Scanning of estrogen receptor α (ERα) and thyroid hormone receptor α (TRα) genes in patients with psychiatric diseases:: Four missense mutations identified in ERα gene

Estrogen and thyroid hormones exert effects on growth, development, and differentiation of the nervous system. Hormone administration can lead to changes in behavior, suggesting that genetic variants of the estrogen receptor alpha (ER alpha) and the thyroid hormone receptor alpha (TR alpha) genes may predispose to psychiatric diseases. To investigate this possibility, regions of likely functional significance tall coding exons and flanking splice junctions) of the ERa and TR alpha. genes were scanned in patients with schizophrenia (113), along with pilot studies in patients with bipolar illness (BPI), puerperal psychosis, autism, attention-deficit hyperactivity disorder (ADHD), and alcoholism. A total of 1.18 megabases of the ER alpha. gene and 1.16 megabases of the TR alpha gene were scanned with Detection of Virtually All Mutations-SSCP (DOVAM-S), a method that detects virtually all mutations. Four missense mutations, seven silent mutations and one deletion were identified in the ER alpha gene, while only four silent mutations were present in the TRa gene. Two of the missense mutations in ER alpha. are conserved in the six available mammalian and bird species (H6Y, K299R) and a third sequence variant (P146Q) is conserved in mammals, birds, and Xenopus laevis, hinting that these sequence changes will be of functional significance. These changes were found in one patient each with BPI, puerperal psychosis, and alcoholism, respectively. Analysis of the ER alpha and TR alpha genes in 240 subjects reveals that missense changes and splice site variants are uncommon (1.7% and 0%, respectively). Further analyses are necessary to determine if the missense mutations identified in this study are associated with predisposition or outcome for either psychiatric or nonpsychiatric diseases. (C) 2001 Wiley-Liss, Inc.