title: Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy.
abstract: BACKGROUND
  Alport syndrome (ATS) is a progressive hereditary nephropathy characterized by hematuria and proteinuria. It can be associated with extrarenal manifestations. In contrast, thin basement membrane nephropathy (TBMN) is characterized by microscopic hematuria, is largely asymptomatic, and is rarely associated with proteinuria and end-stage renal disease. Mutations have been identified in the COL4A5 gene in ATS and in the COL4A3 and COL4A4 genes in ATS and TBMN. To date, more than 1000 different mutations in COL4A5, COL4A3, and COL4A4 are known.
  
  
  METHODS
  In this study mutational analysis by exon sequencing and multiplex ligation-dependent probe amplification was performed in a large European cohort of families with ATS and TBMN.
  
  
  RESULTS
  Molecular diagnostic testing of 216 individuals led to the detection of 47 novel mutations, thereby expanding the spectrum of known mutations causing ATS and TBMN by up to 10 and 6%, respectively, depending on the database. Remarkably, a high number of ATS patients with only single mutations in COL4A3 and COL4A4 were identified. Additionally, three ATS patients presented with synonymous sequence variants that possible affect correct mRNA splicing, as suggested by in silico analysis.
  
  
  CONCLUSIONS
  The results of this study clearly broaden the genotypic spectrum of known mutations for ATS and TBMN, which will in turn now facilitate future studies into genotype-phenotype correlations. Further studies should also examine the significance of single heterozygous mutations in COL4A3 and COL4A4 and of synonymous sequence variants associated with ATS.
authors.affiliation: Pediatric Nephrology, Pediatrics II, University of Duisburg-Essen, Essen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Weber
authors.affiliation: Pediatric Nephrology, Pediatrics II, University of Duisburg-Essen, Essen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Strasser
authors.affiliation: Center for Human Genetics and Laboratory Diagnostics Dr. Klein, Dr. Rost and Colleagues, Martinsried, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Rath
authors.affiliation: Center for Human Genetics and Laboratory Diagnostics Dr. Klein, Dr. Rost and Colleagues, Martinsried, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Kittke
authors.affiliation: Center for Human Genetics and Laboratory Diagnostics Dr. Klein, Dr. Rost and Colleagues, Martinsried, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Beicht
authors.affiliation: Department of Infectious Diseases and Tropical Medicine, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Alberer
authors.affiliation: Pediatric Nephrology, University Children's Hospital, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Lange-Sperandio
authors.affiliation: Pediatric Nephrology, Pediatrics II, University of Duisburg-Essen, Essen, Germany.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Hoyer
authors.affiliation: Pediatric Nephrology, University Children's Hospital, Cologne, Germany.
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Benz
authors.affiliation: Pediatric Nephrology, University Children's Hospital, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Ponsel
authors.affiliation: Pediatric Nephrology, University Children's Hospital, Cologne, Germany.
authors.forename: Lutz T
authors.initials: LT
authors.lastname: Weber
authors.affiliation: Center for Human Genetics and Laboratory Diagnostics Dr. Klein, Dr. Rost and Colleagues, Martinsried, Germany.
authors.forename: Hanns-Georg
authors.initials: HG
authors.lastname: Klein
authors.affiliation: Center for Human Genetics and Laboratory Diagnostics Dr. Klein, Dr. Rost and Colleagues, Martinsried, Germany. julia.hoefele@tum.de.|Institute of Human Genetics, Technische Universität München, Munich, Germany. julia.hoefele@tum.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoefele
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001324:Autoantigens / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D024141:Collagen Type IV / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006417:Hematuria / Q000150:complications / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009394:Nephritis, Hereditary / Q000150:complications / Q000235:genetics*; D011507:Proteinuria / Q000209:etiology / Q000235:genetics; D055815:Young Adult
chemical_list: D001324:Autoantigens; C466620:COL4A4 protein, human; C478159:COL4A5 protein, human; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain
keywords: Alport syndrome; COL4A3; COL4A4; COL4A5; Mutational analysis; Thin basement membrane nephropathy
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