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Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome
Warejko, Jillian K.,Tan, Weizhen,Daga, Ankana,Schapiro, David,Lawson, Jennifer A.,Shril, Shirlee,Lovric, Svjetlana,Ashraf, Shazia,Rao, Jia,Hermle, Tobias,Jobst-Schwan, Tilman,Widmeier, Eugen,Majmundar American Society of Nephrology 2018 Clinical journal of the American Society of Nephro Vol.13 No.1
Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly
Braun, Daniela A,Rao, Jia,Mollet, Geraldine,Schapiro, David,Daugeron, Marie-Claire,Tan, Weizhen,Gribouval, Olivier,Boyer, Olivia,Revy, Patrick,Jobst-Schwan, Tilman,Schmidt, Johanna Magdalena,Lawson, J Nature Pub. Co 2017 Nature genetics Vol.49 No.10
<P>Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.</P>
Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome
Braun, Daniela A.,Lovric, Svjetlana,Schapiro, David,Schneider, Ronen,Marquez, Jonathan,Asif, Maria,Hussain, Muhammad Sajid,Daga, Ankana,Widmeier, Eugen,Rao, Jia,Ashraf, Shazia,Tan, Weizhen,Lusk, C. Pa American Society for Clinical Investigation 2018 The Journal of clinical investigation Vol.128 No.10
Mutations of <i>ADAMTS9</i> Cause Nephronophthisis-Related Ciliopathy
Choi, Yo Jun,Halbritter, Jan,Braun, Daniela A.,Schueler, Markus,Schapiro, David,Rim, John Hoon,Nandadasa, Sumeda,Choi, Won-il,Widmeier, Eugen,Shril, Shirlee,Kö,rber, Friederike,Sethi, Sidharth K. Elsevier 2019 American journal of human genetics Vol.104 No.1
<P>Nephronophthisis-related ciliopathies (NPHP-RCs) are a group of inherited diseases that are associated with defects in primary cilium structure and function. To identify genes mutated in NPHP-RC, we performed homozygosity mapping and whole-exome sequencing for >100 individuals, some of whom were single affected individuals born to consanguineous parents and some of whom were siblings of indexes who were also affected by NPHP-RC. We then performed high-throughput exon sequencing in a worldwide cohort of 800 additional families affected by NPHP-RC. We identified two <I>ADAMTS9</I> mutations (c.4575_4576del [p.Gln1525Hisfs<SUP>∗</SUP>60] and c.194C>G [p.Thr65Arg]) that appear to cause NPHP-RC. Although ADAMTS9 is known to be a secreted extracellular metalloproteinase, we found that ADAMTS9 localized near the basal bodies of primary cilia in the cytoplasm. Heterologously expressed wild-type ADAMTS9, in contrast to mutant proteins detected in individuals with NPHP-RC, localized to the vicinity of the basal body. Loss of ADAMTS9 resulted in shortened cilia and defective sonic hedgehog signaling. Knockout of <I>Adamts9</I> in IMCD3 cells, followed by spheroid induction, resulted in defective lumen formation, which was rescued by an overexpression of wild-type, but not of mutant, ADAMTS9. Knockdown of <I>adamts9</I> in zebrafish recapitulated NPHP-RC phenotypes, including renal cysts and hydrocephalus. These findings suggest that the identified mutations in <I>ADAMTS9</I> cause NPHP-RC and that ADAMTS9 is required for the formation and function of primary cilia.</P>
Daga, Ankana,Majmundar, Amar J.,Braun, Daniela A.,Gee, Heon Yung,Lawson, Jennifer A.,Shril, Shirlee,Jobst-Schwan, Tilman,Vivante, Asaf,Schapiro, David,Tan, Weizhen,Warejko, Jillian K.,Widmeier, Eugen Elsevier 2018 Kidney international Vol.93 No.1
<P>The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.</P>