Contribution of the TTC21B gene to glomerular and cystic kidney diseases
Por:
Bullich, G, Vargas, I, Trujillano, D, Mendizabal, S, Pinero-Fernandez, JA, Fraga, G, Garcia-Solano, J, Ballarin, J, Estivill, X, Torra, R, Ars, E
Publicada:
1 ene 2017
Resumen:
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.
Filiaciones:
Bullich, G:
Univ Autonoma Barcelona, IIB St Pau, Inst Invest Carlos III, Mol Biol Lab,Fundacio Puigvert,REDinREN, Barcelona, Catalonia, Spain
Univ Autonoma Barcelona, IIB St Pau, Inst Invest Carlos III, Nephrol Dept,Fundacio Puigvert,REDinREN, Barcelona, Catalonia, Spain
Vargas, I:
IDI, Dept Informat, Barcelona, Catalonia, Spain
Trujillano, D:
Ctr Genom Regulat CRG, Genom & Dis Grp, Bioinformat & Genom Programme, Barcelona, Catalonia, Spain
Univ Pompeu Fabra, Barcelona, Catalonia, Spain
Hosp Mar, Med Res Inst IMIM, Barcelona, Catalonia, Spain
CIBER Epidemiol & Publ Hlth CIBERESP, Barcelona, Catalonia, Spain
Mendizabal, S:
Hosp Univ La Fe, Pediat Nephrol Dept, Valencia, Spain
Pinero-Fernandez, JA:
Hosp Univ Virgen Arrixaca, Pediat Nephrol Dept, Murcia, Spain
Fraga, G:
Hosp Santa Creu & Sant Pau, Pediat Nephrol Dept, Barcelona, Catalonia, Spain
Garcia-Solano, J:
Hosp Gen Univ Santa Lucia, Pathol Serv, Cartagena, Spain
Ballarin, J:
Univ Autonoma Barcelona, IIB St Pau, Inst Invest Carlos III, Nephrol Dept,Fundacio Puigvert,REDinREN, Barcelona, Catalonia, Spain
Estivill, X:
Ctr Genom Regulat CRG, Genom & Dis Grp, Bioinformat & Genom Programme, Barcelona, Catalonia, Spain
Univ Pompeu Fabra, Barcelona, Catalonia, Spain
Hosp Mar, Med Res Inst IMIM, Barcelona, Catalonia, Spain
CIBER Epidemiol & Publ Hlth CIBERESP, Barcelona, Catalonia, Spain
Torra, R:
Univ Autonoma Barcelona, IIB St Pau, Inst Invest Carlos III, Nephrol Dept,Fundacio Puigvert,REDinREN, Barcelona, Catalonia, Spain
Ars, E:
Univ Autonoma Barcelona, IIB St Pau, Inst Invest Carlos III, Mol Biol Lab,Fundacio Puigvert,REDinREN, Barcelona, Catalonia, Spain
Univ Autonoma Barcelona, IIB St Pau, Inst Invest Carlos III, Nephrol Dept,Fundacio Puigvert,REDinREN, Barcelona, Catalonia, Spain
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