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

TY - JOUR

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

N1 - © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

PY - 2016/8

Y1 - 2016/8

N2 - BACKGROUND: Congenital 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.METHODS: Given 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.RESULTS: We 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.CONCLUSIONS: Our 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 - BACKGROUND: Congenital 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.METHODS: Given 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.RESULTS: We 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.CONCLUSIONS: Our 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 - Adolescent

KW - Animals

KW - Child

KW - DNA Copy Number Variations

KW - Humans

KW - Kidney/abnormalities

KW - Mice

KW - Mice, Knockout

KW - MicroRNAs/genetics

KW - Mutation

KW - Phenotype

KW - Rats

KW - Urinary Tract/abnormalities

KW - Urogenital Abnormalities/genetics

KW - Young Adult

U2 - 10.1093/ndt/gfv447

DO - 10.1093/ndt/gfv447

M3 - SCORING: Journal article

C2 - 26908769

VL - 31

SP - 1280

EP - 1283

JO - NEPHROL DIAL TRANSPL

JF - NEPHROL DIAL TRANSPL

SN - 0931-0509

IS - 8

ER -