@article {496, title = {Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 05 03}, pages = {832-844}, abstract = {

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with \~{}7\% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.

}, keywords = {Adult, Aged, Aged, 80 and over, Alleles, Amino Acid Sequence, Base Sequence, Epithelial Cells, Family, Female, HSP40 Heat-Shock Proteins, Humans, Loop of Henle, Male, Middle Aged, Mutation, Pedigree, Polycystic Kidney, Autosomal Dominant, TRPP Cation Channels, Uromodulin, Whole Exome Sequencing, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.03.013}, author = {Cornec-Le Gall, Emilie and Olson, Rory J and Besse, Whitney and Heyer, Christina M and Gainullin, Vladimir G and Smith, Jessica M and Audr{\'e}zet, Marie-Pierre and Hopp, Katharina and Porath, Binu and Shi, Beili and Baheti, Saurabh and Senum, Sarah R and Arroyo, Jennifer and Madsen, Charles D and F{\'e}rec, Claude and Joly, Dominique and Jouret, Fran{\c c}ois and Fikri-Benbrahim, Oussamah and Charasse, Christophe and Coulibaly, Jean-Marie and Yu, Alan S and Khalili, Korosh and Pei, York and Somlo, Stefan and Le Meur, Yannick and Torres, Vicente E and Harris, Peter C} } @article {405, title = {Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency.}, journal = {J Clin Invest}, volume = {127}, year = {2017}, month = {2017 Mar 01}, pages = {912-928}, abstract = {

Steroid-resistant nephrotic syndrome (SRNS) causes 15\% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30\% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1Δ yeast strains, whereas expression of disease-associated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS.

}, keywords = {Aldehyde-Lyases, Animals, Cell Line, Cell Movement, Drosophila melanogaster, Drosophila Proteins, Female, Humans, Ichthyosis, Lamellar, Male, Mesangial Cells, Mice, Mice, Knockout, Mutation, Nephrotic Syndrome, Protein Transport, Rats}, issn = {1558-8238}, doi = {10.1172/JCI89626}, author = {Lovric, Svjetlana and Goncalves, Sara and Gee, Heon Yung and Oskouian, Babak and Srinivas, Honnappa and Choi, Won-Il and Shril, Shirlee and Ashraf, Shazia and Tan, Weizhen and Rao, Jia and Airik, Merlin and Schapiro, David and Braun, Daniela A and Sadowski, Carolin E and Widmeier, Eugen and Jobst-Schwan, Tilman and Schmidt, Johanna Magdalena and Girik, Vladimir and Capitani, Guido and Suh, Jung H and Lachauss{\'e}e, No{\"e}lle and Arrondel, Christelle and Patat, Julie and Gribouval, Olivier and Furlano, Monica and Boyer, Olivia and Schmitt, Alain and Vuiblet, Vincent and Hashmi, Seema and Wilcken, Rainer and Bernier, Francois P and Innes, A Micheil and Parboosingh, Jillian S and Lamont, Ryan E and Midgley, Julian P and Wright, Nicola and Majewski, Jacek and Zenker, Martin and Schaefer, Franz and Kuss, Navina and Greil, Johann and Giese, Thomas and Schwarz, Klaus and Catheline, Vilain and Schanze, Denny and Franke, Ingolf and Sznajer, Yves and Truant, Anne S and Adams, Brigitte and D{\'e}sir, Julie and Biemann, Ronald and Pei, York and Ars, Elisabet and Lloberas, Nuria and Madrid, Alvaro and Dharnidharka, Vikas R and Connolly, Anne M and Willing, Marcia C and Cooper, Megan A and Lifton, Richard P and Simons, Matias and Riezman, Howard and Antignac, Corinne and Saba, Julie D and Hildebrandt, Friedhelm} } @article {282, title = {ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption.}, journal = {J Clin Invest}, volume = {123}, year = {2013}, month = {2013 Dec}, pages = {5179-89}, abstract = {

Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.

}, keywords = {Adolescent, Adrenal Cortex Hormones, Amino Acid Sequence, Animals, Cells, Cultured, Child, Consanguinity, Conserved Sequence, Disease Models, Animal, DNA Mutational Analysis, Drosophila Proteins, Drug Resistance, Exome, Fibroblasts, Gene Knockdown Techniques, Humans, Mitochondria, Molecular Sequence Data, Mutation, Nephrotic Syndrome, Podocytes, Protein Kinases, Rats, Sequence Alignment, Sequence Homology, Amino Acid, Ubiquinone, Young Adult, Zebrafish, Zebrafish Proteins}, issn = {1558-8238}, doi = {10.1172/JCI69000}, author = {Ashraf, Shazia and Gee, Heon Yung and Woerner, Stephanie and Xie, Letian X and Vega-Warner, Virginia and Lovric, Svjetlana and Fang, Humphrey and Song, Xuewen and Cattran, Daniel C and Avila-Casado, Carmen and Paterson, Andrew D and Nitschk{\'e}, Patrick and Bole-Feysot, Christine and Cochat, Pierre and Esteve-Rudd, Julian and Haberberger, Birgit and Allen, Susan J and Zhou, Weibin and Airik, Rannar and Otto, Edgar A and Barua, Moumita and Al-Hamed, Mohamed H and Kari, Jameela A and Evans, Jonathan and Bierzynska, Agnieszka and Saleem, Moin A and Bockenhauer, Detlef and Kleta, Robert and El Desoky, Sherif and Hacihamdioglu, Duygu O and Gok, Faysal and Washburn, Joseph and Wiggins, Roger C and Choi, Murim and Lifton, Richard P and Levy, Shawn and Han, Zhe and Salviati, Leonardo and Prokisch, Holger and Williams, David S and Pollak, Martin and Clarke, Catherine F and Pei, York and Antignac, Corinne and Hildebrandt, Friedhelm} }