GATA3 haplo-insufficiency causes human HDR syndrome (original) (raw)

• Letter
• Published: 27 July 2000
• Peter Groenen1,
• M. Andrew Nesbit2 na1,
• Simone Schuffenhauer3,
• Peter Lichtner3,
• Gert Vanderlinden1,
• Brian Harding2 na1,
• Rolf Beetz4,
• Rudolf W. Bilous5,
• Ian Holdaway6,
• Nicholas J. Shaw7,
• Jean-Pierre Fryns8,
• Wim Van de Ven1,
• Rajesh V. Thakker2 na1 &
• …
• Koenraad Devriendt8

Nature volume 406, pages 419–422 (2000)Cite this article

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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.

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Acknowledgements

We are grateful to R. Thoelen for the FISH analysis; A. Poffyn for clinical data; P. Romeo for the gift of cosmid clone 1.2; T. Meitinger for his support; the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO), the “Geconcerteerde Onderzoeksactie 1997–2001” and the Interuniversitaire Attractie Polen (IUAP) for support; the Medical Research Council, UK, for support (M.A.N., B.H., R.V.T.). H.V.E. is an Aspirant and K.D. is a Senior Clinical Investigator of the Fund for Scientific Research–Flanders, Belgium (FWO–Vlaanderen).

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Author notes

1. M. Andrew Nesbit, Brian Harding and Rajesh V. Thakker: These authors contributed equally to this work

Authors and Affiliations

1. Laboratory for Molecular Oncology, Centre for Human Genetics, University of Leuven and Flanders Interuniversity Institute for Biotechnology, Herestraat 49, Leuven, B-3000 , Belgium
   Hilde Van Esch, Peter Groenen, Gert Vanderlinden & Wim Van de Ven
2. Nuffield Department of Clinical Medicine, Molecular Endocrinology Group, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK
   M. Andrew Nesbit, Brian Harding & Rajesh V. Thakker
3. Department of Medical Genetics, Children's Hospital, Ludwig-Maximilians-University, Goethestrasse 29, Munich, 80336, Germany
   Simone Schuffenhauer & Peter Lichtner
4. University Children's Hospital, Langenbeckstrasse 1, Mainz, 55101, Germany
   Rolf Beetz
5. Department of Medicine, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
   Rudolf W. Bilous
6. Department of Endocrinology, Auckland Hospital, Park Road, Auckland, 1, New Zealand
   Ian Holdaway
7. Department of Endocrinology, Birmingham Children's Hospital, Steelhouse Lane, Birmingham , B46 1YH, UK
   Nicholas J. Shaw
8. Department of Clinical Genetics, Centre for Human Genetics, University of Leuven, Herestraat 49, Leuven, B-3000, Belgium
   Jean-Pierre Fryns & Koenraad Devriendt

Authors

1. Hilde Van Esch
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2. Peter Groenen
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3. M. Andrew Nesbit
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4. Simone Schuffenhauer
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5. Peter Lichtner
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6. Gert Vanderlinden
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7. Brian Harding
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8. Rolf Beetz
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9. Rudolf W. Bilous
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10. Ian Holdaway
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11. Nicholas J. Shaw
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12. Jean-Pierre Fryns
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13. Wim Van de Ven
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14. Rajesh V. Thakker
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15. Koenraad Devriendt
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Corresponding authors

Correspondence toRajesh V. Thakker or Koenraad Devriendt.

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Van Esch, H., Groenen, P., Nesbit, M. et al. GATA3 haplo-insufficiency causes human HDR syndrome.Nature 406, 419–422 (2000). https://doi.org/10.1038/35019088

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• Received: 04 February 2000
• Accepted: 23 May 2000
• Issue Date: 27 July 2000
• DOI: https://doi.org/10.1038/35019088

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