title: PBX1haploinsufficiency leads to syndromic congenital anomalies of the kidney and urinary tract (CAKUT) in humans.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Département de Génétique et Procréation, CHU Grenoble Alpes, Grenoble, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Le Tanno
authors.affiliation: Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble Alpes, Grenoble, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Breton
authors.affiliation: Université Grenoble Alpes, Grenoble, France.|UF Clinatec, Pôle Recherche, CHU Grenoble Alpes, Grenoble, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Bidart
authors.affiliation: Département de Génétique et Procréation, CHU Grenoble Alpes, Grenoble, France.|Université Grenoble Alpes, Grenoble, France.|Equipe "Génétique, Epigénétique et Thérapies de l'Infertilité", Institut Albert Bonniot, La Tronche, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Satre
authors.affiliation: Département de Génétique et Procréation, CHU Grenoble Alpes, Grenoble, France.
authors.forename: Radu
authors.initials: R
authors.lastname: Harbuz
authors.affiliation: Université Grenoble Alpes, Grenoble, France.|Equipe "Génétique, Epigénétique et Thérapies de l'Infertilité", Institut Albert Bonniot, La Tronche, France.|Laboratoire de Biochimie Génétique et Moléculaire, Institut de Biologie et Pathologie, CHU Grenoble Alpes, Grenoble, France.
authors.forename: Pierre F
authors.initials: PF
authors.lastname: Ray
authors.affiliation: Laboratoire de Biochimie Génétique et Moléculaire, Institut de Biologie et Pathologie, CHU Grenoble Alpes, Grenoble, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bosson
authors.affiliation: Département de Génétique et Procréation, CHU Grenoble Alpes, Grenoble, France.|Université Grenoble Alpes, Grenoble, France.
authors.forename: Klaus
authors.initials: K
authors.lastname: Dieterich
authors.affiliation: CHU Rennes, Service de Cytogénétique et Biologie Cellulaire, Université de Rennes, Rennes, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Jaillard
authors.affiliation: CHU Rennes, Service de Génétique Clinique, Centre de Référence Anomalies du Développement CLAD-Ouest, Hôpital Sud, Rennes, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.affiliation: Genetic Health Service New Zealand Central Hub, Wellington, New Zealand.
authors.forename: Gemma
authors.initials: G
authors.lastname: Poke
authors.affiliation: Genetic Health Service New Zealand Central Hub, Wellington, New Zealand.
authors.forename: Rachel
authors.initials: R
authors.lastname: Beddow
authors.affiliation: Department of Medical Genetics, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Maria Christina
authors.initials: MC
authors.lastname: Digilio
authors.affiliation: Department of Medical Genetics, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Novelli
authors.affiliation: Mendel Laboratory IRCCS "Casa Sollievo della Sofferenza" Hospital, Foggia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Bernardini
authors.affiliation: Service of Medical Genetics, Cardarelli Hospital, Naples, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Pisanti
authors.affiliation: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany.
authors.forename: Luisa
authors.initials: L
authors.lastname: Mackenroth
authors.affiliation: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Hackmann
authors.affiliation: Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Ida
authors.initials: I
authors.lastname: Vogel
authors.affiliation: Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Rikke
authors.initials: R
authors.lastname: Christensen
authors.affiliation: Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Siv
authors.initials: S
authors.lastname: Fokstuen
authors.affiliation: Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Béna
authors.affiliation: Département de Génétique et Procréation, CHU Grenoble Alpes, Grenoble, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Amblard
authors.affiliation: Département de Génétique et Procréation, CHU Grenoble Alpes, Grenoble, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Devillard
authors.affiliation: Département de Génétique et Procréation, CHU Grenoble Alpes, Grenoble, France.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Vieville
authors.affiliation: Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble Alpes, Grenoble, France.
authors.forename: Alexia
authors.initials: A
authors.lastname: Apostolou
authors.affiliation: Département de Génétique et Procréation, CHU Grenoble Alpes, Grenoble, France.|Université Grenoble Alpes, Grenoble, France.
authors.forename: Pierre-Simon
authors.initials: PS
authors.lastname: Jouk
authors.affiliation: Clinique de Néphrologie Dialyse Transplantation, CHU Grenoble Alpes, Grenoble, France.
authors.forename: Fitsum
authors.initials: F
authors.lastname: Guebre-Egziabher
authors.affiliation: Département d'Anatomie et Cytologie Pathologiques, CHU Grenoble Alpes, Grenoble, France.|Université Grenoble Alpes, Grenoble, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Sartelet
authors.affiliation: Département de Génétique et Procréation, CHU Grenoble Alpes, Grenoble, France.|Equipe "Génétique, Epigénétique et Thérapies de l'Infertilité", Institut Albert Bonniot, La Tronche, France.|Université Grenoble Alpes, Grenoble, France.|Génétique et Procréation, Laboratoire de Génétique Chromosomique, CHU Grenoble Alpes, Grenoble, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Coutton
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D005333:Fetus / Q000378:metabolism; D015894:Genome, Human; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D007223:Infant; D007668:Kidney / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D008297:Male; D000075062:Pre-B-Cell Leukemia Transcription Factor 1 / Q000235:genetics*; D013577:Syndrome; D014564:Urogenital Abnormalities / Q000235:genetics*; D014718:Vesico-Ureteral Reflux / Q000235:genetics*
chemical_list: D000075062:Pre-B-Cell Leukemia Transcription Factor 1; C083400:PBX1 protein, human
keywords: 1q23.3q24.1 microdeletion; CAKUT; PBX1; chromosomal microarray analysis; copy number variation