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Hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) syndrome (MIM 146255) is a rare autosomal dominant disorder caused by mutations in the gene encoding GATA3, a dual zinc-finger transcription factor involved in vertebrate embryonic development. In this clinical case study we report on a follow-up of a phenotype associated with a GATA3 mutation. HDR syndrome was clinically diagnosed at age of 1.5 years in a boy with a de novo heterozygous missense (c.815C→T) mutation, Thr272Ile, in exon 4 of the GATA3 gene. Both parents were negative for Thr272Ile. At age of 17 months, the patient had a weight of 10.7, a body length of 78 cm, and a head circumference of 47.5 cm. By the age of 7 years, growth is age-appropriate, severe bilateral hearing loss (dB 60) was corrected by hearing aids. However, cognitive development (auditory sensory me­mory and language abilities) is at the lower ends of the test scores. In conclusion, a mildly impaired clinical course was achieved by the age of 7 years in a patient with HDR syndrome; this report adds to the body of data on genotype-phenotype analysis in HDR syndrome. ·

Context: The hypoparathyroidism, deafness, renal dysplasia (HDR) syndrome is caused by mutations in the gene encoding GATA3, which belongs to a family of dual zinc-finger transcription factors that have a role in vertebrate embryonic development.Objective: The aim of the study was to identify the GATA3 mutation in a HDR patient and determine its functional consequences.Patient and Design: A patient with HDR was studied after approval from the local ethical committee. Leukocyte DNA was used with GATA3-specific primers for PCR amplification, and the DNA sequences of the PCR products were determined. Wild-type and mutant GATA3 constructs were transfected into COS-7 cell, and their functions were assessed by Western blot analysis, immunocytochemistry, EMSAs, luciferase reporter assays, and three-dimensional modeling.Results: A novel missense mutation, Thr272Ile, in zinc finger 1 (ZnF1) of GATA3 was identified. Western blot analysis and immunofluorescence revealed that the mutation did not affect nuclear localization of GATA3. However, EMSAs showed it to reduce DNA binding affinity, but not stability, and yeast two-hybrid assays demonstrated that the mutant GATA3 resulted in a loss of interaction with ZnF1 and ZnF6 of the cofactor FOG2. The mutant GATA3 significantly reduced luciferase reporter activity by more than 65% (P < 0.001), and three-dimensional modeling indicated that the functional abnormalities may be due to a loss of Thr272 polar side chain interaction with Leu268.Conclusions: A novel missense HDR-associated GATA3 mutation, Thr272Ile, has been identified and shown to result in reduced DNA binding, a partial loss of FOG2 interaction, and a decrease in gene transcription.Hypoparathyroidism, Deafness, and Renal Dysplasia syndrome can result from the missense mutation Thr272Il3 in the transcription factor GATA3, which results in reduced DNA binding, partial loss of interaction with the protein cofactor FOG2, and a decrease in transcriptional activity.