title: Contribution of the TTC21B gene to glomerular and cystic kidney diseases.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Molecular Biology Laboratory, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Catalonia, Spain.|Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Catalonia, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Bullich
authors.affiliation: Informatics Department, Institut de diagnòstic per la imatge (IDI), Barcelona, Catalonia, Spain.
authors.forename: Iván
authors.initials: I
authors.lastname: Vargas
authors.affiliation: Genomics and Disease Group, Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), Barcelona, Catalonia, Spain.|Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.|Hospital del Mar Medical Research Institute (IMIM), Barcelona, Catalonia, Spain.|CIBER in Epidemiology and Public Health (CIBERESP), Barcelona, Catalonia, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Trujillano
authors.affiliation: Pediatric Nephrology Department, Hospital Universitario La Fe, Valencia, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Mendizábal
authors.affiliation: Pediatric Nephrology Department, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.
authors.forename: Juan Alberto
authors.initials: JA
authors.lastname: Piñero-Fernández
authors.affiliation: Pediatric Nephrology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Catalonia, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Fraga
authors.affiliation: Pathology Service, Hospital General Universitario Santa Lucía, Cartagena, Spain.
authors.forename: José
authors.initials: J
authors.lastname: García-Solano
authors.affiliation: Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Catalonia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Ballarín
authors.affiliation: Genomics and Disease Group, Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), Barcelona, Catalonia, Spain.|Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.|Hospital del Mar Medical Research Institute (IMIM), Barcelona, Catalonia, Spain.|CIBER in Epidemiology and Public Health (CIBERESP), Barcelona, Catalonia, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.affiliation: Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Catalonia, Spain.
authors.forename: Roser
authors.initials: R
authors.lastname: Torra
authors.affiliation: Molecular Biology Laboratory, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Catalonia, Spain.|Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Catalonia, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Ars
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree
chemical_list: D008869:Microtubule-Associated Proteins; C000594121:TTC21B protein, human
keywords: FSGS; TTC21B; modifier; mutation; tubulointerstitial