Human disorders caused by nuclear receptor gene mutations
J. C. Achermann and J. L. Jameson
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 (TRb,
VDR, ERa, 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 TRb
act in a dominant negative manner to cause hormone resistance. Inactivating
mutations in orphan nuclear receptors have also been identified (PPARg2,
HNF4a, 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, PPARg1). 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.
*Report from a SCOPE/IUPAC project: Implication of
Endocrine Active Substances for Human and Wildlife (J. Miyamoto and
J.Burger, editors). Other reports are published in this issue,
pp. 1617-2615.
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