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Mutations in PRDM15 Are a Novel Cause of Galloway-Mowat Syndrome

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Mutations in PRDM15 Are a Novel Cause of Galloway-Mowat Syndrome. / Mann, Nina; Mzoughi, Slim; Schneider, Ronen; Kühl, Susanne J; Schanze, Denny; Klämbt, Verena; Lovric, Svjetlana; Mao, Youying; Shi, Shasha; Tan, Weizhen; Kühl, Michael; Onuchic-Whitford, Ana C; Treimer, Ernestine; Kitzler, Thomas M; Kause, Franziska; Schumann, Sven; Nakayama, Makiko; Buerger, Florian; Shril, Shirlee; van der Ven, Amelie T; Majmundar, Amar J; Holton, Kristina Marie; Kolb, Amy; Braun, Daniela A; Rao, Jia; Jobst-Schwan, Tilman; Mildenberger, Eva; Lennert, Thomas; Kuechler, Alma; Wieczorek, Dagmar; Gross, Oliver; Ermisch-Omran, Beate; Werberger, Anja; Skalej, Martin; Janecke, Andreas R; Soliman, Neveen A; Mane, Shrikant M; Lifton, Richard P; Kadlec, Jan; Guccione, Ernesto; Schmeisser, Michael J; Zenker, Martin; Hildebrandt, Friedhelm.

in: J AM SOC NEPHROL, Jahrgang 32, Nr. 3, 03.2021, S. 580-596.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Mann, N, Mzoughi, S, Schneider, R, Kühl, SJ, Schanze, D, Klämbt, V, Lovric, S, Mao, Y, Shi, S, Tan, W, Kühl, M, Onuchic-Whitford, AC, Treimer, E, Kitzler, TM, Kause, F, Schumann, S, Nakayama, M, Buerger, F, Shril, S, van der Ven, AT, Majmundar, AJ, Holton, KM, Kolb, A, Braun, DA, Rao, J, Jobst-Schwan, T, Mildenberger, E, Lennert, T, Kuechler, A, Wieczorek, D, Gross, O, Ermisch-Omran, B, Werberger, A, Skalej, M, Janecke, AR, Soliman, NA, Mane, SM, Lifton, RP, Kadlec, J, Guccione, E, Schmeisser, MJ, Zenker, M & Hildebrandt, F 2021, 'Mutations in PRDM15 Are a Novel Cause of Galloway-Mowat Syndrome', J AM SOC NEPHROL, Jg. 32, Nr. 3, S. 580-596. https://doi.org/10.1681/ASN.2020040490

APA

Mann, N., Mzoughi, S., Schneider, R., Kühl, S. J., Schanze, D., Klämbt, V., Lovric, S., Mao, Y., Shi, S., Tan, W., Kühl, M., Onuchic-Whitford, A. C., Treimer, E., Kitzler, T. M., Kause, F., Schumann, S., Nakayama, M., Buerger, F., Shril, S., ... Hildebrandt, F. (2021). Mutations in PRDM15 Are a Novel Cause of Galloway-Mowat Syndrome. J AM SOC NEPHROL, 32(3), 580-596. https://doi.org/10.1681/ASN.2020040490

Vancouver

Mann N, Mzoughi S, Schneider R, Kühl SJ, Schanze D, Klämbt V et al. Mutations in PRDM15 Are a Novel Cause of Galloway-Mowat Syndrome. J AM SOC NEPHROL. 2021 Mär;32(3):580-596. https://doi.org/10.1681/ASN.2020040490

Bibtex

@article{8b682f0e9f7949d19d7ec7ccd76baa8a,
title = "Mutations in PRDM15 Are a Novel Cause of Galloway-Mowat Syndrome",
abstract = "BACKGROUND: Galloway-Mowat syndrome (GAMOS) is characterized by neurodevelopmental defects and a progressive nephropathy, which typically manifests as steroid-resistant nephrotic syndrome. The prognosis of GAMOS is poor, and the majority of children progress to renal failure. The discovery of monogenic causes of GAMOS has uncovered molecular pathways involved in the pathogenesis of disease.METHODS: Homozygosity mapping, whole-exome sequencing, and linkage analysis were used to identify mutations in four families with a GAMOS-like phenotype, and high-throughput PCR technology was applied to 91 individuals with GAMOS and 816 individuals with isolated nephrotic syndrome. In vitro and in vivo studies determined the functional significance of the mutations identified.RESULTS: Three biallelic variants of the transcriptional regulator PRDM15 were detected in six families with proteinuric kidney disease. Four families with a variant in the protein's zinc-finger (ZNF) domain have additional GAMOS-like features, including brain anomalies, cardiac defects, and skeletal defects. All variants destabilize the PRDM15 protein, and the ZNF variant additionally interferes with transcriptional activation. Morpholino oligonucleotide-mediated knockdown of Prdm15 in Xenopus embryos disrupted pronephric development. Human wild-type PRDM15 RNA rescued the disruption, but the three PRDM15 variants did not. Finally, CRISPR-mediated knockout of PRDM15 in human podocytes led to dysregulation of several renal developmental genes.CONCLUSIONS: Variants in PRDM15 can cause either isolated nephrotic syndrome or a GAMOS-type syndrome on an allelic basis. PRDM15 regulates multiple developmental kidney genes, and is likely to play an essential role in renal development in humans.",
keywords = "Amino Acid Sequence, Amino Acid Substitution, Animals, Cell Line, Child, Preschool, DNA-Binding Proteins/chemistry, Female, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Gene Knockout Techniques, Hernia, Hiatal/genetics, High-Throughput Nucleotide Sequencing, Humans, Infant, Infant, Newborn, Male, Microcephaly/genetics, Models, Molecular, Mutation, Missense, Nephrosis/genetics, Nephrotic Syndrome/genetics, Podocytes/metabolism, Polymorphism, Single Nucleotide, Pronephros/embryology, Protein Stability, Transcription Factors/chemistry, Xenopus laevis/embryology, Zinc Fingers/genetics",
author = "Nina Mann and Slim Mzoughi and Ronen Schneider and K{\"u}hl, {Susanne J} and Denny Schanze and Verena Kl{\"a}mbt and Svjetlana Lovric and Youying Mao and Shasha Shi and Weizhen Tan and Michael K{\"u}hl and Onuchic-Whitford, {Ana C} and Ernestine Treimer and Kitzler, {Thomas M} and Franziska Kause and Sven Schumann and Makiko Nakayama and Florian Buerger and Shirlee Shril and {van der Ven}, {Amelie T} and Majmundar, {Amar J} and Holton, {Kristina Marie} and Amy Kolb and Braun, {Daniela A} and Jia Rao and Tilman Jobst-Schwan and Eva Mildenberger and Thomas Lennert and Alma Kuechler and Dagmar Wieczorek and Oliver Gross and Beate Ermisch-Omran and Anja Werberger and Martin Skalej and Janecke, {Andreas R} and Soliman, {Neveen A} and Mane, {Shrikant M} and Lifton, {Richard P} and Jan Kadlec and Ernesto Guccione and Schmeisser, {Michael J} and Martin Zenker and Friedhelm Hildebrandt",
note = "Copyright {\textcopyright} 2021 by the American Society of Nephrology.",
year = "2021",
month = mar,
doi = "10.1681/ASN.2020040490",
language = "English",
volume = "32",
pages = "580--596",
journal = "J AM SOC NEPHROL",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "3",

}

RIS

TY - JOUR

T1 - Mutations in PRDM15 Are a Novel Cause of Galloway-Mowat Syndrome

AU - Mann, Nina

AU - Mzoughi, Slim

AU - Schneider, Ronen

AU - Kühl, Susanne J

AU - Schanze, Denny

AU - Klämbt, Verena

AU - Lovric, Svjetlana

AU - Mao, Youying

AU - Shi, Shasha

AU - Tan, Weizhen

AU - Kühl, Michael

AU - Onuchic-Whitford, Ana C

AU - Treimer, Ernestine

AU - Kitzler, Thomas M

AU - Kause, Franziska

AU - Schumann, Sven

AU - Nakayama, Makiko

AU - Buerger, Florian

AU - Shril, Shirlee

AU - van der Ven, Amelie T

AU - Majmundar, Amar J

AU - Holton, Kristina Marie

AU - Kolb, Amy

AU - Braun, Daniela A

AU - Rao, Jia

AU - Jobst-Schwan, Tilman

AU - Mildenberger, Eva

AU - Lennert, Thomas

AU - Kuechler, Alma

AU - Wieczorek, Dagmar

AU - Gross, Oliver

AU - Ermisch-Omran, Beate

AU - Werberger, Anja

AU - Skalej, Martin

AU - Janecke, Andreas R

AU - Soliman, Neveen A

AU - Mane, Shrikant M

AU - Lifton, Richard P

AU - Kadlec, Jan

AU - Guccione, Ernesto

AU - Schmeisser, Michael J

AU - Zenker, Martin

AU - Hildebrandt, Friedhelm

N1 - Copyright © 2021 by the American Society of Nephrology.

PY - 2021/3

Y1 - 2021/3

N2 - BACKGROUND: Galloway-Mowat syndrome (GAMOS) is characterized by neurodevelopmental defects and a progressive nephropathy, which typically manifests as steroid-resistant nephrotic syndrome. The prognosis of GAMOS is poor, and the majority of children progress to renal failure. The discovery of monogenic causes of GAMOS has uncovered molecular pathways involved in the pathogenesis of disease.METHODS: Homozygosity mapping, whole-exome sequencing, and linkage analysis were used to identify mutations in four families with a GAMOS-like phenotype, and high-throughput PCR technology was applied to 91 individuals with GAMOS and 816 individuals with isolated nephrotic syndrome. In vitro and in vivo studies determined the functional significance of the mutations identified.RESULTS: Three biallelic variants of the transcriptional regulator PRDM15 were detected in six families with proteinuric kidney disease. Four families with a variant in the protein's zinc-finger (ZNF) domain have additional GAMOS-like features, including brain anomalies, cardiac defects, and skeletal defects. All variants destabilize the PRDM15 protein, and the ZNF variant additionally interferes with transcriptional activation. Morpholino oligonucleotide-mediated knockdown of Prdm15 in Xenopus embryos disrupted pronephric development. Human wild-type PRDM15 RNA rescued the disruption, but the three PRDM15 variants did not. Finally, CRISPR-mediated knockout of PRDM15 in human podocytes led to dysregulation of several renal developmental genes.CONCLUSIONS: Variants in PRDM15 can cause either isolated nephrotic syndrome or a GAMOS-type syndrome on an allelic basis. PRDM15 regulates multiple developmental kidney genes, and is likely to play an essential role in renal development in humans.

AB - BACKGROUND: Galloway-Mowat syndrome (GAMOS) is characterized by neurodevelopmental defects and a progressive nephropathy, which typically manifests as steroid-resistant nephrotic syndrome. The prognosis of GAMOS is poor, and the majority of children progress to renal failure. The discovery of monogenic causes of GAMOS has uncovered molecular pathways involved in the pathogenesis of disease.METHODS: Homozygosity mapping, whole-exome sequencing, and linkage analysis were used to identify mutations in four families with a GAMOS-like phenotype, and high-throughput PCR technology was applied to 91 individuals with GAMOS and 816 individuals with isolated nephrotic syndrome. In vitro and in vivo studies determined the functional significance of the mutations identified.RESULTS: Three biallelic variants of the transcriptional regulator PRDM15 were detected in six families with proteinuric kidney disease. Four families with a variant in the protein's zinc-finger (ZNF) domain have additional GAMOS-like features, including brain anomalies, cardiac defects, and skeletal defects. All variants destabilize the PRDM15 protein, and the ZNF variant additionally interferes with transcriptional activation. Morpholino oligonucleotide-mediated knockdown of Prdm15 in Xenopus embryos disrupted pronephric development. Human wild-type PRDM15 RNA rescued the disruption, but the three PRDM15 variants did not. Finally, CRISPR-mediated knockout of PRDM15 in human podocytes led to dysregulation of several renal developmental genes.CONCLUSIONS: Variants in PRDM15 can cause either isolated nephrotic syndrome or a GAMOS-type syndrome on an allelic basis. PRDM15 regulates multiple developmental kidney genes, and is likely to play an essential role in renal development in humans.

KW - Amino Acid Sequence

KW - Amino Acid Substitution

KW - Animals

KW - Cell Line

KW - Child, Preschool

KW - DNA-Binding Proteins/chemistry

KW - Female

KW - Gene Expression Regulation, Developmental

KW - Gene Knockdown Techniques

KW - Gene Knockout Techniques

KW - Hernia, Hiatal/genetics

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Male

KW - Microcephaly/genetics

KW - Models, Molecular

KW - Mutation, Missense

KW - Nephrosis/genetics

KW - Nephrotic Syndrome/genetics

KW - Podocytes/metabolism

KW - Polymorphism, Single Nucleotide

KW - Pronephros/embryology

KW - Protein Stability

KW - Transcription Factors/chemistry

KW - Xenopus laevis/embryology

KW - Zinc Fingers/genetics

U2 - 10.1681/ASN.2020040490

DO - 10.1681/ASN.2020040490

M3 - SCORING: Journal article

C2 - 33593823

VL - 32

SP - 580

EP - 596

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 3

ER -