Pediatric Nephrology

, Volume 31, Issue 6, pp 941–955 | Cite as

Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy

  • Stefanie Weber
  • Katja Strasser
  • Sabine Rath
  • Achim Kittke
  • Sonja Beicht
  • Martin Alberer
  • Bärbel Lange-Sperandio
  • Peter F. Hoyer
  • Marcus R. Benz
  • Sabine Ponsel
  • Lutz T. Weber
  • Hanns-Georg Klein
  • Julia HoefeleEmail author
Original Article



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.


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.


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.


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.


Alport syndrome Thin basement membrane nephropathy Mutational analysis COL4A5 COL4A3 COL4A4 



We sincerely thank the patients and the physicians for participation in this study.

Compliance with ethical standards

Approval for this study was obtained from the Ethics Committee of the Ludwig-Maximilians University, Munich, Germany. Written informed consent was obtained.

Conflict of interest

The authors declare no conflict of interest.


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Copyright information

© IPNA 2016

Authors and Affiliations

  • Stefanie Weber
    • 1
  • Katja Strasser
    • 1
  • Sabine Rath
    • 2
  • Achim Kittke
    • 2
  • Sonja Beicht
    • 2
  • Martin Alberer
    • 3
  • Bärbel Lange-Sperandio
    • 4
  • Peter F. Hoyer
    • 1
  • Marcus R. Benz
    • 5
  • Sabine Ponsel
    • 4
  • Lutz T. Weber
    • 5
  • Hanns-Georg Klein
    • 2
  • Julia Hoefele
    • 2
    • 6
    Email author
  1. 1.Pediatric Nephrology, Pediatrics IIUniversity of Duisburg-EssenEssenGermany
  2. 2.Center for Human Genetics and Laboratory Diagnostics Dr. Klein, Dr. Rost and ColleaguesMartinsriedGermany
  3. 3.Department of Infectious Diseases and Tropical MedicineLudwig-Maximilians UniversityMunichGermany
  4. 4.Pediatric Nephrology, University Children’s HospitalLudwig-Maximilians UniversityMunichGermany
  5. 5.Pediatric NephrologyUniversity Children’s HospitalCologneGermany
  6. 6.Institute of Human GeneticsTechnische Universität MünchenMunichGermany

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