@article {985, title = {Generation of Monogenic Candidate Genes for Human Nephrotic Syndrome Using 3 Independent Approaches.}, journal = {Kidney Int Rep}, volume = {6}, year = {2021}, month = {2021 Feb}, pages = {460-471}, abstract = {

Introduction: Steroid-resistant nephrotic syndrome (SRNS) is the second most common cause of chronic kidney disease during childhood. Identification of 63 monogenic human genes has delineated 12 distinct pathogenic pathways.

Methods: Here, we generated 2 independent sets of nephrotic syndrome (NS) candidate genes to augment the discovery of additional monogenic causes based on whole-exome sequencing (WES) data from 1382 families with NS.

Results: We first identified 63 known monogenic causes of NS in mice from public databases and scientific publications, and 12 of these genes overlapped with the 63 known human monogenic SRNS genes. Second, we used a set of 64 genes that are regulated by the transcription factor Wilms tumor 1 (WT1), which causes SRNS if mutated. Thirteen of these WT1-regulated genes overlapped with human or murine NS genes. Finally, we overlapped these lists of murine and WT1 candidate genes with our list of 120 candidate genes generated from WES in 1382 NS families, to identify novel candidate genes for monogenic human SRNS. Using this approach, we identified 7 overlapping genes, of which 3 genes were shared by all datasets, including . We show that loss-of-function of leads to decreased CDC42 activity and reduced podocyte migration rate, both of which are rescued by overexpression of wild-type complementary DNA (cDNA), but not by cDNA representing the patient mutation.

Conclusion: Thus, we identified 3 novel candidate genes for human SRNS using 3 independent, nonoverlapping hypotheses, and generated functional evidence for as a novel potential monogenic cause of NS.

}, issn = {2468-0249}, doi = {10.1016/j.ekir.2020.11.013}, author = {Kl{\"a}mbt, Verena and Mao, Youying and Schneider, Ronen and Buerger, Florian and Shamseldin, Hanan and Onuchic-Whitford, Ana C and Deutsch, Konstantin and Kitzler, Thomas M and Nakayama, Makiko and Majmundar, Amar J and Mann, Nina and Hugo, Hannah and Widmeier, Eugen and Tan, Weizhen and Rehm, Heidi L and Mane, Shrikant and Lifton, Richard P and Alkuraya, Fowzan S and Shril, Shirlee and Hildebrandt, Friedhelm} } @article {951, title = { variants are associated with multiple congenital anomalies including ciliopathy phenotypes.}, journal = {J Med Genet}, year = {2020}, month = {2020 Jul 06}, abstract = {

BACKGROUND: Cilia are dynamic cellular extensions that generate and sense signals to orchestrate proper development and tissue homeostasis. They rely on the underlying polarisation of cells to participate in signalling. Cilia dysfunction is a well-known cause of several diseases that affect multiple organ systems including the kidneys, brain, heart, respiratory tract, skeleton and retina.

METHODS: Among individuals from four unrelated families, we identified variants in ( that manifested in a variety of pathologies. In our proband, we also examined patient tissues. We depleted in frog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of patient variants through rescue experiments in the frog model.

RESULTS: Patients with variants of were found to have a variety of phenotypes including cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. We also observed a loss of cilia in cystic kidney tissue of our proband. Knockdown of in embryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype in frog embryos depleted of introduction of patient variants was largely ineffective in restoring proper ciliation and tissue morphology in the kidney and brain suggesting that the variants were indeed detrimental to function.

CONCLUSION: These findings in both patient tissues and shed light on how mutations in may lead to tissue-specific manifestations of disease. DLG5 is essential for cilia and many of the patient phenotypes are in the ciliopathy spectrum.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2019-106805}, author = {Marquez, Jonathan and Mann, Nina and Arana, Kathya and Deniz, Engin and Ji, Weizhen and Konstantino, Monica and Mis, Emily K and Deshpande, Charu and Jeffries, Lauren and McGlynn, Julie and Hugo, Hannah and Widmeier, Eugen and Konrad, Martin and Tasic, Velibor and Morotti, Raffaella and Baptista, Julia and Ellard, Sian and Lakhani, Saquib Ali and Hildebrandt, Friedhelm and Khokha, Mustafa K} } @article {587, title = {Genetic variants in the LAMA5 gene in pediatric nephrotic syndrome.}, journal = {Nephrol Dial Transplant}, volume = {34}, year = {2019}, month = {2019 03 01}, pages = {485-493}, abstract = {

BACKGROUND: Nephrotic syndrome (NS), a chronic kidney disease, is characterized by significant loss of protein in the urine causing hypoalbuminemia and edema. In general, \~{}15\% of childhood-onset cases do not respond to steroid therapy and are classified as steroid-resistant NS (SRNS). In \~{}30\% of cases with SRNS, a causative mutation can be detected in one of 44 monogenic SRNS genes. The gene LAMA5 encodes laminin-α5, an essential component of the glomerular basement membrane. Mice with a hypomorphic mutation in the orthologous gene Lama5 develop proteinuria and hematuria.

METHODS: To identify additional monogenic causes of NS, we performed whole exome sequencing in 300 families with pediatric NS. In consanguineous families we applied homozygosity mapping to identify genomic candidate loci for the underlying recessive mutation.

RESULTS: In three families, in whom mutations in known NS genes were excluded, but in whom a recessive, monogenic cause of NS was strongly suspected based on pedigree information, we identified homozygous variants of unknown significance (VUS) in the gene LAMA5. While all affected individuals had nonsyndromic NS with an early onset of disease, their clinical outcome and response to immunosuppressive therapy differed notably.

CONCLUSION: We here identify recessive VUS in the gene LAMA5 in patients with partially treatment-responsive NS. More data will be needed to determine the impact of these VUS in disease management. However, familial occurrence of disease, data from genetic mapping and a mouse model that recapitulates the NS phenotypes suggest that these genetic variants may be inherited factors that contribute to the development of NS in pediatric patients.

}, issn = {1460-2385}, doi = {10.1093/ndt/gfy028}, author = {Braun, Daniela A and Warejko, Jillian K and Ashraf, Shazia and Tan, Weizhen and Daga, Ankana and Schneider, Ronen and Hermle, Tobias and Jobst-Schwan, Tilman and Widmeier, Eugen and Majmundar, Amar J and Nakayama, Makiko and Schapiro, David and Rao, Jia and Schmidt, Johanna Magdalena and Hoogstraten, Charlotte A and Hugo, Hannah and Bakkaloglu, Sevcan A and Kari, Jameela A and El Desoky, Sherif and Daouk, Ghaleb and Mane, Shrikant and Lifton, Richard P and Shril, Shirlee and Hildebrandt, Friedhelm} } @article {701, title = {Mutations in KIRREL1, a slit diaphragm component, cause steroid-resistant nephrotic syndrome.}, journal = {Kidney Int}, volume = {96}, year = {2019}, month = {2019 Oct}, pages = {883-889}, abstract = {

Steroid-resistant nephrotic syndrome is a frequent cause of chronic kidney disease almost inevitably progressing to end-stage renal disease. More than 58 monogenic causes of SRNS have been discovered and majority of known steroid-resistant nephrotic syndrome causing genes are predominantly expressed in glomerular podocytes, placing them at the center of disease pathogenesis. Herein, we describe two unrelated families with steroid-resistant nephrotic syndrome with homozygous mutations in the KIRREL1 gene. One mutation showed high frequency in the European population (minor allele frequency 0.0011) and this patient achieved complete remission following treatment, but later progressed to chronic kidney disease. We found that mutant KIRREL1 proteins failed to localize to the podocyte cell membrane, indicating defective trafficking and impaired podocytes function. Thus, the KIRREL1 gene product has an important role in modulating the integrity of the slit diaphragm and maintaining glomerular filtration function.

}, issn = {1523-1755}, doi = {10.1016/j.kint.2019.06.016}, author = {Solanki, Ashish K and Widmeier, Eugen and Arif, Ehtesham and Sharma, Shailza and Daga, Ankana and Srivastava, Pankaj and Kwon, Sang-Ho and Hugo, Hannah and Nakayama, Makiko and Mann, Nina and Majmundar, Amar J and Tan, Wei and Gee, Heon Yung and Sadowski, Caroline E and Rinat, Choni and Becker-Cohen, Rachel and Bergmann, Carsten and Rosen, Seymour and Somers, Michael and Shril, Shirlee and Huber, Tobias B and Mane, Shrikant and Hildebrandt, Friedhelm and Nihalani, Deepak} } @article {596, title = {Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients.}, journal = {J Am Soc Nephrol}, volume = {30}, year = {2019}, month = {2019 02}, pages = {201-215}, abstract = {

BACKGROUND: Whole-exome sequencing (WES) finds a CKD-related mutation in approximately 20\% of patients presenting with CKD before 25 years of age. Although provision of a molecular diagnosis could have important implications for clinical management, evidence is lacking on the diagnostic yield and clinical utility of WES for pediatric renal transplant recipients.

METHODS: To determine the diagnostic yield of WES in pediatric kidney transplant recipients, we recruited 104 patients who had received a transplant at Boston Children{\textquoteright}s Hospital from 2007 through 2017, performed WES, and analyzed results for likely deleterious variants in approximately 400 genes known to cause CKD.

RESULTS: By WES, we identified a genetic cause of CKD in 34 out of 104 (32.7\%) transplant recipients. The likelihood of detecting a molecular genetic diagnosis was highest for patients with urinary stone disease (three out of three individuals), followed by renal cystic ciliopathies (seven out of nine individuals), steroid-resistant nephrotic syndrome (nine out of 21 individuals), congenital anomalies of the kidney and urinary tract (ten out of 55 individuals), and chronic glomerulonephritis (one out of seven individuals). WES also yielded a molecular diagnosis for four out of nine individuals with ESRD of unknown etiology. The WES-related molecular genetic diagnosis had implications for clinical care for five patients.

CONCLUSIONS: Nearly one third of pediatric renal transplant recipients had a genetic cause of their kidney disease identified by WES. Knowledge of this genetic information can help guide management of both transplant patients and potential living related donors.

}, keywords = {Adolescent, Boston, Child, Child, Preschool, Cohort Studies, Female, Genetic Predisposition to Disease, Genetic Testing, Graft Rejection, Graft Survival, Hospitals, Pediatric, Humans, Kidney Transplantation, Male, Precision Medicine, Prognosis, Renal Insufficiency, Chronic, Retrospective Studies, Risk Assessment, Severity of Illness Index, Survival Analysis, Transplant Recipients, Treatment Outcome, Whole Exome Sequencing}, issn = {1533-3450}, doi = {10.1681/ASN.2018060575}, author = {Mann, Nina and Braun, Daniela A and Amann, Kassaundra and Tan, Weizhen and Shril, Shirlee and Connaughton, Dervla M and Nakayama, Makiko and Schneider, Ronen and Kitzler, Thomas M and van der Ven, Amelie T and Chen, Jing and Ityel, Hadas and Vivante, Asaf and Majmundar, Amar J and Daga, Ankana and Warejko, Jillian K and Lovric, Svjetlana and Ashraf, Shazia and Jobst-Schwan, Tilman and Widmeier, Eugen and Hugo, Hannah and Mane, Shrikant M and Spaneas, Leslie and Somers, Michael J G and Ferguson, Michael A and Traum, Avram Z and Stein, Deborah R and Baum, Michelle A and Daouk, Ghaleb H and Lifton, Richard P and Manzi, Shannon and Vakili, Khashayar and Kim, Heung Bae and Rodig, Nancy M and Hildebrandt, Friedhelm} } @article {513, title = {Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome.}, journal = {J Clin Invest}, volume = {128}, year = {2018}, month = {2018 Oct 01}, pages = {4313-4328}, abstract = {

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.

}, issn = {1558-8238}, doi = {10.1172/JCI98688}, author = {Braun, Daniela A and Lovric, Svjetlana and Schapiro, David and Schneider, Ronen and Marquez, Jonathan and Asif, Maria and Hussain, Muhammad Sajid and Daga, Ankana and Widmeier, Eugen and Rao, Jia and Ashraf, Shazia and Tan, Weizhen and Lusk, C Patrick and Kolb, Amy and Jobst-Schwan, Tilman and Schmidt, Johanna Magdalena and Hoogstraten, Charlotte A and Eddy, Kaitlyn and Kitzler, Thomas M and Shril, Shirlee and Moawia, Abubakar and Schrage, Kathrin and Khayyat, Arwa Ishaq A and Lawson, Jennifer A and Gee, Heon Yung and Warejko, Jillian K and Hermle, Tobias and Majmundar, Amar J and Hugo, Hannah and Budde, Birgit and Motameny, Susanne and Altm{\"u}ller, Janine and Noegel, Angelika Anna and Fathy, Hanan M and Gale, Daniel P and Waseem, Syeda Seema and Khan, Ayaz and Kerecuk, Larissa and Hashmi, Seema and Mohebbi, Nilufar and Ettenger, Robert and Serdaroglu, Erkin and Alhasan, Khalid A and Hashem, Mais and Goncalves, Sara and Ariceta, Gema and Ubetagoyena, Mercedes and Antonin, Wolfram and Baig, Shahid Mahmood and Alkuraya, Fowzan S and Shen, Qian and Xu, Hong and Antignac, Corinne and Lifton, Richard P and Mane, Shrikant and N{\"u}rnberg, Peter and Khokha, Mustafa K and Hildebrandt, Friedhelm} } @article {611, title = {Mutations in WDR4 as a new cause of Galloway-Mowat syndrome.}, journal = {Am J Med Genet A}, volume = {176}, year = {2018}, month = {2018 Nov}, pages = {2460-2465}, abstract = {

Galloway-Mowat syndrome (GAMOS) is a phenotypically heterogeneous disorder characterized by neurodevelopmental defects combined with renal-glomerular disease, manifesting with proteinuria. To identify additional monogenic disease causes, we here performed whole exome sequencing (WES), linkage analysis, and homozygosity mapping in three affected siblings of an Indian family with GAMOS. Applying established criteria for variant filtering, we identify a novel homozygous splice site mutation in the gene WDR4 as the likely disease-causing mutation in this family. In line with previous reports, we observe growth deficiency, microcephaly, developmental delay, and intellectual disability as phenotypic features resulting from WDR4 mutations. However, the newly identified allele additionally gives rise to proteinuria and nephrotic syndrome, a phenotype that was never reported in patients with WDR4 mutations. Our data thus expand the phenotypic spectrum of WDR4 mutations by demonstrating that, depending on the specific mutated allele, a renal phenotype may be present. This finding suggests that GAMOS may occupy a phenotypic spectrum with other microcephalic diseases. Furthermore, WDR4 is an additional example of a gene that encodes a tRNA modifying enzyme and gives rise to GAMOS, if mutated. Our findings thereby support the recent observation that, like neurons, podocytes of the renal glomerulus are particularly vulnerable to cellular defects resulting from altered tRNA modifications.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.40489}, author = {Braun, Daniela A and Shril, Shirlee and Sinha, Aditi and Schneider, Ronen and Tan, Weizhen and Ashraf, Shazia and Hermle, Tobias and Jobst-Schwan, Tilman and Widmeier, Eugen and Majmundar, Amar J and Daga, Ankana and Warejko, Jillian K and Nakayama, Makiko and Schapiro, David and Chen, Jing and Airik, Merlin and Rao, Jia and Schmidt, Johanna Magdalena and Hoogstraten, Charlotte A and Hugo, Hannah and Meena, Jitendra and Lek, Monkol and Laricchia, Kristen M and Bagga, Arvind and Hildebrandt, Friedhelm} } @article {516, title = {Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract.}, journal = {J Am Soc Nephrol}, volume = {29}, year = {2018}, month = {2018 Sep}, pages = {2348-2361}, abstract = {

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12\% of patients with CAKUT.

METHODS: We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT.

RESULTS: In 29 families (13\%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient{\textquoteright}s CAKUT phenotype. In three families (1\%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8\%).

CONCLUSIONS: We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14\% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

}, issn = {1533-3450}, doi = {10.1681/ASN.2017121265}, author = {van der Ven, Amelie T and Connaughton, Dervla M and Ityel, Hadas and Mann, Nina and Nakayama, Makiko and Chen, Jing and Vivante, Asaf and Hwang, Daw-Yang and Schulz, Julian and Braun, Daniela A and Schmidt, Johanna Magdalena and Schapiro, David and Schneider, Ronen and Warejko, Jillian K and Daga, Ankana and Majmundar, Amar J and Tan, Weizhen and Jobst-Schwan, Tilman and Hermle, Tobias and Widmeier, Eugen and Ashraf, Shazia and Amar, Ali and Hoogstraaten, Charlotte A and Hugo, Hannah and Kitzler, Thomas M and Kause, Franziska and Kolvenbach, Caroline M and Dai, Rufeng and Spaneas, Leslie and Amann, Kassaundra and Stein, Deborah R and Baum, Michelle A and Somers, Michael J G and Rodig, Nancy M and Ferguson, Michael A and Traum, Avram Z and Daouk, Ghaleb H and Bogdanovic, Radovan and Staji{\'c}, Natasa and Soliman, Neveen A and Kari, Jameela A and El Desoky, Sherif and Fathy, Hanan M and Milosevic, Danko and Al-Saffar, Muna and Awad, Hazem S and Eid, Loai A and Selvin, Aravind and Senguttuvan, Prabha and Sanna-Cherchi, Simone and Rehm, Heidi L and MacArthur, Daniel G and Lek, Monkol and Laricchia, Kristen M and Wilson, Michael W and Mane, Shrikant M and Lifton, Richard P and Lee, Richard S and Bauer, Stuart B and Lu, Weining and Reutter, Heiko M and Tasic, Velibor and Shril, Shirlee and Hildebrandt, Friedhelm} }