haploinsufficiency leads to syndromic congenital anomalies of the kidney and urinary tract (CAKUT) in humans

Pauline Le Tanno, Julie Breton, Marie Bidart, Véronique Satre, Radu Harbuz, Pierre F Ray, Caroline Bosson, Klaus Dieterich, Sylvie Jaillard, Sylvie Odent, Gemma Poke, Rachel Beddow, Maria Christina Digilio, Antonio Novelli, Laura Bernardini, Maria Antonietta Pisanti, Luisa Mackenroth, Karl Hackmann, Ida Vogel, Rikke ChristensenSiv Fokstuen, Frédérique Béna, Florence Amblard, Francoise Devillard, Gaelle Vieville, Alexia Apostolou, Pierre-Simon Jouk, Fitsum Guebre-Egziabher, Hervé Sartelet, Charles Coutton

Research output: Contribution to journalArticlepeer-review


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 characterisedPBX1expression 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 thePBX1gene. 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 thatPBX1is 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 thatPBX1haploinsufficiency leads to syndromic CAKUT as supported by thePbx1-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.

Original languageEnglish
Pages (from-to)502-510
Number of pages9
JournalJournal of Medical Genetics
Issue number7
Publication statusPublished - Jul 2017


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