Contribution of the TTC21B gene to glomerular and cystic kidney diseases

Gemma Bullich, Ivan Vargas, Daniel Trujillano, Santiago Mendizabal, Juan Alberto Pinero-Fernandez, Gloria Fraga, Jose Garcia-Solano, Jose Ballarin, Xavier P. Estivill, Roser Torra, Elisabet Ars

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)151-156
Number of pages6
JournalNephrology Dialysis Transplantation
Volume32
Issue number1
DOIs
Publication statusPublished - 2017
Externally publishedYes

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Cystic Kidney Diseases
Focal Segmental Glomerulosclerosis
Mutation
Genes
Myopia
Proteinuria
Hypertension
Phenotype
Kidney

Keywords

  • FSGS
  • Modifier
  • Mutation
  • TTC21B
  • Tubulointerstitial

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

Cite this

Bullich, G., Vargas, I., Trujillano, D., Mendizabal, S., Pinero-Fernandez, J. A., Fraga, G., ... Ars, E. (2017). Contribution of the TTC21B gene to glomerular and cystic kidney diseases. Nephrology Dialysis Transplantation, 32(1), 151-156. https://doi.org/10.1093/ndt/gfv453

Contribution of the TTC21B gene to glomerular and cystic kidney diseases. / Bullich, Gemma; Vargas, Ivan; Trujillano, Daniel; Mendizabal, Santiago; Pinero-Fernandez, Juan Alberto; Fraga, Gloria; Garcia-Solano, Jose; Ballarin, Jose; Estivill, Xavier P.; Torra, Roser; Ars, Elisabet.

In: Nephrology Dialysis Transplantation, Vol. 32, No. 1, 2017, p. 151-156.

Research output: Contribution to journalArticle

Bullich, G, Vargas, I, Trujillano, D, Mendizabal, S, Pinero-Fernandez, JA, Fraga, G, Garcia-Solano, J, Ballarin, J, Estivill, XP, Torra, R & Ars, E 2017, 'Contribution of the TTC21B gene to glomerular and cystic kidney diseases', Nephrology Dialysis Transplantation, vol. 32, no. 1, pp. 151-156. https://doi.org/10.1093/ndt/gfv453
Bullich G, Vargas I, Trujillano D, Mendizabal S, Pinero-Fernandez JA, Fraga G et al. Contribution of the TTC21B gene to glomerular and cystic kidney diseases. Nephrology Dialysis Transplantation. 2017;32(1):151-156. https://doi.org/10.1093/ndt/gfv453
Bullich, Gemma ; Vargas, Ivan ; Trujillano, Daniel ; Mendizabal, Santiago ; Pinero-Fernandez, Juan Alberto ; Fraga, Gloria ; Garcia-Solano, Jose ; Ballarin, Jose ; Estivill, Xavier P. ; Torra, Roser ; Ars, Elisabet. / Contribution of the TTC21B gene to glomerular and cystic kidney diseases. In: Nephrology Dialysis Transplantation. 2017 ; Vol. 32, No. 1. pp. 151-156.
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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.",
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AU - Vargas, Ivan

AU - Trujillano, Daniel

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AU - Pinero-Fernandez, Juan Alberto

AU - Fraga, Gloria

AU - Garcia-Solano, Jose

AU - Ballarin, Jose

AU - Estivill, Xavier P.

AU - Torra, Roser

AU - Ars, Elisabet

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N2 - 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.

AB - 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.

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