermuller, N., Koenekoop, R.K., Bergmann, C., Bei, X., Lewis, R.A., Katsanis, N., Lopes, V., Williams, D.S., Lyons, R.H., Dang, C.V., Brito, D.A., Dias, M.B., Zhang, X., Cavalcoli, J.D., Nurnberg, G., Nurnberg, P., Pierce, E.A., Jackson, P.K., Antignac, C., Saunier, S., Roepman, R., Dollfus, H., Khanna, H., Hildebrandt, F., Otto, E.A., Hurd, T.W., Airik, R., Chaki, M., Zhou, W., Stoetzel, C., Patil, S.B., Levy, S., Ghosh, A.K., Murga-Zamalloa, C.A., Reeuwijk, J. van, Letteboer, S.J.F., Sang, L., Giles, R.H., Liu, Q., Coene, K.L.M., Estrada-Cuzcano, A., Collin, R.W.J., McLaughlin, H.M., Held, S., Kasanuki, J.M., Ramaswami, G., Conte, J., Lopez, I., Washburn, J., Macdonald, J., Hu, J., Yamashita, Y., Maher, E.R., Guay-Woodford, L.M., Neumann, H.P., Obermuller, N., Koenekoop, R.K., Bergmann, C., Bei, X., Lewis, R.A., Katsanis, N., Lopes, V., Williams, D.S., Lyons, R.H., Dang, C.V., Brito, D.A., Dias, M.B., Zhang, X., Cavalcoli, J.D., Nurnberg, G., Nurnberg, P., Pierce, E.A., Jackson, P.K., Antignac, C., Saunier, S., Roepman, R., Dollfus, H., Khanna, H., and Hildebrandt, F.

Abstract

01 oktober 2010, Contains fulltext : 88200.pdf (publisher's version ) (Closed access), Nephronophthisis-related ciliopathies (NPHP-RC) are recessive disorders that feature dysplasia or degeneration occurring preferentially in the kidney, retina and cerebellum. Here we combined homozygosity mapping with candidate gene analysis by performing 'ciliopathy candidate exome capture' followed by massively parallel sequencing. We identified 12 different truncating mutations of SDCCAG8 (serologically defined colon cancer antigen 8, also known as CCCAP) in 10 families affected by NPHP-RC. We show that SDCCAG8 is localized at both centrioles and interacts directly with OFD1 (oral-facial-digital syndrome 1), which is associated with NPHP-RC. Depletion of sdccag8 causes kidney cysts and a body axis defect in zebrafish and induces cell polarity defects in three-dimensional renal cell cultures. This work identifies loss of SDCCAG8 function as a cause of a retinal-renal ciliopathy and validates exome capture analysis for broadly heterogeneous single-gene disorders.

Published
2010

29. More on clinical renal genetics.

Author

Grunfeld, J.P., Hwu, W., Chien, Y., Lee, N., Chiang, S., Dobrovolny, R., Huang, A., Yeh, H., Chao, M., Lin, S., Kitagawa, T., Desnick, R., Hsu, L., Keimpema, L. van, Nevens, F., Vanslembrouck, R., Oijen, G. Van, Hoffmann, A., Dekker, H., Man, R. de, Drenth, J.P.H., Alamovitch, S., Plaisier, E., Favrole, P., Prost, C., Chen, Z., Agrmael, T. Van, Marro, B., Ronco, P., Zivna, M., Hulkova, H., Matignon, M., Hodanova, K., Vylet'al, P., Kalbacova, M., Baresova, V., Sikora, J., Blazkova, H., Zivny, J., Ivanek, R., Stranecky, V., Sovova, J., Claes, K., Lerut, E., Fryns, J.P., Hart, P. t, Hart, T., Adams, J., Pawtowski, A., Clemessy, M., Gasc, J., Gubler, M., Antignac, C., Elleder, M., Kapp, K., Grimbert, P., Bleyer, A., Kmoch, S., Brown, E., Schlondorff, J., Becker, D.J., Tsukaguchi, H., Uschinski, A., Higgs, H., Henderson, J., Pollak, M., Grunfeld, J.P., Hwu, W., Chien, Y., Lee, N., Chiang, S., Dobrovolny, R., Huang, A., Yeh, H., Chao, M., Lin, S., Kitagawa, T., Desnick, R., Hsu, L., Keimpema, L. van, Nevens, F., Vanslembrouck, R., Oijen, G. Van, Hoffmann, A., Dekker, H., Man, R. de, Drenth, J.P.H., Alamovitch, S., Plaisier, E., Favrole, P., Prost, C., Chen, Z., Agrmael, T. Van, Marro, B., Ronco, P., Zivna, M., Hulkova, H., Matignon, M., Hodanova, K., Vylet'al, P., Kalbacova, M., Baresova, V., Sikora, J., Blazkova, H., Zivny, J., Ivanek, R., Stranecky, V., Sovova, J., Claes, K., Lerut, E., Fryns, J.P., Hart, P. t, Hart, T., Adams, J., Pawtowski, A., Clemessy, M., Gasc, J., Gubler, M., Antignac, C., Elleder, M., Kapp, K., Grimbert, P., Bleyer, A., Kmoch, S., Brown, E., Schlondorff, J., Becker, D.J., Tsukaguchi, H., Uschinski, A., Higgs, H., Henderson, J., and Pollak, M.

Abstract

01 april 2010, Contains fulltext : 89212.pdf (publisher's version ) (Closed access)

Published
2010

30. More on clinical renal genetics.

Author

Grunfeld, J.P., Hwu, W., Chien, Y., Lee, N., Chiang, S., Dobrovolny, R., Huang, A., Yeh, H., Chao, M., Lin, S., Kitagawa, T., Desnick, R., Hsu, L., Keimpema, L. van, Nevens, F., Vanslembrouck, R., Oijen, G. Van, Hoffmann, A., Dekker, H., Man, R. de, Drenth, J.P.H., Alamovitch, S., Plaisier, E., Favrole, P., Prost, C., Chen, Z., Agrmael, T. Van, Marro, B., Ronco, P., Zivna, M., Hulkova, H., Matignon, M., Hodanova, K., Vylet'al, P., Kalbacova, M., Baresova, V., Sikora, J., Blazkova, H., Zivny, J., Ivanek, R., Stranecky, V., Sovova, J., Claes, K., Lerut, E., Fryns, J.P., Hart, P. t, Hart, T., Adams, J., Pawtowski, A., Clemessy, M., Gasc, J., Gubler, M., Antignac, C., Elleder, M., Kapp, K., Grimbert, P., Bleyer, A., Kmoch, S., Brown, E., Schlondorff, J., Becker, D.J., Tsukaguchi, H., Uschinski, A., Higgs, H., Henderson, J., Pollak, M., Grunfeld, J.P., Hwu, W., Chien, Y., Lee, N., Chiang, S., Dobrovolny, R., Huang, A., Yeh, H., Chao, M., Lin, S., Kitagawa, T., Desnick, R., Hsu, L., Keimpema, L. van, Nevens, F., Vanslembrouck, R., Oijen, G. Van, Hoffmann, A., Dekker, H., Man, R. de, Drenth, J.P.H., Alamovitch, S., Plaisier, E., Favrole, P., Prost, C., Chen, Z., Agrmael, T. Van, Marro, B., Ronco, P., Zivna, M., Hulkova, H., Matignon, M., Hodanova, K., Vylet'al, P., Kalbacova, M., Baresova, V., Sikora, J., Blazkova, H., Zivny, J., Ivanek, R., Stranecky, V., Sovova, J., Claes, K., Lerut, E., Fryns, J.P., Hart, P. t, Hart, T., Adams, J., Pawtowski, A., Clemessy, M., Gasc, J., Gubler, M., Antignac, C., Elleder, M., Kapp, K., Grimbert, P., Bleyer, A., Kmoch, S., Brown, E., Schlondorff, J., Becker, D.J., Tsukaguchi, H., Uschinski, A., Higgs, H., Henderson, J., and Pollak, M.

Abstract

01 april 2010, Contains fulltext : 89212.pdf (publisher's version ) (Closed access)

Published
2010

31. Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy.

Author

Otto, E.A., Hurd, T.W., Airik, R., Chaki, M., Zhou, W., Stoetzel, C., Patil, S.B., Levy, S., Ghosh, A.K., Murga-Zamalloa, C.A., Reeuwijk, J. van, Letteboer, S.J.F., Sang, L., Giles, R.H., Liu, Q., Coene, K.L.M., Estrada-Cuzcano, A., Collin, R.W.J., McLaughlin, H.M., Held, S., Kasanuki, J.M., Ramaswami, G., Conte, J., Lopez, I., Washburn, J., Macdonald, J., Hu, J., Yamashita, Y., Maher, E.R., Guay-Woodford, L.M., Neumann, H.P., Obermuller, N., Koenekoop, R.K., Bergmann, C., Bei, X., Lewis, R.A., Katsanis, N., Lopes, V., Williams, D.S., Lyons, R.H., Dang, C.V., Brito, D.A., Dias, M.B., Zhang, X., Cavalcoli, J.D., Nurnberg, G., Nurnberg, P., Pierce, E.A., Jackson, P.K., Antignac, C., Saunier, S., Roepman, R., Dollfus, H., Khanna, H., Hildebrandt, F., Otto, E.A., Hurd, T.W., Airik, R., Chaki, M., Zhou, W., Stoetzel, C., Patil, S.B., Levy, S., Ghosh, A.K., Murga-Zamalloa, C.A., Reeuwijk, J. van, Letteboer, S.J.F., Sang, L., Giles, R.H., Liu, Q., Coene, K.L.M., Estrada-Cuzcano, A., Collin, R.W.J., McLaughlin, H.M., Held, S., Kasanuki, J.M., Ramaswami, G., Conte, J., Lopez, I., Washburn, J., Macdonald, J., Hu, J., Yamashita, Y., Maher, E.R., Guay-Woodford, L.M., Neumann, H.P., Obermuller, N., Koenekoop, R.K., Bergmann, C., Bei, X., Lewis, R.A., Katsanis, N., Lopes, V., Williams, D.S., Lyons, R.H., Dang, C.V., Brito, D.A., Dias, M.B., Zhang, X., Cavalcoli, J.D., Nurnberg, G., Nurnberg, P., Pierce, E.A., Jackson, P.K., Antignac, C., Saunier, S., Roepman, R., Dollfus, H., Khanna, H., and Hildebrandt, F.

Abstract

01 oktober 2010, Contains fulltext : 88200.pdf (publisher's version ) (Closed access), Nephronophthisis-related ciliopathies (NPHP-RC) are recessive disorders that feature dysplasia or degeneration occurring preferentially in the kidney, retina and cerebellum. Here we combined homozygosity mapping with candidate gene analysis by performing 'ciliopathy candidate exome capture' followed by massively parallel sequencing. We identified 12 different truncating mutations of SDCCAG8 (serologically defined colon cancer antigen 8, also known as CCCAP) in 10 families affected by NPHP-RC. We show that SDCCAG8 is localized at both centrioles and interacts directly with OFD1 (oral-facial-digital syndrome 1), which is associated with NPHP-RC. Depletion of sdccag8 causes kidney cysts and a body axis defect in zebrafish and induces cell polarity defects in three-dimensional renal cell cultures. This work identifies loss of SDCCAG8 function as a cause of a retinal-renal ciliopathy and validates exome capture analysis for broadly heterogeneous single-gene disorders.

Published
2010

32. EUNEFRON, the European Network for the Study of Orphan Nephropathies.

Author

Devuyst, O., Meij, I., Jeunemaitre, X., Ronco, P., Antignac, C., Christensen, E.I., Slobbe-Knoers, V.V.A.M., Levtchenko, E.N., Deen, P.M.T., Muller, D., Wagner, C.A., Rampoldi, L., Hoff, W.G. van 't, Devuyst, O., Meij, I., Jeunemaitre, X., Ronco, P., Antignac, C., Christensen, E.I., Slobbe-Knoers, V.V.A.M., Levtchenko, E.N., Deen, P.M.T., Muller, D., Wagner, C.A., Rampoldi, L., and Hoff, W.G. van 't

Abstract

Contains fulltext : 80881.pdf (publisher's version ) (Closed access)

Published
2009

33. EUNEFRON, the European Network for the Study of Orphan Nephropathies.

Author

Devuyst, O., Meij, I., Jeunemaitre, X., Ronco, P., Antignac, C., Christensen, E.I., Slobbe-Knoers, V.V.A.M., Levtchenko, E.N., Deen, P.M.T., Muller, D., Wagner, C.A., Rampoldi, L., Hoff, W.G. van 't, Devuyst, O., Meij, I., Jeunemaitre, X., Ronco, P., Antignac, C., Christensen, E.I., Slobbe-Knoers, V.V.A.M., Levtchenko, E.N., Deen, P.M.T., Muller, D., Wagner, C.A., Rampoldi, L., and Hoff, W.G. van 't

Abstract

Contains fulltext : 80881.pdf (publisher's version ) (Closed access)

Published
2009

34. EUNEFRON, the European Network for the Study of Orphan Nephropathies.

Author

Devuyst, O., Meij, I., Jeunemaitre, X., Ronco, P., Antignac, C., Christensen, E.I., Slobbe-Knoers, V.V.A.M., Levtchenko, E.N., Deen, P.M.T., Muller, D., Wagner, C.A., Rampoldi, L., Hoff, W.G. van 't, Devuyst, O., Meij, I., Jeunemaitre, X., Ronco, P., Antignac, C., Christensen, E.I., Slobbe-Knoers, V.V.A.M., Levtchenko, E.N., Deen, P.M.T., Muller, D., Wagner, C.A., Rampoldi, L., and Hoff, W.G. van 't

Abstract

Contains fulltext : 80881.pdf (publisher's version ) (Closed access)

Published
2009

35. EUNEFRON, the European Network for the Study of Orphan Nephropathies

Author

Devuyst, O, Meij, I, Jeunemaitre, X, Ronco, P, Antignac, C, Christensen, E I, Knoers, N V, Levtchenko, E N, Deen, P M, Müller, D, Wagner, C A, Rampoldi, L, Van't Hoff, W G, Devuyst, O, Meij, I, Jeunemaitre, X, Ronco, P, Antignac, C, Christensen, E I, Knoers, N V, Levtchenko, E N, Deen, P M, Müller, D, Wagner, C A, Rampoldi, L, and Van't Hoff, W G

Published
2009

36. Stem cell therapy for Alport syndrome: the hope beyond the hype

Author

Gross, O, Borza, D B, Andres, H J, Licht, C, Weber, M, Segerer, S, Torra, R, Gubler, M C, Heidet, L, Harvey, S, Cosgrove, D, Lees, G, Kashtan, C, Gregory, M, Savige, J, Ding, J, Thorner, P, Abrahamson, D R, Antignac, C, Tryggvason, K, Hudson, B, Miner, J H, Gross, O, Borza, D B, Andres, H J, Licht, C, Weber, M, Segerer, S, Torra, R, Gubler, M C, Heidet, L, Harvey, S, Cosgrove, D, Lees, G, Kashtan, C, Gregory, M, Savige, J, Ding, J, Thorner, P, Abrahamson, D R, Antignac, C, Tryggvason, K, Hudson, B, and Miner, J H

Published
2009

37. A novel renal carbonic anhydrase type III plays a role in proximal tubule dysfunction

Author

UCL - MD/FSIO - Département de physiologie et pharmacologie, UCL - MD/MINT - Département de médecine interne, UCL - MD/BICL - Département de biochimie et de biologie cellulaire, UCL - (SLuc) Service de néphrologie, UCL - (SLuc) Service de neurologie, UCL - (SLuc) Service de biochimie médicale, Gailly, Philippe, Jouret, François, Martin, Denis, Debaix, Huguette, Parreira, Kleber Simônio, Nishita, T, Blanchard, A, Antignac, C., Willnow, T E, Courtoy, Pierre J., Scheinman, S J, Christensen, E I, Devuyst, Olivier, UCL - MD/FSIO - Département de physiologie et pharmacologie, UCL - MD/MINT - Département de médecine interne, UCL - MD/BICL - Département de biochimie et de biologie cellulaire, UCL - (SLuc) Service de néphrologie, UCL - (SLuc) Service de neurologie, UCL - (SLuc) Service de biochimie médicale, Gailly, Philippe, Jouret, François, Martin, Denis, Debaix, Huguette, Parreira, Kleber Simônio, Nishita, T, Blanchard, A, Antignac, C., Willnow, T E, Courtoy, Pierre J., Scheinman, S J, Christensen, E I, and Devuyst, Olivier

Abstract

Dysfunction of the proximal tubule (PT) is associated with variable degrees of solute wasting and low-molecular-weight proteinuria. We measured metabolic consequences and adaptation mechanisms in a model of inherited PT disorders using PT cells of ClC-5-deficient (Clcn5Y/-) mice, a well-established model of Dent's disease. Compared to cells taken from control mice, those from the mutant mice had increased expression of markers of proliferation (Ki67, proliferative cell nuclear antigen (PCNA), and cyclin E) and oxidative scavengers (superoxide dismutase I and thioredoxin). Transcriptome and protein analyses showed fourfold induction of type III carbonic anhydrase in a kidney-specific manner in the knockout mice located in scattered PT cells. Kidney-specific carbonic anhydrase type III (CAIII) upregulation was confirmed in other mice lacking the multiligand receptor megalin and in a patient with Dent's disease due to an inactivating CLCN5 mutation. The type III enzyme was specifically detected in the urine of mice lacking ClC-5 or megalin, patients with Dent's disease, and in PT cell lines exposed to oxidative stress. Our study shows that lack of PT ClC-5 in mice and men is associated with CAIII induction, increased cell proliferation, and oxidative stress.Kidney International advance online publication, 5 March 2008; doi:10.1038/sj.ki.5002794.

Published
2008

38. Gene transfer may be preventive but not curative for a lysosomal transport disorder

Author

Hippert, C, Dubois, G, Morin, C, Disson, O, Ibanes, S, Jacquet, C, Schwendener, R, Antignac, C, Kremer, E J, Kalatzis, V, Hippert, C, Dubois, G, Morin, C, Disson, O, Ibanes, S, Jacquet, C, Schwendener, R, Antignac, C, Kremer, E J, and Kalatzis, V

Abstract

Cystinosis belongs to a growing class of lysosomal storage disorders (LSDs) caused by defective transmembrane proteins. The causative CTNS gene encodes the lysosomal cystine transporter, cystinosin. Currently the aminothiol cysteamine is the only drug available for reducing cystine storage but this treatment has non-negligible side effects and administration constraints. In this study, for the first time, we report viral vector-mediated CTNS gene transfer and evaluate the feasibility of this strategy as a complementary treatment. Initially, we transduced human CTNS(-/-) fibroblast cell lines and primary murine Ctns(-/-) hepatocyte cultures in vitro and demonstrated that gene transfer can reduce cystine storage. Because of age-related increase in cystine levels, we transduced hepatocytes from young (/=5 months of age) mice. Our in vitro data suggested that the efficiency of correction was age-dependent. We tested these observations in vivo: short-term (1 week) and long-term (4 weeks) CTNS-transduction significantly reduced hepatic cystine levels in young, but not older, Ctns(-/-) mice. Our data provide the proof-of-concept that gene transfer is feasible for correcting defective lysosomal transport, but suggest that, in the case of cystinosis, it could be preventive but not curative in some tissues.

Published
2008

39. Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure.

Author

Birkenhager, R., Otto, E., Schurmann, M.J., Volmer, M., Ruf, E.M., Maier-Lutz, I., Beekmann, F., Fekete, A., Omran, H., Feldmann, D., Milford, D.V., Jeck, N., Konrad, M., Landau, D., Knoers, N.V.A.M., Antignac, C., Sudbrak, R., Kispert, A., Hildebrandt, F., Birkenhager, R., Otto, E., Schurmann, M.J., Volmer, M., Ruf, E.M., Maier-Lutz, I., Beekmann, F., Fekete, A., Omran, H., Feldmann, D., Milford, D.V., Jeck, N., Konrad, M., Landau, D., Knoers, N.V.A.M., Antignac, C., Sudbrak, R., Kispert, A., and Hildebrandt, F.

Abstract

Item does not contain fulltext, Antenatal Bartter syndrome (aBS) comprises a heterogeneous group of autosomal recessive salt-losing nephropathies. Identification of three genes that code for renal transporters and channels as responsible for aBS has resulted in new insights into renal salt handling, diuretic action and blood-pressure regulation. A gene locus of a fourth variant of aBS called BSND, which in contrast to the other forms is associated with sensorineural deafness (SND) and renal failure, has been mapped to chromosome 1p. We report here the identification by positional cloning, in a region not covered by the human genome sequencing projects, of a new gene, BSND, as the cause of BSND. We examined ten families with BSND and detected seven different mutations in BSND that probably result in loss of function. In accordance with the phenotype, BSND is expressed in the thin limb and the thick ascending limb of the loop of Henle in the kidney and in the dark cells of the inner ear. The gene encodes a hitherto unknown protein with two putative transmembrane alpha-helices and thus might function as a regulator for ion-transport proteins involved in aBS, or else as a new transporter or channel itself.

Published
2001

40. Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure.

Author

Birkenhager, R., Otto, E., Schurmann, M.J., Volmer, M., Ruf, E.M., Maier-Lutz, I., Beekmann, F., Fekete, A., Omran, H., Feldmann, D., Milford, D.V., Jeck, N., Konrad, M., Landau, D., Knoers, N.V.A.M., Antignac, C., Sudbrak, R., Kispert, A., Hildebrandt, F., Birkenhager, R., Otto, E., Schurmann, M.J., Volmer, M., Ruf, E.M., Maier-Lutz, I., Beekmann, F., Fekete, A., Omran, H., Feldmann, D., Milford, D.V., Jeck, N., Konrad, M., Landau, D., Knoers, N.V.A.M., Antignac, C., Sudbrak, R., Kispert, A., and Hildebrandt, F.

Abstract

Item does not contain fulltext, Antenatal Bartter syndrome (aBS) comprises a heterogeneous group of autosomal recessive salt-losing nephropathies. Identification of three genes that code for renal transporters and channels as responsible for aBS has resulted in new insights into renal salt handling, diuretic action and blood-pressure regulation. A gene locus of a fourth variant of aBS called BSND, which in contrast to the other forms is associated with sensorineural deafness (SND) and renal failure, has been mapped to chromosome 1p. We report here the identification by positional cloning, in a region not covered by the human genome sequencing projects, of a new gene, BSND, as the cause of BSND. We examined ten families with BSND and detected seven different mutations in BSND that probably result in loss of function. In accordance with the phenotype, BSND is expressed in the thin limb and the thick ascending limb of the loop of Henle in the kidney and in the dark cells of the inner ear. The gene encodes a hitherto unknown protein with two putative transmembrane alpha-helices and thus might function as a regulator for ion-transport proteins involved in aBS, or else as a new transporter or channel itself.

Published
2001

41. Identification and characterisation of the murine homologue of the gene responsible for cystinosis, Ctns.

Author

Cherqui, S, Cherqui, S, Kalatzis, V, Forestier, L, Poras, I, Antignac, C, Cherqui, S, Cherqui, S, Kalatzis, V, Forestier, L, Poras, I, and Antignac, C

Abstract

BackgroundCystinosis is an autosomal recessive disorder characterised by an intralysosomal accumulation of cystine, and affected individuals progress to end-stage renal failure before the age of ten. The causative gene, CTNS, was cloned in 1998 and the encoded protein, cystinosin, was predicted to be a lysosomal membrane protein.ResultsWe have cloned the murine homologue of CTNS, Ctns, and the encoded amino acid sequence is 92.6% similar to cystinosin. We localised Ctns to mouse chromosome 11 in a region syntenic to human chromosome 17 containing CTNS. Ctns is widely expressed in all tissues tested with the exception of skeletal muscle, in contrast to CTNS.ConclusionsWe have isolated, characterised and localised Ctns, the murine homologue of CTNS underlying cystinosis. Furthermore, our work has brought to light the existence of a differential pattern of expression between the human and murine homologues, providing critical information for the generation of a mouse model for cystinosis.

Published
2000

42. Antenatal Bartter syndrome with sensorineural deafness: refinement of the locus on chromosome 1p31

Author

Volmer, M., Jeck, N., Lemmink, H.H., Vargas-Poussou, R., Feldmann, D., Konrad, M., Beekmann, F., Heuvel, L.P.W.J. van den, Deschenes, G., Guay-Woodford, L.M., Antignac, C., Seyberth, H.W., Hildebrandt, F., Knoers, N.V.A.M., Volmer, M., Jeck, N., Lemmink, H.H., Vargas-Poussou, R., Feldmann, D., Konrad, M., Beekmann, F., Heuvel, L.P.W.J. van den, Deschenes, G., Guay-Woodford, L.M., Antignac, C., Seyberth, H.W., Hildebrandt, F., and Knoers, N.V.A.M.

Abstract

Item does not contain fulltext

Published
2000

43. Autosomal dominant Alport syndrome caused by a Col 4A3 splice site mutation

Author

Loop, F. van de, Heidi, L., Timmer, E., Bosch, B. van den, Leinonen, A., Antignac, C., Jefferson, A., Maxwell, A.P., Monnens, L.A.H., Schröder, C.H., Smeets, H.J.M., Loop, F. van de, Heidi, L., Timmer, E., Bosch, B. van den, Leinonen, A., Antignac, C., Jefferson, A., Maxwell, A.P., Monnens, L.A.H., Schröder, C.H., and Smeets, H.J.M.

Abstract

Item does not contain fulltext

Published
2000

44. Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome.

Author

Konrad, M., Volmer, M., Lemmink, H.H., Heuvel, L.P.W.J. van den, Jeck, N., Vargas-Poussou, R., Lakings, A., Ruf, R., Deschenes, G., Antignac, C., Guay-Woodford, L.M., Knoers, N.V.A.M., Seyberth, H.W., Feldmann, D., Hildebrandt, F., Konrad, M., Volmer, M., Lemmink, H.H., Heuvel, L.P.W.J. van den, Jeck, N., Vargas-Poussou, R., Lakings, A., Ruf, R., Deschenes, G., Antignac, C., Guay-Woodford, L.M., Knoers, N.V.A.M., Seyberth, H.W., Feldmann, D., and Hildebrandt, F.

Abstract

Item does not contain fulltext

Published
2000

45. Identification and characterisation of the murine homologue of the gene responsible for cystinosis, Ctns.

Author

Cherqui, S, Cherqui, S, Kalatzis, V, Forestier, L, Poras, I, Antignac, C, Cherqui, S, Cherqui, S, Kalatzis, V, Forestier, L, Poras, I, and Antignac, C

Abstract

BackgroundCystinosis is an autosomal recessive disorder characterised by an intralysosomal accumulation of cystine, and affected individuals progress to end-stage renal failure before the age of ten. The causative gene, CTNS, was cloned in 1998 and the encoded protein, cystinosin, was predicted to be a lysosomal membrane protein.ResultsWe have cloned the murine homologue of CTNS, Ctns, and the encoded amino acid sequence is 92.6% similar to cystinosin. We localised Ctns to mouse chromosome 11 in a region syntenic to human chromosome 17 containing CTNS. Ctns is widely expressed in all tissues tested with the exception of skeletal muscle, in contrast to CTNS.ConclusionsWe have isolated, characterised and localised Ctns, the murine homologue of CTNS underlying cystinosis. Furthermore, our work has brought to light the existence of a differential pattern of expression between the human and murine homologues, providing critical information for the generation of a mouse model for cystinosis.

Published
2000

46. Antenatal Bartter syndrome with sensorineural deafness: refinement of the locus on chromosome 1p31

Author

Volmer, M., Jeck, N., Lemmink, H.H., Vargas-Poussou, R., Feldmann, D., Konrad, M., Beekmann, F., Heuvel, L.P.W.J. van den, Deschenes, G., Guay-Woodford, L.M., Antignac, C., Seyberth, H.W., Hildebrandt, F., Knoers, N.V.A.M., Volmer, M., Jeck, N., Lemmink, H.H., Vargas-Poussou, R., Feldmann, D., Konrad, M., Beekmann, F., Heuvel, L.P.W.J. van den, Deschenes, G., Guay-Woodford, L.M., Antignac, C., Seyberth, H.W., Hildebrandt, F., and Knoers, N.V.A.M.

Abstract

Item does not contain fulltext

Published
2000

47. Autosomal dominant Alport syndrome caused by a Col 4A3 splice site mutation

Author

Loop, F. van de, Heidi, L., Timmer, E., Bosch, B. van den, Leinonen, A., Antignac, C., Jefferson, A., Maxwell, A.P., Monnens, L.A.H., Schröder, C.H., Smeets, H.J.M., Loop, F. van de, Heidi, L., Timmer, E., Bosch, B. van den, Leinonen, A., Antignac, C., Jefferson, A., Maxwell, A.P., Monnens, L.A.H., Schröder, C.H., and Smeets, H.J.M.

Abstract

Item does not contain fulltext

Published
2000

48. Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome.

Author

Konrad, M., Volmer, M., Lemmink, H.H., Heuvel, L.P.W.J. van den, Jeck, N., Vargas-Poussou, R., Lakings, A., Ruf, R., Deschenes, G., Antignac, C., Guay-Woodford, L.M., Knoers, N.V.A.M., Seyberth, H.W., Feldmann, D., Hildebrandt, F., Konrad, M., Volmer, M., Lemmink, H.H., Heuvel, L.P.W.J. van den, Jeck, N., Vargas-Poussou, R., Lakings, A., Ruf, R., Deschenes, G., Antignac, C., Guay-Woodford, L.M., Knoers, N.V.A.M., Seyberth, H.W., Feldmann, D., and Hildebrandt, F.

Abstract

Item does not contain fulltext

Published
2000

49. Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome.

Author

Konrad, M., Volmer, M., Lemmink, H.H., Heuvel, L.P.W.J. van den, Jeck, N., Vargas-Poussou, R., Lakings, A., Ruf, R., Deschenes, G., Antignac, C., Guay-Woodford, L.M., Knoers, N.V.A.M., Seyberth, H.W., Feldmann, D., Hildebrandt, F., Konrad, M., Volmer, M., Lemmink, H.H., Heuvel, L.P.W.J. van den, Jeck, N., Vargas-Poussou, R., Lakings, A., Ruf, R., Deschenes, G., Antignac, C., Guay-Woodford, L.M., Knoers, N.V.A.M., Seyberth, H.W., Feldmann, D., and Hildebrandt, F.

Abstract

Item does not contain fulltext

Published
2000

50. Antenatal Bartter syndrome with sensorineural deafness: refinement of the locus on chromosome 1p31

Author

Volmer, M., Jeck, N., Lemmink, H.H., Vargas-Poussou, R., Feldmann, D., Konrad, M., Beekmann, F., Heuvel, L.P.W.J. van den, Deschenes, G., Guay-Woodford, L.M., Antignac, C., Seyberth, H.W., Hildebrandt, F., Knoers, N.V.A.M., Volmer, M., Jeck, N., Lemmink, H.H., Vargas-Poussou, R., Feldmann, D., Konrad, M., Beekmann, F., Heuvel, L.P.W.J. van den, Deschenes, G., Guay-Woodford, L.M., Antignac, C., Seyberth, H.W., Hildebrandt, F., and Knoers, N.V.A.M.

Abstract

Item does not contain fulltext

Published
2000

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