Contribution of theTTC21Bgene to glomerular and cystic kidney diseases
- 2 March 2016
- journal article
- Published by Oxford University Press (OUP) in Nephrology Dialysis Transplantation
- Vol. 32 (1), gfv453-156
- https://doi.org/10.1093/ndt/gfv453
Abstract
Background The TTC21B gene was initially described as causative of nephronophthisis (NPHP). Recently, the homozygous TTC21B p.P209L mutation has been identified in families with focal segmental glomerulosclerosis (FSGS) and tubulointerstitial lesions. Heterozygous TTC21B variants have been proposed as genetic modifiers in ciliopathies. We aimed to study the causative and modifying role of the TTC21B gene in glomerular and cystic kidney diseases. Methods Mutation analysis of the TTC21B gene was performed by massive parallel sequencing. We studied the causative role of the TTC21B gene in 17 patients with primary diagnosis of FSGS or NPHP and its modifying role in 184 patients with inherited glomerular or cystic kidney diseases. Results Disease-causing TTC21B mutations were identified in three families presenting nephrotic proteinuria with FSGS and tubulointerstitial lesions in which some family members presented hypertension and myopia. Two families carried the homozygous p.P209L and the third was compound heterozygous for the p.P209L and a novel p.H426D mutation. Rare heterozygous TTC21B variants predicted to be pathogenic were found in five patients. These TTC21B variants were significantly more frequent in renal patients compared with controls (P = 0.0349). Two patients with a heterozygous deleterious TTC21B variant in addition to the disease-causing mutation presented a more severe phenotype than expected. Conclusions Our results confirm the causal role of the homozygous p.P209L TTC21B mutation in two new families with FSGS and tubulointerstitial disease. We identified a novel TTC21B mutation demonstrating that p.P209L is not the unique causative mutation of this nephropathy. Thus, TTC21B mutation analysis should be considered for the genetic diagnosis of families with FSGS and tubulointerstitial lesions. Finally, we provide evidence that heterozygous deleterious TTC21B variants may act as genetic modifiers of the severity of glomerular and cystic kidney diseases.Keywords
This publication has 12 references indexed in Scilit:
- Whole exome sequencing is an efficient, sensitive and specific method for determining the genetic cause of short‐rib thoracic dystrophiesClinical Genetics, 2014
- Targeted next-generation sequencing in steroid-resistant nephrotic syndrome: mutations in multiple glomerular genes may influence disease severityEuropean Journal of Human Genetics, 2014
- A Homozygous Missense Mutation in the Ciliary Gene TTC21B Causes Familial FSGSJournal of the American Society of Nephrology, 2014
- Diagnosis of autosomal dominant polycystic kidney disease using efficient PKD1 and PKD2 targeted next‐generation sequencingMolecular Genetics & Genomic Medicine, 2014
- Next generation diagnostics of cystic fibrosis andCFTR-related disorders by targeted multiplex high-coverage resequencing ofCFTRJournal of Medical Genetics, 2013
- An integrated map of genetic variation from 1,092 human genomesNature, 2012
- Mutations in Multiple PKD Genes May Explain Early and Severe Polycystic Kidney DiseaseJournal of the American Society of Nephrology, 2011
- TTC21B contributes both causal and modifying alleles across the ciliopathy spectrumNature Genetics, 2011
- Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategyJournal of Medical Genetics, 2010
- THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in ciliaNature Genetics, 2008