GATA3 haplo-insufficiency causes human HDR syndrome

Hilde Van Esch, Peter Groenen, M. Andrew Nesbit, Simone Schuffenhauer, Peter Lichtner, Gert Vanderlinden, Brian Harding, Rolf Beetz, Rudolf W. Bilous, Ian Holdaway, Nicholas J. Shaw, Jean-Pierre Fryns, Wim Van de Ven, Rajesh V. Thakker () and Koenraad Devriendt ()
Additional contact information
Hilde Van Esch: University of Leuven and Flanders Interuniversity Institute for Biotechnology
Peter Groenen: University of Leuven and Flanders Interuniversity Institute for Biotechnology
M. Andrew Nesbit: Molecular Endocrinology Group, University of Oxford, John Radcliffe Hospital
Simone Schuffenhauer: Children's Hospital, Ludwig-Maximilians-University
Peter Lichtner: Children's Hospital, Ludwig-Maximilians-University
Gert Vanderlinden: University of Leuven and Flanders Interuniversity Institute for Biotechnology
Brian Harding: Molecular Endocrinology Group, University of Oxford, John Radcliffe Hospital
Rolf Beetz: University Children's Hospital
Rudolf W. Bilous: University of Newcastle upon Tyne
Ian Holdaway: Auckland Hospital
Nicholas J. Shaw: Birmingham Children's Hospital
Jean-Pierre Fryns: Centre for Human Genetics, University of Leuven
Wim Van de Ven: University of Leuven and Flanders Interuniversity Institute for Biotechnology
Rajesh V. Thakker: Molecular Endocrinology Group, University of Oxford, John Radcliffe Hospital
Koenraad Devriendt: Centre for Human Genetics, University of Leuven

Nature, 2000, vol. 406, issue 6794, 419-422

Abstract: Abstract Terminal deletions of chromosome 10p result in a DiGeorge-like phenotype that includes hypoparathyroidism, heart defects, immune deficiency, deafness and renal malformations1. Studies in patients with 10p deletions have defined two non-overlapping regions that contribute to this complex phenotype. These are the DiGeorge critical region II (refs 1, 2), which is located on 10p13-14, and the region for the hypoparathyroidism, sensorineural deafness, renal anomaly (HDR) syndrome3 (Mendelian Inheritance in Man number 146255)4, which is located more telomeric (10p14–10pter)5,6. We have performed deletion-mapping studies in two HDR patients, and here we define a critical 200-kilobase region which contains the GATA3 gene7. This gene belongs to a family of zinc-finger transcription factors that are involved in vertebrate embryonic development8,9,10. Investigation for GATA3 mutations in three other HDR probands identified one nonsense mutation and two intragenic deletions that predicted a loss of function, as confirmed by absence of DNA binding by the mutant GATA3 protein. These results show that GATA3 is essential in the embryonic development of the parathyroids, auditory system and kidneys, and indicate that other GATA family members may be involved in the aetiology of human malformations.

Date: 2000
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DOI: 10.1038/35019088

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