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Pure Appl. Chem., 2003, Vol. 75, No. 11-12, pp. 1785-1796

Human disorders caused by nuclear receptor gene mutations

J. C. Achermann1 and J. L. Jameson2*

1 Centre for Human Growth and Maturation,I nstitute of Child Health and Department of Medicine, University College London, London, UK
2 Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, IL 60611, USA

Abstract: The identification of naturally occurring nuclear receptor mutations highlights the critical role that many of these transcription factors play in human endocrine development and function. Inactivating mutations in the ligand-dependent nuclear receptors (TRβ, VDR, ERα, GR, MR, AR) are well characterized in patients with conditions such as androgen insensitivity syndrome (AIS) and vitamin D resistance. On the other hand, mutations in TRβ act in a dominant negative manner to cause hormone resistance. Inactivating mutations in orphan nuclear receptors have also been identified (PPARγ2, HNF4α, PNR, NURR1, SF1, DAX1, SHP) and reveal important developmental and metabolic functions for this group of receptors with previously elusive physiologic roles. In addition to loss of function mutations, receptor activation can result from mutations that confer constitutive activity or altered ligand responsiveness to the receptor (MR, AR), or from genetic duplication (DAX1) or the expression of fusion proteins (RARA, PPARγ1). Together, these naturally occurring mutations provide fascinating insight into key structural and functional receptor domains to reveal the diverse role nuclear receptors play in human biology.