title: A novel loss-of-function mutation of GATA3 (p.R299Q) in a Japanese family with Hypoparathyroidism, Deafness, and Renal Dysplasia (HDR) syndrome.
abstract: BACKGROUND
  Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder caused by mutations in the zinc finger transcription factor gene, GATA3. GATA3 has 2 zinc finger domains, which play an important role in the increase in target gene transcription activity.
  
  
  METHODS
  A 50-year-old woman and her 27-year-old daughter were followed up because of hypoparathyroidism. They had bilateral sensorineural deafness. Abdominal computed tomography scanning revealed renal dysplasia in the mother, but no renal anomaly in the daughter. Direct sequencing of GATA3 gene revealed a novel heterozygous missense mutation at codon 299 (p.R299Q) in exon 4. This mutation is located at the junction between the 2 zinc fingers. The structure prediction showed that it caused a conformation change in this junction area, affecting the spatial position of the zinc fingers. Additionally, a more marked conformation change was observed in the N-terminal zinc finger region compared to that in the C-terminal region. Functional analysis of this mutant protein using an in vitro luciferase reporter assay system confirmed that the mutation abolished the enhancing effects of wild-type GATA3 on the promoter activity of the consensus GATA responsive element and that of human PTH gene.
  
  
  CONCLUSIONS
  We identified a novel R299Q mutation in GATA3 in a Japanese family with HDR syndrome. We confirmed that R299Q is a loss-of-function mutation, due to the extensive conformational change in the zinc fingers of GATA3.
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya Ekisaikai Hospital, 4-66 Shounen-cho, Nakagawawa-ku, Nagoya, 454-8502, Japan. tetsujimd@emobile.ne.jp.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Okawa
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya Ekisaikai Hospital, 4-66 Shounen-cho, Nakagawawa-ku, Nagoya, 454-8502, Japan. yoshidaz@ekisai.or.jp.
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, 612-8555, Japan. tusui1220@gmail.com.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Usui
authors.affiliation: Laboratory of Protein Informatics, Research Center for State-of-the-Art Functional Protein Analysis, Institute for Protein Research, Osaka University, Suita, 565-0871, Japan. t-kudou@protein.osaka-u.ac.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kudou
authors.affiliation: Health Care Center, Kochi University, Kochi, 780-8520, Japan. iwasakiyasumasa@gmail.com.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Iwasaki
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya Ekisaikai Hospital, 4-66 Shounen-cho, Nakagawawa-ku, Nagoya, 454-8502, Japan. kazukifukuoka@nifty.com.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Fukuoka
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya Ekisaikai Hospital, 4-66 Shounen-cho, Nakagawawa-ku, Nagoya, 454-8502, Japan. norio_03_02@ybb.ne.jp.
authors.forename: Norio
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya Ekisaikai Hospital, 4-66 Shounen-cho, Nakagawawa-ku, Nagoya, 454-8502, Japan. myavp@zm.commufa.jp.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Uehara
authors.affiliation: Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan. yutakamd@med.nagoya-u.ac.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oiso
mesh_terms: D003638:Deafness / Q000150:complications* / Q000235:genetics / Q000473:pathology; D005190:Family; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics*; D006801:Humans; D007011:Hypoparathyroidism / Q000150:complications* / Q000235:genetics / Q000473:pathology; D007668:Kidney / Q000002:abnormalities*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D013577:Syndrome
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human