GATA3 haplo-insufficiency causes human HDR syndrome

Terminal deletions of chromosome 10p result in a DiGeorge-like phenotype th at includes hypoparathyroidism, heart defects, immune deficiency, deafness and renal malformations(1). Studies in patients with 10p deletions have def ined 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 deafnes s, renal anomaly (HDR) syndrome(3) (Mendelian Inheritance in Man number 146 255)(4), which is located more telomeric (10p14-10pter)(5,6). We have perfo rmed deletion-mapping studies in two HDR patients, and here we define a cri tical 200-kilobase region which contains the GATA3 gene(7). This gene belon gs to a family of zinc-finger transcription factors that are involved in ve rtebrate embryonic development(8-10). Investigation for GATA3 mutations in three other HDR probands identified one nonsense mutation and two intrageni c deletions that predicted a loss of function, as confirmed by absence of D NA binding by the mutant GATA3 protein. These results show that GATA3 is es sential in the embryonic development of the parathyroids, auditory system a nd kidneys, and indicate that other GATA family members may be involved in the aetiology of human malformations.