Perspectives in Biology and Medicine

PERSPECTIVES IN BIOLOGY AND MEDICINE Volume 37 · Number 3 · Spring 1994 HOW CLINICAL OBSERVATIONS OF A CONGENITAL DISEASE CAN BE TRANSLATED IN TERMS OF MOLECULAR BIOLOGY SAMUEL REFETOFF* Introduction Although in scientific terms congenital diseases are as diverse and multifactorial as those presenting later in life, almost all societies have viewed them as a distinct entity. This is probably due to the perception that the progenitors and thus indirectly the society, rather than the victim, bear the responsibility for their occurrence. Through the ages, societies have chosen different means to deal with this common guilt. The Spartans elected to eliminate the products of nature's errors by simple euthanasia. In contrast, some societies of South America have Reproduced in part from a lecture delivered at the Symposium on the Discipline of Medicine held at the Royal Netherlands Academy of Arts and Sciences, May 25-26, 1993 with permission from the editor and the publishers of the Proceeding of the Symposium. This work was supported in part by National Institutes of Health grants DK-15Ö70 and RR-00055. The author thanks the following colleagues and students who over the period of thirty years have provided invaluable advice and intellectual, as well as outright manual, assistance : Bernard Bénard (Canada), Reuben Matalón (USA), Mario Bigazzi (Italy), Juan Bernal (Spain), Charles P. Barsano (USA), Angel Salazar (Ecuador), TerryJ. Smith (USA), Neal H. Scherberg (USA), Allen L. Horwitz (USA), Yoshiharu Murata (Japan), Kenneth B. Ain (USA), Paola Ceccarelli (Italy), David H. Same (USA), Robert L. Rosenfield (USA), Jean-Paul Farriaux (France), Sylwester Sobieszczyk (Poland), Kyoko Takeda (Japan), Akihiro Sakurai (Japan), Graeme I. Bell (USA), Stefano Balzano (Italy), Roy E. Weiss (USA), Hisao Seo (Japan), Yoshitaka Hayashi (Japan), Onno E. Janssen (Germany), Paul Yen (USA), Claudio Marcocci (Italy), Thongkum Sunthornthepvarakul (Thailand), and Stephen J. Usala (USA). Acknowledgments are also due to more than 300 investigators of the GRTH syndrome whose contributions could not be sited in the references due to space limitations. Finally, in accordance with teachings of Hippocrates, the guidance received from the author's mentors, Charles P. Leblond, Lorren T. DeWind, Herbert A. Selenkow, and Leslie J. DeGroot is also acknowledged. *Departments of Medicine and Pediatrics and the J. P. Kennedy, Jr. Mental Retardation Research Center, The University of Chicago, MC 3090, 5841 South Maryland Avenue, Chicago, Illinois 60637.© 1994 by The University of Chicago. All rights reserved. 0031-5982/94/3703-0877$01.00 Perspectives in Biology and Medicine, 37, 3 ¦ Spring 1994 315 espoused the view that congenital malformations are gifts of God and thus the victims of such defects should be nurtured as "God's children." Twenty-four centuries ago the great Greek philosopher Aristotle said "We can learn what health is by studying bodies from which health is absent." This concept has been adopted by modern scientists who see congenital diseases as windows that nature provides to divulge its innermost secrets. These experiments of nature have been used effectively toward understanding the normal pathways of organ function. In the field of the thyroid, studies of inborn errors of thyroid hormone synthesis were instrumental in the elucidation of the normal steps involved in thyroid hormone formation [I]. More recently, the identification of the syndrome of Generalized Resistance to Thyroid Hormone (GRTH) and its study using modern techniques of molecular biology was crucial to understanding the mechanism of thyroid hormone action. This monograph provides an overview of how a clinical observation stimulated a quest for further empirical information, which evolved into a concept that contributed to our understanding of how thyroid hormone acts at the molecular level. It serves as a paradigm for similar observations and studies on substances that act through receptor molecules that evolved from a common ancestral gene, an homologue of the viral oncogene v-erb A. These receptors belong to a family of protein molecules of similar structure that mediate the action of steroid hormones of adrenal cortical origin (glucocorticoid receptor and mineralocorticoid receptor) and gonadal origin (estrogen receptor, progesterone receptor, and androgen receptor), vitamin D receptor, retinoic acid receptor , and several other proteins with less well-defined functions (orphan receptors) [2]. They are located in the cell nucleus where, under the influence of the...