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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EThis article discusses single-gene (monogenic) mutations that cause steroid-resistant nephrotic syndrome, polycystic kidney disease, cystic kidney disease, early-onset chronic kidney disease, as well as new monogenic disease genes and pathogenic pathways.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ETreatments\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ENephrosis\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ERenal Failure Cystic Kidney Diseases\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ETreatments\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ENephrosis\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ERenal Failure\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ENephrology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECystic Kidney Diseases\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EFocal segmental glomerulosclerosis (FSGS) in patients with steroid-resistant nephrotic syndrome (SRNS) may be caused by single-gene (monogenic) mutations in 1 of 30 genes. A monogenic mutation represents one of the strongest cause-and-effect relationships in clinical medicine, because a mutation in 1 of the 3.3 billion base pairs of the total genome is sufficient to cause FSGS. In his Homer W. Smith Award lecture, Friedhelm Hildebrandt, MD, Boston Children\u0027s Hospital, Boston, Massachusetts, USA, stated that FSGS is an example of the many monogenic diseases caused by a mutation in only 1 of the approximately 22 000 genes identified in the human genome.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EA gene can be recessive, in which both parental copies of the gene are mutated and cause disease while the parents are heterozygous healthy carriers; recessive polycystic kidney disease (PKD) is an example. Alternatively, the gene can be dominant, as in dominant PKD, in which a mutation in 1 of the 2 parental genes is sufficient to cause disease. However, the term \u003Cem\u003Emonogenic\u003C\/em\u003E does not exclude the possibility that different genes in different patients can cause a similar disease\u2014that is, genetic heterogeneity, as with the podocin or nephrin genes, which can both cause FSGS. Presently, \u0026gt; 30 genes have been identified that will cause SRNS if mutated.\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EGene analysis has uncovered the role of the glomerular podocyte in the pathogenesis of SRNS, and identification of single-gene causes of SRNS has elucidated essential components of glomerular function, including the integrin\/laminin and actin-binding proteins.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EThe causative mutation (CM) has been identified in 29.5% of the 1783 families worldwide with SRNS that developed before 25 years of age [Sadowski CE et al. \u003Cem\u003EJ Am Soc Nephrol\u003C\/em\u003E. 2014]. Podocin, nephrin, WT1, and PLCE1 compose 24% of the CM in the 26 genes identified. A relation was found between younger age at SRNS onset and proportion of CM identified, ranging from about 60% in infants to about 10% in adolescents.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EThe North American Pediatric Renal Trials and Collaborative Studies list the disease categories that cause early-onset chronic kidney disease (CKD) [Smith JM et al. \u003Cem\u003EPediatr Transplant\u003C\/em\u003E. 2013]. When mutation analysis was performed in the monogenic genes known to cause these disorders, Dr Hildebrandt\u0027s laboratory identified CMs in a higher percentage of individuals (\u003Ca id=\u0022xref-table-wrap-1-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E). Therefore, simple criteria were developed to guide the decision to perform a mutation analysis in persons that develop CKD before age 25 years (\u003Ca id=\u0022xref-table-wrap-2-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T2\u0022\u003ETable 2\u003C\/a\u003E).\u003C\/p\u003E\n         \u003Cdiv id=\u0022T1\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022\/\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/15302\/expansion?postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 html=\u00221\u0022 fragment=\u0022#\u0022 external=\u00221\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/15302\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15302\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETable 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-7\u0022 class=\u0022first-child\u0022\u003ECKDs Caused by a Single-Gene Defect Before Age 25 Years\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cdiv id=\u0022T2\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022\/\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/15303\/expansion?postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 html=\u00221\u0022 fragment=\u0022#\u0022 external=\u00221\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/15303\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15303\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETable 2.\u003C\/span\u003E \n               \u003Cp id=\u0022p-11\u0022 class=\u0022first-child\u0022\u003EIndications for Performing Mutation Analysis for Single-Gene Causes of CKD\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-16\u0022\u003EAccording to Dr Hildebrandt, whole exome sequencing (WES) has made it possible to identify new monogenic disease genes and pathogenic pathways. One pathway that leads to SRNS has been identified in 2 siblings with FSGS whose parents were first-degree cousins, therefore representing a treatable cause of SRNS. Homozygosity mapping and WES determined that mutations in the \u003Cem\u003EADCK4\u003C\/em\u003E gene caused SRNS [Ashraf S et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E. 2013]. The \u003Cem\u003EADCK4\u003C\/em\u003E gene has been shown to play a role in the biosynthesis of coenzyme Q10 (CoQ10), which has an important role in mitochondrial respiratory activity [DiMauro S et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E. 2007]. Podocyte migration assays showed that an \u003Cem\u003EADCK4\u003C\/em\u003E mutation causes a loss of function and that the addition of CoQ10 restored function. One patient had a partial remission after CoQ10 treatment [Ashraf S et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E. 2013]. Investigators also showed that CoQ10 reduced proteinuria in a 5-year-old patient with a CoQ6 mutation [Heeringa SF et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E. 2011].\u003C\/p\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EAnother pathway implicated in the pathogenesis of SRNS involves the \u003Cem\u003EARHGDIA\u003C\/em\u003E homozygous truncated gene, which is a regulator of the GTPases RHOA, RAC, and CDC42 and in turn regulates podocyte cell migration and proliferation [Gee HY et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E. 2013]. ARHGDIA does not bind to the GTPases when a mutation is present, leading to the development of SRNS. The mutation was identified via homozygosity mapping and WES in 2 siblings with infantile SRNS.\u003C\/p\u003E\n         \u003Cp id=\u0022p-18\u0022\u003EIn the zebrafish model of nephrotic syndrome developed by the Hildebrandt laboratory, knockdown of ARHGDIA resulted in features seen in SRNS, including edema, periorbital edema, and proteinuria. Treatment with a RAC1 inhibitor, not a RHOA inhibitor, mitigated the disease process.\u003C\/p\u003E\n         \u003Cp id=\u0022p-19\u0022\u003ECurrently, there is no effective treatment for SRNS. Dr Hildebrandt and colleagues will use podocyte migration assays and the zebrafish model to screen small molecules and to identify and develop new treatments for the disease. Some of these new drugs will likely target the genes implicated in the pathogenesis of SRNS.\u003C\/p\u003E\n         \u003Cp id=\u0022p-20\u0022\u003ECystic kidney disease, often called \u003Cem\u003Eciliopathies\u003C\/em\u003E, is another cause of kidney disease before age 25. Hildebrandt and colleagues have identified 35 of the 95 genes that cause ciliopathies [Hildebrandt F et al. \u003Cem\u003EN Engl J Med.\u003C\/em\u003E 2014]. Many signaling pathways have been implicated in the pathogenesis of nephronophthisis-related ciliopathies, but it is likely that mutation analysis will identify, for individual patients, which of these pathogenic pathways is relevant, as a means of \u201cpersonalized medicine.\u201d\u003C\/p\u003E\n         \u003Cp id=\u0022p-21\u0022\u003EIn closing, Dr Hildebrandt stated that all patients who have a kidney disease known to be caused by a gene mutation should be given the opportunity to identify their gene mutation. It is now feasible to conduct the mutation analysis, which provides an unequivocal diagnosis. The analysis may reveal potential treatments; it allows for etiologic classification for therapeutic and clinical trials; and it provides additional information to elucidate the pathogenic pathways. Finally, it enables the generation of gene-specific animal models and screening for therapeutic molecules.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2015 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/49\/6.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzltsp\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_tables.js?nzltsp\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}