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1.  The biology of APOL1 with insights into the association of APOL1 variants with chronic kidney disease 
Recent studies have identified genetic variants in APOL1 that may contribute to the increased incidence of kidney disease in populations with African ancestry. Herein, we review the biology of APOL1 present in the circulation and localized to the kidney as it may contribute to the pathogenesis of APOL1 associated kidney disease.
doi:10.1007/s10157-013-0907-4
PMCID: PMC4022720  PMID: 24233469
Genetics; apolipoprotein; HDL; APOL1; kidney; focal segmental glomerulosclerosis; HIV; HIV associated neprhopathy; hypertensive nephrosclerosis; chronic kidney disease
2.  Renal manifestations of genetic mitochondrial disease 
Mitochondrial diseases can be related to mutations in either the nuclear or mitochondrial genome. Childhood presentations are commonly associated with renal tubular dysfunction, but renal involvement is less commonly reported outside of this age-group. Mitochondrial diseases are notable for the significant variability in their clinical presentation and the broad spectrum of genes implicated in their etiology. These features contribute to the challenges of establishing a definitive diagnosis and understanding the pathogenetic mechanisms leading to kidney involvement in these diseases. Here, we review the deoxyribonucleic acid variants in the mitochondrial and nuclear genomes that have been associated with a kidney phenotype, and examine some of the possible pathogenic mechanisms that may contribute to the expression of a renal phenotype.
doi:10.2147/IJNRD.S37887
PMCID: PMC3916636  PMID: 24516335
genetics; kidney; mitochondria
3.  A reduction of cytochrome c mediates an age-related decline of oxidative phosphorylation in rat kidney mitochondria 
The Biochemical journal  2010;427(1):105-112.
Synopsis
Kidney function declines with advancing age and mitochondria have been implicated. We have examined the integrated function of mitochondria isolated from kidneys of 6 and 24 month Fischer 344 rats. Oxidative phosphorylation (OXPHOS) of intact mitochondria and cytochrome c oxidase activity in permeabilized mitochondria were determined with polarographic assays. The activities of the electron transport chain (ETC) complexes and the cytochrome content in solubilized mitochondria were measured using spectrophotometric methods. The respiratory complexes were evaluated with blue-native gel electrophoresis. Mitochondrial preparations were evaluated by immunoblotting for cytochrome c, Smac/Diablo, and the voltage dependant ion channel (VDAC). Mitochondrial morphology was examined by electron microscopy. OXPHOS of mitochondria isolated from 24 month animals was decreased 15–25% with complex I, II, III, IV and fatty acid substrates. The electron microscopic appearance of mitochondria, the activity of the ETC complexes and the protein abundance of individual complexes and supercomplexes were unchanged. The content of cytochrome c was decreased by 37% in aged mitochondria as determined by spectrophotometric methods and confirmed with immunoblotting. Polarographic determination of cytochrome c oxidase activity with endogenous cytochrome c demonstrated a 23% reduction in aged mitochondria, which was corrected with the addition of exogenous cytochrome c. Renal mitochondrial OXPHOS decreased with aging in the Fischer 344 rat. Decreased mitochondrial cytochrome c content is a major factor contributing to the OXPHOS defect of mitochondria isolated from kidneys of elderly animals.
doi:10.1042/BJ20091373
PMCID: PMC3759985  PMID: 20100174
Aging; mitochondria; oxidative phosphorylation; electron transport chain; cytochrome c; cytochrome c oxidase
4.  Kidney disease: new technologies translate mechanisms to cure 
The Journal of Clinical Investigation  2014;124(6):2294-2298.
Kidney disease is one of the most prevalent chronic conditions and is a frequent complication of diabetes, cardiovascular disease, and obesity. Recent advances in biomedical research and novel technologies have created opportunities to study kidney disease in a variety of platforms, applied to human populations. The Reviews in this series discuss the kidney in hypertension, diabetes, and monogenic forms of kidney disease, as well as the cellular and molecular mediators of acute kidney injury and fibrosis, IgA nephropathy and idiopathic membranous nephropathy, and kidney transplantation. In this introduction, we briefly review new insights into focal segmental glomerulosclerosis and the role of podocytes in health and disease. Additionally, we discuss how new technologies, therapeutics, and the availability of patient data can help shape the study of kidney disease and ultimately inform policies concerning biomedical research and health care.
doi:10.1172/JCI76825
PMCID: PMC4089455  PMID: 24892702
5.  Whole exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies 
Kidney international  2013;85(4):880-887.
Rare single-gene disorders cause chronic disease. However, half of the 6,000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sib-ships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy we detect the causative gene. In six sib-ships we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sib-ships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus whole exome resequencing establishes an efficient, non-invasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms.
doi:10.1038/ki.2013.450
PMCID: PMC3972265  PMID: 24257694
6.  Mutation analysis of NPHP6/CEP290 in patients with Joubert syndrome and Senior–Løken syndrome 
Journal of Medical Genetics  2007;44(10):657-663.
Background
Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that constitutes the most common genetic cause of renal failure in the first three decades of life. Using positional cloning, six genes (NPHP1‐6) have been identified as mutated in NPHP. In Joubert syndrome (JBTS), NPHP may be associated with cerebellar vermis aplasia/hypoplasia, retinal degeneration and mental retardation. In Senior–Løken syndrome (SLSN), NPHP is associated with retinal degeneration. Recently, mutations in NPHP6/CEP290 were identified as a new cause of JBTS.
Methods
Mutational analysis was performed on a worldwide cohort of 75 families with SLSN, 99 families with JBTS and 21 families with isolated nephronophthisis.
Results
Six novel and six known truncating mutations, one known missense mutation and one novel 3 bp pair in‐frame deletion were identified in a total of seven families with JBTS, two families with SLSN and one family with isolated NPHP.
doi:10.1136/jmg.2007.052027
PMCID: PMC2597962  PMID: 17617513
NPHP6/CEP290 ; Joubert syndrome; Senior–Løken syndrome; nephronophthisis; mutational analysis
7.  Mitochondrial Aminopeptidase Deletion Increases Chronological Lifespan and Oxidative Stress Resistance while Decreasing Respiratory Metabolism in S. cerevisiae 
PLoS ONE  2013;8(10):e77234.
Recessive mutations in XPNPEP3, encoding a mitochondrial x-prolyl aminopeptidase, have been identified in families with a rare hereditary tubulointerstitial kidney disease. The yeast ortholog of XPNPEP3, Icp55p, participates in the proteolytic processing and stabilization of mitochondrial proteins and its deletion accelerates the degradation of its protein targets. We used icp55 deletion strains of S. cerevisiae to model loss of XPNPEP3 enzymatic function and study its phenotypic consequences on mitochondrial function. We found that Icp55p is not required for respiratory competence; however, compared to controls deletion strains had reduced mitochondrial oxygen consumption when grown in glucose containing media. The reduced mitochondrial respiration of icp55 deletion strains in glucose media requires the mitochondrial peptide transporter, Mdl1p, and was corrected by Tor1p inhibition with rapamycin. Under similar growth conditions the abundance of the mitochondrial ATP synthase complex was decreased in the icp55 deletion strain and was corrected by concurrent deletion of tor1. The icp55 deletion strain demonstrated an increased chronological lifespan and decreased reactive oxygen species. These changes were additive to similar changes known to occur in tor1 deletion strains suggesting independent mechanisms. Together, these results demonstrate that loss of Icp55p function reduces mitochondrial oxygen consumption and ATP synthase complex assembly in glucose media, while also promoting stress resistance, decreasing reactive oxygen species and increasing chronological lifespan through mechanisms that are distinct from decreased Tor1p activity.
doi:10.1371/journal.pone.0077234
PMCID: PMC3792884  PMID: 24116217
8.  Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination 
Nature genetics  2003;34(4):413-420.
Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, leads to chronic renal failure in children. The genes mutated in NPHP1 and NPHP4 have been identified, and a gene locus associated with infantile nephronophthisis (NPHP2) was mapped. The kidney phenotype of NPHP2 combines clinical features of NPHP and polycystic kidney disease (PKD). Here, we identify inversin (INVS) as the gene mutated in NPHP2 with and without situs inversus. We show molecular interaction of inversin with nephrocystin, the product of the gene mutated in NPHP1 and interaction of nephrocystin with β-tubulin, a main component of primary cilia. We show that nephrocystin, inversin and β-tubulin colocalize to primary cilia of renal tubular cells. Furthermore, we produce a PKD-like renal cystic phenotype and randomization of heart looping by knockdown of invs expression in zebrafish. The interaction and colocalization in cilia of inversin, nephrocystin and β-tubulin connect pathogenetic aspects of NPHP to PKD, to primary cilia function and to left-right axis determination.
doi:10.1038/ng1217
PMCID: PMC3732175  PMID: 12872123
9.  Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling 
Chaki, Moumita | Airik, Rannar | Ghosh, Amiya K. | Giles, Rachel H. | Chen, Rui | Slaats, Gisela G. | Wang, Hui | Hurd, Toby W. | Zhou, Weibin | Cluckey, Andrew | Gee, Heon-Yung | Ramaswami, Gokul | Hong, Chen-Jei | Hamilton, Bruce A. | Červenka, Igor | Ganji, Ranjani Sri | Bryja, Vitezslav | Arts, Heleen H. | van Reeuwijk, Jeroen | Oud, Machteld M. | Letteboer, Stef J.F. | Roepman, Ronald | Husson, Hervé | Ibraghimov-Beskrovnaya, Oxana | Ysunaga, Takayuki | Walz, Gerd | Eley, Lorraine | Sayer, John A. | Schermer, Bernhard | Liebau, Max C. | Benzing, Thomas | Le Corre, Stephanie | Drummond, Iain | Joles, Jaap A. | Janssen, Sabine | Allen, Susan J. | Natarajan, Sivakumar | O Toole, John F. | Attanasio, Massimo | Saunier, Sophie | Antignac, Corinne | Koenekoop, Robert K. | Ren, Huanan | Lopez, Irma | Nayir, Ahmet | Stoetzel, Corinne | Dollfus, Helene | Massoudi, Rustin | Gleeson, Joseph G. | Andreoli, Sharon P. | Doherty, Dan G. | Lindstrad, Anna | Golzio, Christelle | Katsanis, Nicholas | Pape, Lars | Abboud, Emad B. | Al-Rajhi, Ali A. | Lewis, Richard A. | Lupski, James R. | Omran, Heymut | Lee, Eva | Wang, Shaohui | Sekiguchi, JoAnn M. | Saunders, Rudel | Johnson, Colin A. | Garner, Elizabeth | Vanselow, Katja | Andersen, Jens S. | Shlomai, Joseph | Nurnberg, Gudrun | Nurnberg, Peter | Levy, Shawn | Smogorzewska, Agata | Otto, Edgar A. | Hildebrandt, Friedhelm
Cell  2012;150(3):533-548.
SUMMARY
Nephronophthisis-related ciliopathies (NPHP-RC) are degenerative recessive diseases that affect kidney, retina and brain. Genetic defects in NPHP gene products that localize to cilia and centrosomes defined them as ‘ciliopathies’. However, disease mechanisms remain poorly understood. Here we identify by whole exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway, hitherto not implicated in ciliopathies. We demonstrate that, upon induced DNA damage, the NPHP-RC proteins ZNF423, CEP164 and NPHP10 colocalize to nuclear foci positive for TIP60, known to activate ATM at sites of DNA damage. We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents, and that cep164 knockdown in zebrafish results in dysregulated DDR and an NPHP-RC phenotype. We identify TTBK2, CCDC92, NPHP3 and DVL3 as novel CEP164 interaction partners. Our findings link degenerative diseases of kidney and retina, disorders of increasing prevalence, to mechanisms of DDR.
doi:10.1016/j.cell.2012.06.028
PMCID: PMC3433835  PMID: 22863007
10.  Mapping the Nephronophthisis-Joubert-Meckel-Gruber Protein Network Reveals Ciliopathy Disease Genes and Pathways 
Cell  2011;145(4):513-528.
Nephronophthisis (NPHP), Joubert (JBTS) and Meckel-Gruber (MKS) syndromes are autosomal-recessive ciliopathies presenting with cystic kidneys, retinal degeneration, and cerebellar/neural tube malformation. Whether defects in kidney, retinal, or neural disease primarily involve ciliary, Hedgehog, or cell polarity pathways remains unclear. Using high-confidence proteomics, we identified 850 interactors copurifying with nine NPHP/JBTS/MKS proteins, and discovered three connected modules: “NPHP1-4-8” functioning at the apical surface; “NPHP5-6” at centrosomes; and “MKS” linked to Hedgehog signaling. Assays for ciliogenesis and epithelial morphogenesis in 3D renal cultures link renal cystic disease to apical organization defects, whereas ciliary and Hedgehog pathway defects lead to retinal or neural deficits. Using 38 interactors as candidates, linkage and sequencing analysis of 250 patients identified ATXN10 and TCTN2 as new NPHP-JBTS genes and our Tctn2 mouse knockout shows neural tube and Hedgehog signaling defects. Our study further illustrates the power of linking proteomic networks and human genetics to uncover critical disease pathways.
doi:10.1016/j.cell.2011.04.019
PMCID: PMC3383065  PMID: 21565611
11.  AHI1 is required for outer segment development and is a modifier for retinal degeneration in nephronophthisis 
Nature genetics  2010;42(2):175-180.
Photoreceptor degeneration is a common feature of ciliopathies, owing to the importance of the highly specialized ciliary structure of these cells. Absence of AHI1, which encodes a cilium-localized protein, has been shown to cause a form of Joubert syndrome highly penetrant for retinal degeneration1,2. We show that Ahi1 knockout mice fail to form outer segments (OS), and show abnormal distribution of opsin throughout photoreceptors. Apoptotic cell death occurs rapidly between 2-4 weeks of age and is significantly delayed by reduced dosage of opsin. This phenotype also displays dosage-sensitive genetic interactions with Nphp1, another ciliopathy gene. Although not a primary cause of retinal blindness in humans, an allele of AHI1 modifies the relative risk of retinal degeneration greater than 7 fold within a nephronophthisis cohort. Our data support context-specific roles for AHI1 as a contributor to retinopathy and may explain a proportion of the variability of retinal phenotypes observed in nephronophthisis.
doi:10.1038/ng.519
PMCID: PMC2884967  PMID: 20081859
13.  Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy  
The autosomal recessive kidney disease nephronophthisis (NPHP) constitutes the most frequent genetic cause of terminal renal failure in the first 3 decades of life. Ten causative genes (NPHP1–NPHP9 and NPHP11), whose products localize to the primary cilia-centrosome complex, support the unifying concept that cystic kidney diseases are “ciliopathies”. Using genome-wide homozygosity mapping, we report here what we believe to be a new locus (NPHP-like 1 [NPHPL1]) for an NPHP-like nephropathy. In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene. In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells. However, in vivo analyses also revealed a likely cilia-related function; suppression of zebrafish xpnpep3 phenocopied the developmental phenotypes of ciliopathy morphants, and this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal. Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish. Our data highlight an emerging link between mitochondria and ciliary dysfunction, and suggest that further understanding the enzymatic activity and substrates of XPNPEP3 will illuminate novel cystogenic pathways.
doi:10.1172/JCI40076
PMCID: PMC2827951  PMID: 20179356
14.  A Systematic Approach to Mapping Recessive Disease Genes in Individuals from Outbred Populations 
PLoS Genetics  2009;5(1):e1000353.
The identification of recessive disease-causing genes by homozygosity mapping is often restricted by lack of suitable consanguineous families. To overcome these limitations, we apply homozygosity mapping to single affected individuals from outbred populations. In 72 individuals of 54 kindred ascertained worldwide with known homozygous mutations in 13 different recessive disease genes, we performed total genome homozygosity mapping using 250,000 SNP arrays. Likelihood ratio Z-scores (ZLR) were plotted across the genome to detect ZLR peaks that reflect segments of homozygosity by descent, which may harbor the mutated gene. In 93% of cases, the causative gene was positioned within a consistent ZLR peak of homozygosity. The number of peaks reflected the degree of inbreeding. We demonstrate that disease-causing homozygous mutations can be detected in single cases from outbred populations within a single ZLR peak of homozygosity as short as 2 Mb, containing an average of only 16 candidate genes. As many specialty clinics have access to cohorts of individuals from outbred populations, and as our approach will result in smaller genetic candidate regions, the new strategy of homozygosity mapping in single outbred individuals will strongly accelerate the discovery of novel recessive disease genes.
Author Summary
Many childhood diseases are caused by single-gene mutations of recessive genes, in which a child has inherited one mutated gene copy from each parent causing disease in the child, but not in the parents who are healthy heterozygous carriers. As the two mutations represent the disease cause, gene mapping helped understand disease mechanisms. “Homozygosity mapping” has been particularly useful. It assumes that the parents are related and that a disease-causing mutation together with a chromosomal segment of identical markers (i.e., homozygous markers) is transmitted to the affected child through the paternal and the maternal line from an ancestor common to both parents. Homozygosity mapping seeks out those homozygous regions to map the disease-causing gene. Homozygosity mapping requires families, in which the parents are knowingly related, and have multiple affected children. To overcome these limitations, we applied homozygosity mapping to single affected individuals from outbred populations. In 72 individuals with known homozygous mutations in 13 different recessive disease genes, we performed homozygosity mapping. In 93% we detected the causative gene in a segment of homozygosity. We demonstrate that disease-causing homozygous mutations can be detected in single cases from outbred populations. This will strongly accelerate the discovery of novel recessive disease genes.
doi:10.1371/journal.pgen.1000353
PMCID: PMC2621355  PMID: 19165332
15.  In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse 
Human molecular genetics  2006;15(11):1847-1857.
Centrosome- and cilia-associated proteins play crucial roles in establishing polarity and regulating intracellular transport in post-mitotic cells. Using genetic mapping and positional candidate strategy, we have identified an in-frame deletion in a novel centrosomal protein CEP290 (also called NPHP6), leading to early-onset retinal degeneration in a newly identified mouse mutant, rd16. We demonstrate that CEP290 localizes primarily to centrosomes of dividing cells and to the connecting cilium of retinal photoreceptors. We show that, in the retina, CEP290 associates with several microtubule-based transport proteins including RPGR, which is mutated in ~15% of patients with retinitis pigmentosa. A truncated CEP290 protein (ΔCEP290) is detected in the rd16 retina, but in considerably reduced amounts; however, the mutant protein exhibits stronger association with specific RPGR isoform(s). Immunogold labeling studies demonstrate the redistribution of RPGR and of phototransduction proteins in the photoreceptors of rd16 retina. Our findings suggest a critical function for CEP290 in ciliary transport and provide insights into the mechanism of early-onset photoreceptor degeneration.
doi:10.1093/hmg/ddl107
PMCID: PMC1592550  PMID: 16632484

Results 1-15 (15)