title: CHD1L: a new candidate gene for congenital anomalies of the kidneys and urinary tract (CAKUT).
abstract: BACKGROUND
  Recently, we identified a microduplication in chromosomal band 1q21.1 encompassing the CHD1L/ALC1 gene encoding a chromatin-remodelling enzyme in congenital anomalies of the kidneys and urinary tract (CAKUT) patient.
  
  
  METHODS
  To explore the role of CHD1L in CAKUT, we screened 85 CAKUT patients for mutations in the CHD1L gene and performed functional analyses of the three heterozygous missense variants detected. In addition, we quantitatively determined CHD1L expression in multiple human fetal and adult tissues and analysed expression of CHD1L protein in human embryonal, adult and hydronephrotic kidney sections.
  
  
  RESULTS
  Two of three novel heterozygous missense variants identified in three patients were not found in >400 control chromosomes. All variants lead to amino acid substitutions in or near the CHD1L macro domain, a poly-ADP-ribose (PAR)-binding module interacting with PAR polymerase 1 (PARP1), and showed decreased interaction with PARP1 by pull-down assay of transfected cell lysates. Quantitative messenger RNA analysis demonstrated high CHD1L expression in human fetal kidneys, and levels were four times higher than in adult kidneys. In the human embryo at 7-11 weeks gestation, CHD1L immunolocalized in the early ureteric bud and the S- and comma-shaped bodies, critical stages of kidney development. In normal postnatal sections, CHD1L was expressed in the cytoplasm of tubular cells in all tubule segments. CHD1L expression appeared higher in the hydronephrotic kidney of one patient with a hypofunctional CHD1L variant than in normal kidneys, recapitulating high fetal levels.
  
  
  CONCLUSIONS
  Our data suggest that CHD1L plays a role in kidney development and may be a new candidate gene for CAKUT.
authors.affiliation: Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Brockschmidt
authors.forename: Boidinh
authors.initials: B
authors.lastname: Chung
authors.forename: Stefanie
authors.initials: S
authors.lastname: Weber
authors.forename: Dagmar-Christiane
authors.initials: DC
authors.lastname: Fischer
authors.forename: Maria
authors.initials: M
authors.lastname: Kolatsi-Joannou
authors.forename: Laura
authors.initials: L
authors.lastname: Christ
authors.forename: André
authors.initials: A
authors.lastname: Heimbach
authors.forename: Diamant
authors.initials: D
authors.lastname: Shtiza
authors.forename: Günter
authors.initials: G
authors.lastname: Klaus
authors.forename: Giacomo D
authors.initials: GD
authors.lastname: Simonetti
authors.forename: Martin
authors.initials: M
authors.lastname: Konrad
authors.forename: Paul
authors.initials: P
authors.lastname: Winyard
authors.forename: Dieter
authors.initials: D
authors.lastname: Haffner
authors.forename: Franz
authors.initials: F
authors.lastname: Schaefer
authors.forename: Ruthild G
authors.initials: RG
authors.lastname: Weber
mesh_terms: D000328:Adult; D015153:Blotting, Western; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D000013:Congenital Abnormalities / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005333:Fetus; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007223:Infant; D007231:Infant, Newborn; D007668:Kidney / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014551:Urinary Tract / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D004265:DNA Helicases; C543585:CHD1L protein, human