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, Vol. 32, No. 3, 03.2021, p. 580-596.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -