ZNF764 haploinsufficiency may explain partial glucocorticoid, androgen, and thyroid hormone resistance associated with 16p11.2 microdeletion

Tomoshige Kino, Maria G. Pavlatou, Andreas G. Moraitis, Robin L. Nemery, Margarita Raygada, Constantine A. Stratakis

Research output: Contribution to journalArticle

8 Citations (Scopus)


Context: Nuclear hormone receptors exert their transcriptional effects through shared cofactor molecules; thus, defects in such intermediate proteins may be associated with multiple hormone resistance. Microdeletion of small chromosomal segments results in hereditary or sporadic diseases by affecting expression of residing genes. Objectives: We describe a 7-yr-old boy with partial resistance to glucocorticoids, thyroid hormones, and possibly androgens. He was diagnosed as being in the autism spectrum disorder and had developmental delay and several facial morphological manifestations. We explored genes responsible for multiple hormone resistance of this case. Results: We found in this patient an approximately 1.1-Mb heterozygous 16p11.2 microdeletion, which included an approximately 500-kb unique deletion along with the common, previously reported approximately 600-kb 16p11.2 microdeletion. The small interfering RNA-based screening revealed that knockdown of ZNF764, which is located in the deleted segment unique to our case, significantly reduced glucocorticoid-, androgen-, and thyroid hormone-induced transcriptional activity of their responsive genes in HeLa cells, whereas its overexpression enhanced their transcriptional activity. The activities of the estrogen and progesterone receptors, cAMP response element-binding protein, and p53 were not affected in these cells. ZNF764 (zinc finger protein 764) expression was reduced in the patient's peripheral blood mononuclear cells, whereas exogenously supplemented ZNF764 recovered responsiveness to glucocorticoids in the patient's Epstein-Barr virus-transformed lymphocytes. The effect of ZNF764 on the glucocorticoid receptor transcriptional activity was mediated through cooperation with a general nuclear hormone receptor coactivator, transcriptional intermediary factor 1. Conclusions: ZNF764 haploinsufficiency caused by microdeletion maybe responsible for the partial multiple hormone resistance observed in our patient. ZNF764 appears to be involved in glucocorticoid, androgen, and thyroid hormone action.

Original languageEnglish
Pages (from-to)E1557-E1566
JournalJournal of Clinical Endocrinology and Metabolism
Issue number8
Publication statusPublished - 1 Aug 2012


ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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