Targeted sequencing of 96 renal developmental microRNAs in 1213 individuals from 980 families with congenital anomalies of the kidney and urinary tract

Stefan Kohl, Jing Chen, Asaf Vivante, Daw Yang Hwang, Shirlee Shril, Gabriel C. Dworschak, Amelie Van Der Ven, Simone Sanna-Cherchi, Stuart B. Bauer, Richard S. Lee, Neveen A. Soliman, Elijah O. Kehinde, Heiko M. Reutter, Velibor Tasic, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

BackgroundCongenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney diseases in children and young adults, accounting for ∼50% of cases. These anomalies represent maldevelopment of the genitourinary system and can be genetically explained in only 10-16% of cases by mutations or by copy number variations in protein coding sequences. Knock-out mouse models, lacking components of the microRNA (miRNA) processing machinery (i.e. Dicer, Drosha, Dgcr8), exhibit kidney malformations resembling human CAKUT. MethodsGiven the Dicer-null mouse phenotype, which implicates a central role for miRNAs gene regulation during kidney development, we hypothesized that miRNAs expressed during kidney development may cause CAKUT in humans if mutated. To evaluate this possibility we carried out Next-Generation sequencing of 96 stem-loop regions of 73 renal developmental miRNA genes in 1248 individuals with non-syndromic CAKUT from 980 families. ResultsWe sequenced 96 stem-loop regions encoded by 73 miRNA genes that are expressed during kidney development in humans, mice and rats. Overall, we identified in 31/1213 individuals from 26 families with 17 different single nucleotide variants. Two variants did not segregate with the disease and hence were not causative. Thirteen variants were likely benign variants because they occurred in control populations and/or they affected nucleotides of weak evolutionary conservation. Two out of 1213 unrelated individuals had potentially pathogenic variants with unknown biologic relevance affecting miRNAs MIR19B1 and MIR99A. ConclusionsOur results indicate that mutations affecting mature microRNAs in individuals with CAKUT are rare and thus most likely not a common cause of CAKUT in humans.

Original languageEnglish
Pages (from-to)1280-1283
Number of pages4
JournalNephrology Dialysis Transplantation
Volume31
Issue number8
DOIs
Publication statusPublished - Aug 1 2016
Externally publishedYes

Fingerprint

MicroRNAs
Kidney
Nucleotides
Urogenital System
Developmental Genes
Mutation
Human Development
Cakut
Urinary Tract
Chronic Renal Insufficiency
Knockout Mice
Genes
Young Adult
Phenotype
Population
Proteins

Keywords

  • CAKUT
  • MicroRNA
  • MiRNA
  • Stem-loop

ASJC Scopus subject areas

  • Medicine(all)
  • Nephrology
  • Transplantation

Cite this

Targeted sequencing of 96 renal developmental microRNAs in 1213 individuals from 980 families with congenital anomalies of the kidney and urinary tract. / Kohl, Stefan; Chen, Jing; Vivante, Asaf; Hwang, Daw Yang; Shril, Shirlee; Dworschak, Gabriel C.; Van Der Ven, Amelie; Sanna-Cherchi, Simone; Bauer, Stuart B.; Lee, Richard S.; Soliman, Neveen A.; Kehinde, Elijah O.; Reutter, Heiko M.; Tasic, Velibor; Hildebrandt, Friedhelm.

In: Nephrology Dialysis Transplantation, Vol. 31, No. 8, 01.08.2016, p. 1280-1283.

Research output: Contribution to journalArticle

Kohl, S, Chen, J, Vivante, A, Hwang, DY, Shril, S, Dworschak, GC, Van Der Ven, A, Sanna-Cherchi, S, Bauer, SB, Lee, RS, Soliman, NA, Kehinde, EO, Reutter, HM, Tasic, V & Hildebrandt, F 2016, 'Targeted sequencing of 96 renal developmental microRNAs in 1213 individuals from 980 families with congenital anomalies of the kidney and urinary tract', Nephrology Dialysis Transplantation, vol. 31, no. 8, pp. 1280-1283. https://doi.org/10.1093/ndt/gfv447
Kohl, Stefan ; Chen, Jing ; Vivante, Asaf ; Hwang, Daw Yang ; Shril, Shirlee ; Dworschak, Gabriel C. ; Van Der Ven, Amelie ; Sanna-Cherchi, Simone ; Bauer, Stuart B. ; Lee, Richard S. ; Soliman, Neveen A. ; Kehinde, Elijah O. ; Reutter, Heiko M. ; Tasic, Velibor ; Hildebrandt, Friedhelm. / Targeted sequencing of 96 renal developmental microRNAs in 1213 individuals from 980 families with congenital anomalies of the kidney and urinary tract. In: Nephrology Dialysis Transplantation. 2016 ; Vol. 31, No. 8. pp. 1280-1283.
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abstract = "BackgroundCongenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney diseases in children and young adults, accounting for ∼50{\%} of cases. These anomalies represent maldevelopment of the genitourinary system and can be genetically explained in only 10-16{\%} of cases by mutations or by copy number variations in protein coding sequences. Knock-out mouse models, lacking components of the microRNA (miRNA) processing machinery (i.e. Dicer, Drosha, Dgcr8), exhibit kidney malformations resembling human CAKUT. MethodsGiven the Dicer-null mouse phenotype, which implicates a central role for miRNAs gene regulation during kidney development, we hypothesized that miRNAs expressed during kidney development may cause CAKUT in humans if mutated. To evaluate this possibility we carried out Next-Generation sequencing of 96 stem-loop regions of 73 renal developmental miRNA genes in 1248 individuals with non-syndromic CAKUT from 980 families. ResultsWe sequenced 96 stem-loop regions encoded by 73 miRNA genes that are expressed during kidney development in humans, mice and rats. Overall, we identified in 31/1213 individuals from 26 families with 17 different single nucleotide variants. Two variants did not segregate with the disease and hence were not causative. Thirteen variants were likely benign variants because they occurred in control populations and/or they affected nucleotides of weak evolutionary conservation. Two out of 1213 unrelated individuals had potentially pathogenic variants with unknown biologic relevance affecting miRNAs MIR19B1 and MIR99A. ConclusionsOur results indicate that mutations affecting mature microRNAs in individuals with CAKUT are rare and thus most likely not a common cause of CAKUT in humans.",
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author = "Stefan Kohl and Jing Chen and Asaf Vivante and Hwang, {Daw Yang} and Shirlee Shril and Dworschak, {Gabriel C.} and {Van Der Ven}, Amelie and Simone Sanna-Cherchi and Bauer, {Stuart B.} and Lee, {Richard S.} and Soliman, {Neveen A.} and Kehinde, {Elijah O.} and Reutter, {Heiko M.} and Velibor Tasic and Friedhelm Hildebrandt",
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T1 - Targeted sequencing of 96 renal developmental microRNAs in 1213 individuals from 980 families with congenital anomalies of the kidney and urinary tract

AU - Kohl, Stefan

AU - Chen, Jing

AU - Vivante, Asaf

AU - Hwang, Daw Yang

AU - Shril, Shirlee

AU - Dworschak, Gabriel C.

AU - Van Der Ven, Amelie

AU - Sanna-Cherchi, Simone

AU - Bauer, Stuart B.

AU - Lee, Richard S.

AU - Soliman, Neveen A.

AU - Kehinde, Elijah O.

AU - Reutter, Heiko M.

AU - Tasic, Velibor

AU - Hildebrandt, Friedhelm

PY - 2016/8/1

Y1 - 2016/8/1

N2 - BackgroundCongenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney diseases in children and young adults, accounting for ∼50% of cases. These anomalies represent maldevelopment of the genitourinary system and can be genetically explained in only 10-16% of cases by mutations or by copy number variations in protein coding sequences. Knock-out mouse models, lacking components of the microRNA (miRNA) processing machinery (i.e. Dicer, Drosha, Dgcr8), exhibit kidney malformations resembling human CAKUT. MethodsGiven the Dicer-null mouse phenotype, which implicates a central role for miRNAs gene regulation during kidney development, we hypothesized that miRNAs expressed during kidney development may cause CAKUT in humans if mutated. To evaluate this possibility we carried out Next-Generation sequencing of 96 stem-loop regions of 73 renal developmental miRNA genes in 1248 individuals with non-syndromic CAKUT from 980 families. ResultsWe sequenced 96 stem-loop regions encoded by 73 miRNA genes that are expressed during kidney development in humans, mice and rats. Overall, we identified in 31/1213 individuals from 26 families with 17 different single nucleotide variants. Two variants did not segregate with the disease and hence were not causative. Thirteen variants were likely benign variants because they occurred in control populations and/or they affected nucleotides of weak evolutionary conservation. Two out of 1213 unrelated individuals had potentially pathogenic variants with unknown biologic relevance affecting miRNAs MIR19B1 and MIR99A. ConclusionsOur results indicate that mutations affecting mature microRNAs in individuals with CAKUT are rare and thus most likely not a common cause of CAKUT in humans.

AB - BackgroundCongenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney diseases in children and young adults, accounting for ∼50% of cases. These anomalies represent maldevelopment of the genitourinary system and can be genetically explained in only 10-16% of cases by mutations or by copy number variations in protein coding sequences. Knock-out mouse models, lacking components of the microRNA (miRNA) processing machinery (i.e. Dicer, Drosha, Dgcr8), exhibit kidney malformations resembling human CAKUT. MethodsGiven the Dicer-null mouse phenotype, which implicates a central role for miRNAs gene regulation during kidney development, we hypothesized that miRNAs expressed during kidney development may cause CAKUT in humans if mutated. To evaluate this possibility we carried out Next-Generation sequencing of 96 stem-loop regions of 73 renal developmental miRNA genes in 1248 individuals with non-syndromic CAKUT from 980 families. ResultsWe sequenced 96 stem-loop regions encoded by 73 miRNA genes that are expressed during kidney development in humans, mice and rats. Overall, we identified in 31/1213 individuals from 26 families with 17 different single nucleotide variants. Two variants did not segregate with the disease and hence were not causative. Thirteen variants were likely benign variants because they occurred in control populations and/or they affected nucleotides of weak evolutionary conservation. Two out of 1213 unrelated individuals had potentially pathogenic variants with unknown biologic relevance affecting miRNAs MIR19B1 and MIR99A. ConclusionsOur results indicate that mutations affecting mature microRNAs in individuals with CAKUT are rare and thus most likely not a common cause of CAKUT in humans.

KW - CAKUT

KW - MicroRNA

KW - MiRNA

KW - Stem-loop

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