Publications by authors named "Isabel Ottlewski"

5 Publications

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Recessive variants impair actin remodeling and cause glomerulopathy in humans and mice.

Sci Adv 2021 Jan 1;7(1). Epub 2021 Jan 1.

Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Nephrotic syndrome (NS) is a leading cause of chronic kidney disease. We found recessive variants in two families with early-onset NS by exome sequencing. Overexpression of wild-type (WT) , but not cDNA constructs bearing patient variants, increased active CDC42 and promoted filopodia and podosome formation. Pharmacologic inhibition of CDC42 or its effectors, formin proteins, reduced NOS1AP-induced filopodia formation. knockdown reduced podocyte migration rate (PMR), which was rescued by overexpression of WT but not by constructs bearing patient variants. PMR in knockdown podocytes was also rescued by constitutively active or the formin Modeling a patient variant in knock-in human kidney organoids revealed malformed glomeruli with increased apoptosis. mice recapitulated the human phenotype, exhibiting proteinuria, foot process effacement, and glomerulosclerosis. These findings demonstrate that recessive variants impair CDC42/DIAPH-dependent actin remodeling, cause aberrant organoid glomerulogenesis, and lead to a glomerulopathy in humans and mice.
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http://dx.doi.org/10.1126/sciadv.abe1386DOI Listing
January 2021

Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.

Authors:
Dervla M Connaughton Rufeng Dai Danielle J Owen Jonathan Marquez Nina Mann Adda L Graham-Paquin Makiko Nakayama Etienne Coyaud Estelle M N Laurent Jonathan R St-Germain Lot Snijders Blok Arianna Vino Verena Klämbt Konstantin Deutsch Chen-Han Wilfred Wu Caroline M Kolvenbach Franziska Kause Isabel Ottlewski Ronen Schneider Thomas M Kitzler Amar J Majmundar Florian Buerger Ana C Onuchic-Whitford Mao Youying Amy Kolb Daanya Salmanullah Evan Chen Amelie T van der Ven Jia Rao Hadas Ityel Steve Seltzsam Johanna M Rieke Jing Chen Asaf Vivante Daw-Yang Hwang Stefan Kohl Gabriel C Dworschak Tobias Hermle Mariëlle Alders Tobias Bartolomaeus Stuart B Bauer Michelle A Baum Eva H Brilstra Thomas D Challman Jacob Zyskind Carrie E Costin Katrina M Dipple Floor A Duijkers Marcia Ferguson David R Fitzpatrick Roger Fick Ian A Glass Peter J Hulick Antonie D Kline Ilona Krey Selvin Kumar Weining Lu Elysa J Marco Ingrid M Wentzensen Heather C Mefford Konrad Platzer Inna S Povolotskaya Juliann M Savatt Natalia V Shcherbakova Prabha Senguttuvan Audrey E Squire Deborah R Stein Isabelle Thiffault Victoria Y Voinova Michael J G Somers Michael A Ferguson Avram Z Traum Ghaleb H Daouk Ankana Daga Nancy M Rodig Paulien A Terhal Ellen van Binsbergen Loai A Eid Velibor Tasic Hila Milo Rasouly Tze Y Lim Dina F Ahram Ali G Gharavi Heiko M Reutter Heidi L Rehm Daniel G MacArthur Monkol Lek Kristen M Laricchia Richard P Lifton Hong Xu Shrikant M Mane Simone Sanna-Cherchi Andrew D Sharrocks Brian Raught Simon E Fisher Maxime Bouchard Mustafa K Khokha Shirlee Shril Friedhelm Hildebrandt

Am J Hum Genet 2020 10 4;107(4):727-742. Epub 2020 Sep 4.

Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.
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http://dx.doi.org/10.1016/j.ajhg.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536580PMC
October 2020

Phenotype expansion of heterozygous FOXC1 pathogenic variants toward involvement of congenital anomalies of the kidneys and urinary tract (CAKUT).

Genet Med 2020 10 1;22(10):1673-1681. Epub 2020 Jun 1.

Department of Pediatrics, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA.

Purpose: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in childhood and adolescence. We aim to identify novel monogenic causes of CAKUT.

Methods: Exome sequencing was performed in 550 CAKUT-affected families.

Results: We discovered seven FOXC1 heterozygous likely pathogenic variants within eight CAKUT families. These variants are either never reported, or present in <5 alleles in the gnomAD database with ~141,456 controls. FOXC1 is a causal gene for Axenfeld-Rieger syndrome type 3 and anterior segment dysgenesis 3. Pathogenic variants in FOXC1 have not been detected in patients with CAKUT yet. Interestingly, mouse models for Foxc1 show severe CAKUT phenotypes with incomplete penetrance and variable expressivity. The FOXC1 variants are enriched in the CAKUT cohort compared with the control. Genotype-phenotype correlations showed that Axenfeld-Rieger syndrome or anterior segment dysgenesis can be caused by both truncating and missense pathogenic variants, and the missense variants are located at the forkhead domain. In contrast, for CAKUT, there is no truncating pathogenic variant, and all variants except one are located outside the forkhead domain.

Conclusion: We thereby expanded the phenotype of FOXC1 pathogenic variants toward involvement of CAKUT, which can potentially be explained by allelism.
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http://dx.doi.org/10.1038/s41436-020-0844-zDOI Listing
October 2020

Whole exome sequencing identified ATP6V1C2 as a novel candidate gene for recessive distal renal tubular acidosis.

Kidney Int 2020 03 22;97(3):567-579. Epub 2019 Oct 22.

Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Distal renal tubular acidosis is a rare renal tubular disorder characterized by hyperchloremic metabolic acidosis and impaired urinary acidification. Mutations in three genes (ATP6V0A4, ATP6V1B1 and SLC4A1) constitute a monogenic causation in 58-70% of familial cases of distal renal tubular acidosis. Recently, mutations in FOXI1 have been identified as an additional cause. Therefore, we hypothesized that further monogenic causes of distal renal tubular acidosis remain to be discovered. Panel sequencing and/or whole exome sequencing was performed in a cohort of 17 families with 19 affected individuals with pediatric onset distal renal tubular acidosis. A causative mutation was detected in one of the three "classical" known distal renal tubular acidosis genes in 10 of 17 families. The seven unsolved families were then subjected to candidate whole exome sequencing analysis. Potential disease causing mutations in three genes were detected: ATP6V1C2, which encodes another kidney specific subunit of the V-type proton ATPase (1 family); WDR72 (2 families), previously implicated in V-ATPase trafficking in cells; and SLC4A2 (1 family), a paralog of the known distal renal tubular acidosis gene SLC4A1. Two of these mutations were assessed for deleteriousness through functional studies. Yeast growth assays for ATP6V1C2 revealed loss-of-function for the patient mutation, strongly supporting ATP6V1C2 as a novel distal renal tubular acidosis gene. Thus, we provided a molecular diagnosis in a known distal renal tubular acidosis gene in 10 of 17 families (59%) with this disease, identified mutations in ATP6V1C2 as a novel human candidate gene, and provided further evidence for phenotypic expansion in WDR72 mutations from amelogenesis imperfecta to distal renal tubular acidosis.
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http://dx.doi.org/10.1016/j.kint.2019.09.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039771PMC
March 2020

Value of renal gene panel diagnostics in adults waiting for kidney transplantation due to undetermined end-stage renal disease.

Kidney Int 2019 07 15;96(1):222-230. Epub 2019 Mar 15.

Division of Nephrology, Department of Internal Medicine, University Hospital Leipzig, Leipzig, Germany. Electronic address:

End-stage renal disease (ESRD) of undetermined etiology is highly prevalent and constitutes a significant clinical challenge, particularly in the context of kidney transplantation (KT). Despite the identification of numerous rare hereditary nephropathies over the last few decades, patients with undetermined ESRD are not being systematically investigated for rare genetic causes in clinical practice. To address this, we utilized mutation analysis in patients on the kidney transplant waitlist and scrutinized underlying renal diagnoses of 142 patients in a single center KT-waitlist. This cohort was stratified into 85 cases of determined and 57 cases of undetermined ESRD. The latter patients were analyzed by a renal gene panel for mutations in 209 genes associated with ESRD. The most likely genetic diagnoses in 12% of the tested individuals with undetermined ESRD were established. All of these patients showed mutations in genes encoding components of the glomerular filtration barrier. Taken together, hereditary nephropathies, including autosomal dominant polycystic kidney disease, were identified in 35 of the 142 patients of the waitlist cohort. By significantly increasing the proportion of hereditary diagnoses from 29 to 35 patients, the rate of undetermined ESRD significantly decreased from 57 to 51 patients. This study demonstrates the beneficial use of genetic diagnostics in significantly unraveling undetermined ESRD cases prior to KT. Thus, in the absence of renal histology or the presence of unspecific histological conditions, such as hypertensive nephrosclerosis, focal segmental glomerulosclerosis or thrombotic microangiopathy, genetic analysis may provide a robust and specific renal diagnosis and allow for optimizing pre- and post-KT management.
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http://dx.doi.org/10.1016/j.kint.2019.01.038DOI Listing
July 2019