title: Targeted sequencing of 96 renal developmental microRNAs in 1213 individuals from 980 families with congenital anomalies of the kidney and urinary tract.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA Department of Pediatrics, Cologne Children's Hospital, Cologne, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kohl
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Vivante
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA Division of Nephrology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Daw-Yang
authors.initials: DY
authors.lastname: Hwang
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Shirlee
authors.initials: S
authors.lastname: Shril
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Gabriel C
authors.initials: GC
authors.lastname: Dworschak
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Amelie
authors.initials: A
authors.lastname: Van Der Ven
authors.affiliation: Department of Medicine, Columbia University, New York, NY, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Sanna-Cherchi
authors.affiliation: Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Bauer
authors.affiliation: Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt Egyptian Group for Orphan Renal Diseases (EGORD), Cairo, Egypt.
authors.forename: Neveen A
authors.initials: NA
authors.lastname: Soliman
authors.affiliation: Division of Urology, Department of Surgery, Kuwait University, Safat, Kuwait.
authors.forename: Elijah O
authors.initials: EO
authors.lastname: Kehinde
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Neonatology, Children's Hospital, University of Bonn, Bonn, Germany.
authors.forename: Heiko M
authors.initials: HM
authors.lastname: Reutter
authors.affiliation: Medical Faculty Skopje, University Children's Hospital, Skopje, Macedonia.
authors.forename: Velibor
authors.initials: V
authors.lastname: Tasic
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA Howard Hughes Medical Institute, Chevy Chase, MD, USA.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D000293:Adolescent; D000818:Animals; D002648:Child; D056915:DNA Copy Number Variations; D006801:Humans; D007668:Kidney / Q000002:abnormalities*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D051381:Rats; D014551:Urinary Tract / Q000002:abnormalities*; D014564:Urogenital Abnormalities / Q000235:genetics*; D055815:Young Adult
chemical_list: D035683:MicroRNAs
keywords: CAKUT; miRNA; microRNA; stem-loop