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Original Article
PBX1 haploinsufficiency leads to syndromic congenital anomalies of the kidney and urinary tract (CAKUT) in humans
  1. Pauline Le Tanno1,
  2. Julie Breton2,
  3. Marie Bidart3,4,
  4. Véronique Satre1,3,5,
  5. Radu Harbuz1,
  6. Pierre F Ray3,5,6,
  7. Caroline Bosson6,
  8. Klaus Dieterich1,3,
  9. Sylvie Jaillard7,
  10. Sylvie Odent8,
  11. Gemma Poke9,
  12. Rachel Beddow9,
  13. Maria Christina Digilio10,
  14. Antonio Novelli10,
  15. Laura Bernardini11,
  16. Maria Antonietta Pisanti12,
  17. Luisa Mackenroth13,
  18. Karl Hackmann13,
  19. Ida Vogel14,
  20. Rikke Christensen14,
  21. Siv Fokstuen15,
  22. Frédérique Béna15,
  23. Florence Amblard1,
  24. Francoise Devillard1,
  25. Gaelle Vieville1,
  26. Alexia Apostolou2,
  27. Pierre-Simon Jouk1,3,
  28. Fitsum Guebre-Egziabher16,
  29. Hervé Sartelet2,3,
  30. Charles Coutton1,5,3,17
  1. 1 Département de Génétique et Procréation, CHU Grenoble Alpes, Grenoble, France
  2. 2 Département d’Anatomie et Cytologie Pathologiques, CHU Grenoble Alpes, Grenoble, France
  3. 3 Université Grenoble Alpes, Grenoble, France
  4. 4 UF Clinatec, Pôle Recherche, CHU Grenoble Alpes, Grenoble, France
  5. 5 Equipe “Génétique, Epigénétique et Thérapies de l'Infertilité”, Institut Albert Bonniot, La Tronche, France
  6. 6 Laboratoire de Biochimie Génétique et Moléculaire, Institut de Biologie et Pathologie, CHU Grenoble Alpes, Grenoble, France
  7. 7 CHU Rennes, Service de Cytogénétique et Biologie Cellulaire, Université de Rennes, Rennes, France
  8. 8 CHU Rennes, Service de Génétique Clinique, Centre de Référence Anomalies du Développement CLAD-Ouest, Hôpital Sud, Rennes, France
  9. 9 Genetic Health Service New Zealand Central Hub, Wellington, New Zealand
  10. 10 Department of Medical Genetics, Bambino Gesù Children’s Hospital, Rome, Italy
  11. 11 Mendel Laboratory IRCCS “Casa Sollievo della Sofferenza” Hospital, Foggia, Italy
  12. 12 Service of Medical Genetics, Cardarelli Hospital, Naples, Italy
  13. 13 Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany
  14. 14 Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
  15. 15 Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland
  16. 16 Clinique de Néphrologie Dialyse Transplantation, CHU Grenoble Alpes, Grenoble, France
  17. 17 Génétique et Procréation, Laboratoire de Génétique Chromosomique, CHU Grenoble Alpes, Grenoble, France
  1. Correspondence to Dr Charles Coutton, Département de Génétique et Procréation, CHU Grenoble Alpes, Grenoble, France; CCoutton{at}


Background Congenital anomalies of the kidney and urinary tract (CAKUT) represent a significant healthcare burden since it is the primary cause of chronic kidney in children. CNVs represent a recurrent molecular cause of CAKUT but the culprit gene remains often elusive. Our study aimed to define the gene responsible for CAKUT in patients with an 1q23.3q24.1 microdeletion.

Methods We describe eight patients presenting with CAKUT carrying an 1q23.3q24.1 microdeletion as identified by chromosomal microarray analysis (CMA). Clinical features were collected, especially the renal and urinary tract phenotype, and extrarenal features. We characterised PBX1 expression and localisation in fetal and adult kidneys using quantitative RT-PCR and immunohistochemistry.

Results We defined a 276-kb minimal common region (MCR) that only overlaps with the PBX1 gene. All eight patients presented with syndromic CAKUT. CAKUT were mostly bilateral renal hypoplasia (75%). The most frequent extrarenal symptoms were developmental delay and ear malformations. We demonstrate that PBX1 is strongly expressed in fetal kidneys and brain and expression levels decreased in adult samples. In control fetal kidneys, PBX1 was localised in nuclei of medullary, interstitial and mesenchymal cells, whereas it was present in endothelial cells in adult kidneys.

Conclusions Our results indicate that PBX1 haploinsufficiency leads to syndromic CAKUT as supported by the Pbx1-null mice model. Correct PBX1 dosage appears to be critical for normal nephrogenesis and seems important for brain development in humans. CMA should be recommended in cases of fetal renal anomalies to improve genetic counselling and pregnancy management.

  • copy number variation
  • chromosomal microarray analysis
  • PBX1
  • 1q23.3q24.1 microdeletion

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  • Contributors PLT, CC, VS, RH, KD, SJ, SO, GP, RB, MCD, AN, LB, MAP, LM, KH, IV, RC, SF, FSB, FD, FA and PSJ recruited patients and collected clinical information. MB and GV performed molecular analyses. JB, AA and HS performed IHC experiments. PLT, JB, MB, PFR, CB, GV and AA performed data analysis and interpretation. PLT, CC, MB, HS and FGE designed the study and wrote the manuscript.

  • Competing interests None declared.

  • Ethics approval Local medical ethical committee (Grenoble institutional review board).

  • Provenance and peer review Not commissioned; externally peer reviewed.