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Deletion of the 5′exons of COL4A6 is not needed for the development of diffuse leiomyomatosis in patients with Alport syndrome
  1. Maria João Nabais Sá1,2,
  2. Nathalie Fieremans3,
  3. Arjan P M de Brouwer4,
  4. Rita Sousa5,
  5. Fernando Teixeira e Costa6,
  6. Maria José Brito7,
  7. Fernanda Carvalho8,
  8. Márcia Rodrigues9,
  9. Francisco Teixeira de Sousa10,
  10. Joana Felgueiras10,
  11. Fernando Neves11,
  12. Adelino Carvalho11,
  13. Umbelina Ramos12,
  14. José Ramón Vizcaíno12,
  15. Susana Alves1,
  16. Filipa Carvalho1,
  17. Guy Froyen3,
  18. João Paulo Oliveira1,2
  1. 1Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal
  2. 2Unit of Research and Development in Nephrology (FCT-725), Faculty of Medicine, University of Porto, Porto, Portugal
  3. 3Human Genome Laboratory, Department of Human Genetics, VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium
  4. 4Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  5. 5Department of Gastroenterology, Hospital Garcia de Orta, Almada, Portugal
  6. 6Department of Nephrology, Hospital Garcia de Orta, Almada, Portugal
  7. 7Department of Pathology, Hospital Garcia de Orta, Almada, Portugal
  8. 8Unit of Renal Morphology, Department of Nephrology, Hospital Curry Cabral, Lisboa, Portugal
  9. 9Department of Genetics, Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisboa, Portugal
  10. 10Nephrocare Montijo, Fresenius Medical Care Portugal, Montijo, Portugal
  11. 11Nephrocare Santarém, Fresenius Medical Care Portugal, Santarém, Portugal
  12. 12Department of Pathology, Hospital de Santo António—Centro Hospitalar do Porto, Porto, Portugal
  1. Correspondence to Dr Maria João Nabais Sá, Department of Genetics, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200 - 319 Porto, Portugal; mjs.jano{at}


Background Alport syndrome (AS), a hereditary type IV collagen nephropathy, is a major cause of end-stage renal disease in young people. About 85% of the cases are X-linked (ATS), due to mutations in the COL4A5 gene. Rarely, families have a contiguous gene deletion comprising at least exon 1 of COL4A5 and the first exons of COL4A6, associated with the development of diffuse leiomyomatosis (ATS-DL). We report three novel deletions identified in families with AS, one of which challenges the current concepts on genotype-phenotype correlations of ATS/ATS-DL.

Methods In the setting of a multicentric study aiming to describe the genetic epidemiology and molecular pathology of AS in Portugal, three novel COL4A5 deletions were identified in two families with x-linked Alport syndrome (ATS) and in one family with ATS-DL. These mutations were initially detected by PCR and Multiplex Ligation-dependent Probe Amplification, and further mapped by high-resolution X chromosome-specific oligo-array and PCR.

Results In the ATS-DL family, a COL4A5 deletion spanning exons 2 through 51, extending distally beyond COL4A5 but proximally not into COL4A6, segregated with the disease phenotype. A COL4A5 deletion encompassing exons 2 through 29 was identified in one of the ATS families. In the second ATS family, a deletion of exon 13 of COL4A5 through exon 3 of COL4A6 was detected.

Conclusions These observations suggest that deletion of the 5′ exons of COL4A6 and of the common promoter of the COL4A5 and COL4A6 genes is not essential for the development of leiomyomatosis in patients with ATS, and that COL4A5_COL4A6 deletions extending into COL4A6 exon 3 may not result in ATS-DL.

  • Genetics
  • Clinical genetics
  • Molecular genetics
  • Renal Medicine
  • Oesophagus

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