GATA3 haplo-insufficiency causes human HDR syndrome.
Terminal deletions of chromosome 10p result in a DiGeorge-like phenotype that includes hypoparathyroidism, heart defects, immune deficiency, deafness and renal malformations. 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) syndrome (Mendelian Inheritance in Man number 146255), which is located more telomeric (10p14-10pter). We have performed deletion-mapping studies in two HDR patients, and here we define a critical 200-kilobase region which contains the GATA3 gene. This gene belongs to a family of zinc-finger transcription factors that are involved in vertebrate embryonic development. 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.
Van Esch
H
H
Laboratory for Molecular Oncology, Centre for Human Genetics, University of Leuven and Flanders Interuniversity Institute for Biotechnology, Belgium.
Groenen
P
P
Nesbit
M A
MA
Schuffenhauer
S
S
Lichtner
P
P
Vanderlinden
G
G
Harding
B
B
Beetz
R
R
Bilous
R W
RW
Holdaway
I
I
Shaw
N J
NJ
Fryns
J P
JP
Van de Ven
W
W
Thakker
R V
RV
Devriendt
K
K
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002879:Chromosomes, Human, Pair 10; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D003638:Deafness / Q000235:genetics*; D005260:Female; D050990:GATA3 Transcription Factor; D017353:Gene Deletion; D006801:Humans; D007011:Hypoparathyroidism / Q000235:genetics*; D007668:Kidney / Q000002:abnormalities*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010375:Pedigree; D020161:Physical Chromosome Mapping; D013577:Syndrome; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C494748:Gata3 protein, mouse; D015534:Trans-Activators