BACKGROUND: Nephronophthisis 13 (NPHP 13) is associated with mutations in the WDR19 gene, which encodes for a protein in the intraflagellar transport complex. Herein, we describe six additional cases accompanied by Caroli syndrome or disease. METHODS: Targeted exome sequencing covering 96 ciliopathy-related genes was performed for 48 unrelated Korean patients with a clinical suspicion of NPHP. Mutations were confirmed by Sanger sequencing. We evaluated the expression of WDR19 in the biopsied kidney by immunohistochemistry in patients and controls. RESULTS: We detected three (3/48, 6.3 %) unrelated index cases with WDR19 mutations. One of the cases involved two siblings with the same mutation. Later, we detected an additional index case with a similar phenotype of kidney and liver involvement by Sanger sequencing of WDR19. The p.R1178Q mutation was common in all patients. All of the six affected patients from four families progressed to chronic kidney disease. Of note, all six patients had Caroli syndrome or disease. Immunohistochemistry for WDR19 showed localized expression along the luminal borders of the renal tubular epithelium in controls, whereas it showed diffuse cytoplasmic staining in the affected patients. CONCLUSIONS: Caroli disease is a major extra-renal phenotype associated with mutations in WDR19 in the Korean population. In this study, we visually validated the expression pattern of mutant WDR19 protein in the kidneys of NPHP 13 patients. More data are needed to identify the true frequency of p.R1178Q. Functional studies including transfection assay will provide solid grounds for the pathogenicity of each mutation.
BACKGROUND:Nephronophthisis 13 (NPHP 13) is associated with mutations in the WDR19 gene, which encodes for a protein in the intraflagellar transport complex. Herein, we describe six additional cases accompanied by Caroli syndrome or disease. METHODS: Targeted exome sequencing covering 96 ciliopathy-related genes was performed for 48 unrelated Korean patients with a clinical suspicion of NPHP. Mutations were confirmed by Sanger sequencing. We evaluated the expression of WDR19 in the biopsied kidney by immunohistochemistry in patients and controls. RESULTS: We detected three (3/48, 6.3 %) unrelated index cases with WDR19 mutations. One of the cases involved two siblings with the same mutation. Later, we detected an additional index case with a similar phenotype of kidney and liver involvement by Sanger sequencing of WDR19. The p.R1178Q mutation was common in all patients. All of the six affected patients from four families progressed to chronic kidney disease. Of note, all six patients had Caroli syndrome or disease. Immunohistochemistry for WDR19 showed localized expression along the luminal borders of the renal tubular epithelium in controls, whereas it showed diffuse cytoplasmic staining in the affected patients. CONCLUSIONS:Caroli disease is a major extra-renal phenotype associated with mutations in WDR19 in the Korean population. In this study, we visually validated the expression pattern of mutant WDR19 protein in the kidneys of NPHP 13 patients. More data are needed to identify the true frequency of p.R1178Q. Functional studies including transfection assay will provide solid grounds for the pathogenicity of each mutation.
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Authors: Cecilie Bredrup; Sophie Saunier; Machteld M Oud; Torunn Fiskerstrand; Alexander Hoischen; Damien Brackman; Sabine M Leh; Marit Midtbø; Emilie Filhol; Christine Bole-Feysot; Patrick Nitschké; Christian Gilissen; Olav H Haugen; Jan-Stephan F Sanders; Irene Stolte-Dijkstra; Dorus A Mans; Eric J Steenbergen; Ben C J Hamel; Marie Matignon; Rolph Pfundt; Cécile Jeanpierre; Helge Boman; Eyvind Rødahl; Joris A Veltman; Per M Knappskog; Nine V A M Knoers; Ronald Roepman; Heleen H Arts Journal: Am J Hum Genet Date: 2011-10-20 Impact factor: 11.025
Authors: Moumita Chaki; Julia Hoefele; Susan J Allen; Gokul Ramaswami; Sabine Janssen; Carsten Bergmann; John R Heckenlively; Edgar A Otto; Friedhelm Hildebrandt Journal: Kidney Int Date: 2011-08-24 Impact factor: 10.612
Authors: Eujin Park; Jiwon M Lee; Yo Han Ahn; Hee Gyung Kang; I I Soo Ha; Joo Hoon Lee; Young Seo Park; Nayoung K D Kim; Woong-Yang Park; Hae Ii Cheong Journal: Pediatr Nephrol Date: 2015-08-11 Impact factor: 3.714