Abstract
Hypoparathyroidism is a disease characterized by hypocalcemia and hyperphosphatemia derived from deficient actions of parathyroid hormone (PTH). We report the case of 43-year-old Japanese man with PTH-deficient hypoparathyroidism introduced to an endocrinologist in our hospital. As he had complained of hearing disturbance since the age of 20, we decided to investigate the GATA3 gene. Direct sequencing of PCR products identified a novel heterozygous mutation, 432insG, in the GATA3 gene. The mutation introduces a premature stop codon at exon 4 (K302X), which results in a loss of both zinc finger domains of the GATA3 protein. However, because the mutation in the GATA3 gene found in this patient is highly likely to impair GATA3 function, we speculate that it is extremely unlikely that this patient has mutations in other genes that cause PTH-deficient hypoparathyroidism, in addition to the GATA3 mutation described here.
Similar content being viewed by others
References
Goltzman D, Cole DEC (2006) Hypoparathyroidism. In: Favus MJ (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism, 6th edn. American Society for Bone and Mineral Research, Washington, pp 216–219
Levine MA (2006) Parathyroid hormone resistance syndromes. In: Favus MJ (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism, 6th edn. American Society for Bone and Mineral Research, Washington, pp 220–224
Pollak MR, Brown EM, Estep HL, McLaine PN, Kifor O, Park J, Hebert SC, Seidman CE, Seidman JG (1994) Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation. Nat Genet 8:303–307
Pearce SH, Williamson C, Kifor O, Bai M, Coulthard MG, Davies M, Lewis-Barned N, McCredie D, Powell H, Kendall-Taylor P, Brown EM, Thakker RV (1996) A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor. N Engl J Med 335:1115–1122
Ding C, Buckingham B, Levine MA (2001) Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB. J Clin Invest 108:1215–1220
Arnold A, Horst SA, Gardella TJ, Baba H, Levine MA, Kronenberg HM (1990) Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism. J Clin Invest 86:1084–1087
Parkinson DB, Thakker RV (1992) A donor splice site mutation in the parathyroid hormone gene is associated with autosomal recessive hypoparathyroidism. Nat Genet 1:149–152
Van Esch H, Groenen P, Nesbit MA, Schuffenhauer S, Lichtner P, Vanderlinden G, Harding B, Beetz R, Bilous RW, Holdaway I, Shaw NJ, Fryns JP, Van de Ven W, Thakker RV, Devriendt K (2000) GATA3 haplo-insufficiency causes human HDR syndrome. Nature 406:419–422
Parvari R, Hershkovitz E, Grossman N, Gorodischer R, Loeys B, Zecic A, Mortier G, Gregory S, Sharony R, Kambouris M, Sakati N, Meyer BF, Al Aqeel AI, Al Humaidan AK, Al Zanhrani F, Al Swaid A, Al Othman J, Diaz GA, Weiner R, Khan KT, Gordon R, Gelb BD (2002) Mutation of TBCE causes hypoparathyroidism–retardation–dysmorphism and autosomal recessive Kenny–Caffey syndrome. Nat Genet 32:448–452
Lee ME, Temizer DH, Clifford JA, Quertermo T (1991) Cloning of the GATA-binding protein that regulates endothelin-1 gene expression in endothelial cells. J Biol Chem 266:16188–16192
Ko LJ, Engel JD (1993) DNA-binding specificities of the GATA transcription factor family. Mol Cell Biol 13:4011–4022
Molkentin JD (2000) The zinc finger-containing transcription factors GATA-4, -5, and -6. J Biol Chem 275:38949–38952
Ho IC, Vorhees P, Marin N, Oakley BK, Tsai SF, Orkin SH, Leiden JM (1991) Human GATA-3: a lineage-restricted transcription factor that regulates the expression of the T cell receptor alpha gene. EMBO J 10:1187–1192
Yang Z, Gu L, Romeo PH, Bories D, Motohashi H, Yamamoto M, Engel JD (1994) Human GATA-3 trans-activation, DNA-binding, and nuclear localization activities are organized into distinct structural domains. Mol Cell Biol 14:2201–2212
Nesbit MA, Bowl MR, Harding B, Ali A, Ayala A, Crowe C, Dobbie A, Hampson G, Holdaway I, Levine MA, McWilliams R, Rigden S, Sampson J, Williams AJ, Thakker RV (2004) Characterization of GATA3 mutations in the hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome. J Biol Chem 279:22624–22634
Pandolfi PP, Roth ME, Karis A, Leonard MW, Dzierzak E, Grosveld FG, Engel JD, Lindenbaum MH (1995) Targeted disruption of the GATA3 gene causes severe abnormalities in the nervous system and in fetal liver haematopoiesis. Nat Genet 11:40–44
Lim KC, Lakshmanan G, Crawford SE, Gu Y, Grosveld F, Engel JD (2000) Gata3 loss leads to embryonic lethality due to noradrenaline deficiency of the sympathetic nervous system. Nat Genet 25:209–212
Yamamoto M, Furukawa Y, Konagaya Y, Sohn HE, Tomita A, Fujita T, Ogata E (1989) Human PTH(1–34) infusion test in differential diagnosis of various types of hypoparathyroidism: an attempt to establish a standard clinical test. Bone Miner 6:199–212
Ali A, Christie PT, Grigorieva IV, Harding B, Van Esch H, Ahmed SF, Bitner-Glindzicz M, Blind E, Bloch C, Christin P, Clayton P, Gecz J, Gilbert-Dussardier B, Guillen-Navarro E, Hackett A, Halac I, Hendy GN, Lalloo F, Mache CJ, Mughal Z, Ong AC, Rinat C, Shaw N, Smithson SF, Tolmie J, Weill J, Nesbit MA, Thakker RV (2007) Functional characterization of GATA3 mutations causing the hypoparathyroidism–deafness–renal (HDR) dysplasia syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor. Hum Mol Genet 16:265–275
Zahirieh A, Nesbit MA, Ali A, Wang K, He N, Stangou M, Bamichas G, Sombolos K, Thakker RV, Pei Y (2005) Functional analysis of a novel GATA3 mutation in a family with the hypoparathyroidism, deafness, and renal dysplasia syndrome. J Clin Endocrinol Metab 90:2445–2450
Acknowledgments
This work was supported in part by grants from Ministry of Health, Labour and Welfare, and from Ministry of Education, Culture, Sports, Science and Technology, Japan.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Saito, T., Fukumoto, S., Ito, N. et al. A novel mutation in the GATA3 gene of a Japanese patient with PTH-deficient hypoparathyroidism. J Bone Miner Metab 27, 386–389 (2009). https://doi.org/10.1007/s00774-008-0015-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00774-008-0015-9