Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT)
Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved..
Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below age 30 years. Many monogenic forms have been discovered due to comprehensive genetic testing like exome sequencing. However, disease-causing variants in known disease-associated genes only explain a proportion of cases. Here, we aim to unravel underlying molecular mechanisms of syndromic CAKUT in three unrelated multiplex families with presumed autosomal recessive inheritance. Exome sequencing in the index individuals revealed three different rare homozygous variants in FOXD2, encoding a transcription factor not previously implicated in CAKUT in humans: a frameshift in the Arabic and a missense variant each in the Turkish and the Israeli family with segregation patterns consistent with autosomal recessive inheritance. CRISPR/Cas9-derived Foxd2 knockout mice presented with a bilateral dilated kidney pelvis accompanied by atrophy of the kidney papilla and mandibular, ophthalmologic, and behavioral anomalies, recapitulating the human phenotype. In a complementary approach to study pathomechanisms of FOXD2-dysfunction-mediated developmental kidney defects, we generated CRISPR/Cas9-mediated knockout of Foxd2 in ureteric bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important for kidney/urogenital development, including Pax2 and Wnt4 as well as gene expression changes indicating a shift toward a stromal cell identity. Histology of Foxd2 knockout mouse kidneys confirmed increased fibrosis. Further, genome-wide association studies suggest that FOXD2 could play a role for maintenance of podocyte integrity during adulthood. Thus, our studies help in genetic diagnostics of monogenic CAKUT and in understanding of monogenic and multifactorial kidney diseases.
| Errataetall: | |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:105 |
|---|---|
| Enthalten in: |
Kidney international - 105(2024), 4 vom: 01. Apr., Seite 844-864 |
| Sprache: |
Englisch |
|---|
| Links: |
|---|
| Themen: |
CAKUT |
|---|
| Anmerkungen: |
Date Completed 25.03.2024 Date Revised 02.04.2024 published: Print-Electronic UpdateOf: medRxiv. 2023 Mar 22;:. - PMID 36993625 Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.kint.2023.11.032 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM36645207X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM36645207X | ||
| 003 | DE-627 | ||
| 005 | 20240403000015.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240108s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.kint.2023.11.032 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1361.xml |
| 035 | |a (DE-627)NLM36645207X | ||
| 035 | |a (NLM)38154558 | ||
| 035 | |a (PII)S0085-2538(23)00917-1 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Riedhammer, Korbinian M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT) |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 25.03.2024 | ||
| 500 | |a Date Revised 02.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a UpdateOf: medRxiv. 2023 Mar 22;:. - PMID 36993625 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below age 30 years. Many monogenic forms have been discovered due to comprehensive genetic testing like exome sequencing. However, disease-causing variants in known disease-associated genes only explain a proportion of cases. Here, we aim to unravel underlying molecular mechanisms of syndromic CAKUT in three unrelated multiplex families with presumed autosomal recessive inheritance. Exome sequencing in the index individuals revealed three different rare homozygous variants in FOXD2, encoding a transcription factor not previously implicated in CAKUT in humans: a frameshift in the Arabic and a missense variant each in the Turkish and the Israeli family with segregation patterns consistent with autosomal recessive inheritance. CRISPR/Cas9-derived Foxd2 knockout mice presented with a bilateral dilated kidney pelvis accompanied by atrophy of the kidney papilla and mandibular, ophthalmologic, and behavioral anomalies, recapitulating the human phenotype. In a complementary approach to study pathomechanisms of FOXD2-dysfunction-mediated developmental kidney defects, we generated CRISPR/Cas9-mediated knockout of Foxd2 in ureteric bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important for kidney/urogenital development, including Pax2 and Wnt4 as well as gene expression changes indicating a shift toward a stromal cell identity. Histology of Foxd2 knockout mouse kidneys confirmed increased fibrosis. Further, genome-wide association studies suggest that FOXD2 could play a role for maintenance of podocyte integrity during adulthood. Thus, our studies help in genetic diagnostics of monogenic CAKUT and in understanding of monogenic and multifactorial kidney diseases | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a CAKUT | |
| 650 | 4 | |a FOXD2 | |
| 650 | 4 | |a PAX2 | |
| 650 | 4 | |a WNT4 | |
| 650 | 4 | |a chronic kidney disease | |
| 650 | 4 | |a renal hypoplasia | |
| 650 | 4 | |a urinary albumin-to-creatinine ratio (UACR) | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 650 | 7 | |a Foxd2 protein, mouse |2 NLM | |
| 650 | 7 | |a Forkhead Transcription Factors |2 NLM | |
| 700 | 1 | |a Nguyen, Thanh-Minh T |e verfasserin |4 aut | |
| 700 | 1 | |a Koşukcu, Can |e verfasserin |4 aut | |
| 700 | 1 | |a Calzada-Wack, Julia |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Assia Batzir, Nurit |e verfasserin |4 aut | |
| 700 | 1 | |a Saygılı, Seha |e verfasserin |4 aut | |
| 700 | 1 | |a Wimmers, Vera |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Gwang-Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Chrysanthou, Marialena |e verfasserin |4 aut | |
| 700 | 1 | |a Bakey, Zeineb |e verfasserin |4 aut | |
| 700 | 1 | |a Sofrin-Drucker, Efrat |e verfasserin |4 aut | |
| 700 | 1 | |a Kraiger, Markus |e verfasserin |4 aut | |
| 700 | 1 | |a Sanz-Moreno, Adrián |e verfasserin |4 aut | |
| 700 | 1 | |a Amarie, Oana V |e verfasserin |4 aut | |
| 700 | 1 | |a Rathkolb, Birgit |e verfasserin |4 aut | |
| 700 | 1 | |a Klein-Rodewald, Tanja |e verfasserin |4 aut | |
| 700 | 1 | |a Garrett, Lillian |e verfasserin |4 aut | |
| 700 | 1 | |a Hölter, Sabine M |e verfasserin |4 aut | |
| 700 | 1 | |a Seisenberger, Claudia |e verfasserin |4 aut | |
| 700 | 1 | |a Haug, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Schlosser, Pascal |e verfasserin |4 aut | |
| 700 | 1 | |a Marschall, Susan |e verfasserin |4 aut | |
| 700 | 1 | |a Wurst, Wolfgang |e verfasserin |4 aut | |
| 700 | 1 | |a Fuchs, Helmut |e verfasserin |4 aut | |
| 700 | 1 | |a Gailus-Durner, Valerie |e verfasserin |4 aut | |
| 700 | 1 | |a Wuttke, Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a Hrabe de Angelis, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Ćomić, Jasmina |e verfasserin |4 aut | |
| 700 | 1 | |a Akgün Doğan, Özlem |e verfasserin |4 aut | |
| 700 | 1 | |a Özlük, Yasemin |e verfasserin |4 aut | |
| 700 | 1 | |a Taşdemir, Mehmet |e verfasserin |4 aut | |
| 700 | 1 | |a Ağbaş, Ayşe |e verfasserin |4 aut | |
| 700 | 1 | |a Canpolat, Nur |e verfasserin |4 aut | |
| 700 | 1 | |a Orenstein, Naama |e verfasserin |4 aut | |
| 700 | 1 | |a Çalışkan, Salim |e verfasserin |4 aut | |
| 700 | 1 | |a Weber, Ruthild G |e verfasserin |4 aut | |
| 700 | 1 | |a Bergmann, Carsten |e verfasserin |4 aut | |
| 700 | 1 | |a Jeanpierre, Cecile |e verfasserin |4 aut | |
| 700 | 1 | |a Saunier, Sophie |e verfasserin |4 aut | |
| 700 | 1 | |a Lim, Tze Y |e verfasserin |4 aut | |
| 700 | 1 | |a Hildebrandt, Friedhelm |e verfasserin |4 aut | |
| 700 | 1 | |a Alhaddad, Bader |e verfasserin |4 aut | |
| 700 | 1 | |a Basel-Salmon, Lina |e verfasserin |4 aut | |
| 700 | 1 | |a Borovitz, Yael |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Kaman |e verfasserin |4 aut | |
| 700 | 1 | |a Antony, Dinu |e verfasserin |4 aut | |
| 700 | 1 | |a Matschkal, Julia |e verfasserin |4 aut | |
| 700 | 1 | |a Schaaf, Christian W |e verfasserin |4 aut | |
| 700 | 1 | |a Renders, Lutz |e verfasserin |4 aut | |
| 700 | 1 | |a Schmaderer, Christoph |e verfasserin |4 aut | |
| 700 | 1 | |a Rogg, Manuel |e verfasserin |4 aut | |
| 700 | 1 | |a Schell, Christoph |e verfasserin |4 aut | |
| 700 | 1 | |a Meitinger, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Heemann, Uwe |e verfasserin |4 aut | |
| 700 | 1 | |a Köttgen, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Arnold, Sebastian J |e verfasserin |4 aut | |
| 700 | 1 | |a Ozaltin, Fatih |e verfasserin |4 aut | |
| 700 | 1 | |a Schmidts, Miriam |e verfasserin |4 aut | |
| 700 | 1 | |a Hoefele, Julia |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Kidney international |d 1972 |g 105(2024), 4 vom: 01. Apr., Seite 844-864 |w (DE-627)NLM000007188 |x 1523-1755 |7 nnns |
| 773 | 1 | 8 | |g volume:105 |g year:2024 |g number:4 |g day:01 |g month:04 |g pages:844-864 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.kint.2023.11.032 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 105 |j 2024 |e 4 |b 01 |c 04 |h 844-864 | ||