Walter L. Miller (endocrinologist)

Walter L. Miller is an American endocrinologist and professor emeritus of pediatrics at the University of California, San Francisco (UCSF).[1] Miller is expert in the field of human steroid biosynthesis and disorders of steroid metabolism. Over the past 40 years Miller's group at UCSF has described molecular basis of several metabolic disorders including, congenital adrenal hyperplasia, pseudo vitamin D dependent rickets, severe, recessive form of Ehlers-Danlos syndrome, 17,20 lyase deficiency caused by CYP17A1 defects, P450scc deficiency caused by CYP11A1 defects, P450 oxidoreductase (Cytochrome P450 reductase) deficiency (also referred as Antley-Bixler syndrome).[2]

Walter L. Miller
NationalityAmerican
Alma materMassachusetts Institute of Technology
Duke University School of Medicine
Scientific career
FieldsPediatric endocrinology
InstitutionsUniversity of California, San Francisco

Miller has published more than 420 research papers, reviews and book chapters in endocrinology, biochemistry and metabolism.[3] Miller’s reviews on the molecular biology of steroid hormone synthesis are among the most widely cited papers in the field.

Biography

Research
  • Miller first achieved international prominence in 1980 for cloning bovine growth hormone and prolactin. This has permitted an increase in milk production worldwide.
  • Beginning in 1983, Miller focused on human steroid hormone production and regulation in health and disease. He systematically studied and cloned many genes for enzymes involved in steroid metabolism. Most notable were CYP11A1 (also known as P450scc), which is the initial, rate-limiting enzyme in steroid hormone production from cholesterol[4] and CYP17A1 (also known as P450c17), which catalyzes two distinct enzyme activities, 17-hydroxylase activity which is required for cortisol production and the 17,20 lyase activity, which is required for sex steroid biosynthesis. His laboratory then identified the first mutations that caused isolated 17,20 lyase deficiency. His laboratory also showed that there is post-translational regulation of 17,20 lyase activity by serine phosphorylation[5] and by cytochrome b5,[6] that regulate sex steroid biosynthesis.
  • In studies of the common form of congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency, Miller’s group discovered the gene for Tenascin-X, overlapping the CYP21A2 gene.[7] They then discovered a contiguous gene syndrome from a deletion encompassing both CYP21A2 and TNX, causing CAH and Ehlers-Danlos syndrome (EDS).[8] This led to the full description of TNX deficiency as the cause of severe, recessive EDS.[9]
  • To enter mitochondria, where the P450scc enzyme resides, cholesterol requires the action of a protein called StAR, (steroidogenic acute regulatory protein), which was first cloned from mice by Dr. Douglas Stocco.[10] Miller's laboratory established the biological role of StAR by identifying human mutations in StAR gene that caused congenital lipoid adrenal hyperplasia.[11][12] They then showed that StAR acts exclusively on the outer mitochondrial membrane in a ‘molten globule’ configuration.[13][14]
  • In collaboration with AA Portale, Miller’s group was first to clone the vitamin D 1α-hydroxylase (CYP27B1), which is the regulated step in the bioactivation of vitamin D[15] and showed that its mutation causes the genetic form of rickets variously called ‘vitamin D-dependent rickets’ or ‘pseudo vitamin D-deficient rickets.[16]
  • In 2004 Miller's laboratory identified the first mutations in human Cytochrome P450 Oxidoreductase (POR), thus describing a new form of congenital adrenal hyperplasia.[2] In a large follow-up study they showed that both POR deficiency and activating mutations of FGFR3 can cause the skeletal malformation syndrome known as Antley-Bixler syndrome (ABS),[17] and that not all patients with POR deficiency have ABS.
  • Most recently along with his collaborators in Switzerland, Miller described a novel disorder of fetal androgen synthesis involving aldo-keto reductases (AKR1C2 and AKR1C4), showing that both the conventional and alternative ("backdoor") pathways of androgen synthesis are needed for normal male fetal development.[18]
  • In addition to scientific work, Miller has led opposition to the prenatal use of dexamethasone in congenital adrenal hyperplasia (CAH)[19][20] and has co-authored the clinical practice guidelines for CAH prepared by the Lawson Wilkins Pediatric Endocrine Society and by The Endocrine Society.[21]

Awards and honors
  • Ross Research Award from the Western Society for Pediatric Research (1982)[22]
  • Edwin B. Astwood Award from the Endocrine Society (1988)[23]
  • Henning Andersen Prize from the European Society for Paediatric Research (1993)[24]
  • The Clinical Endocrinology Trust Medal from the British Endocrine Societies (1993)
  • Albion O. Bernstein Award from the New York State Medical Society (1993)[25]
  • Fellow of the American Association for the Advancement of Science (1994)[26]
  • Samuel Rosenthal Foundation Prize for Excellence in Academic Pediatrics (1999)
  • Clinical Investigator Award from The Endocrine Society (2006)[27][28]
  • UCSF Distinguished Clinical Research Lectureship (2009)[29]
  • Duke University School of Medicine Distinguished Alumnus Award (2010)[30]
  • Judson J. VanWyk Prize for Career Achievement, from the Pediatric Endocrine Society (2012)[31]
  • International Award, from the European Society for Paediatric Endocrinology (Inaugural recipient, 2012)
  • Fred Conrad Koch Lifetime Achievement Award of the Endocrine Society (2017)[32][33][34]

References
  1. "Walter Miller, MD". University of California. Retrieved 21 May 2017.
  2. Flück, Christa E; Tajima, Toshihro; Pandey, Amit V; Arlt, Wiebke; Okuhara, Kouji; Verge, Charles F; Jabs, Ethylin Wang; Mendonça, Berenice B; Fujieda, Kenji; Miller, Walter L (2004). "Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome". Nature Genetics. 36 (3): 228–30. doi:10.1038/ng1300. PMID 14758361.
  3. Search Results for author Miller WL on PubMed.
  4. Chung, B. C; Matteson, K. J; Voutilainen, R; Mohandas, T. K; Miller, W. L (1986). "Human cholesterol side-chain cleavage enzyme, P450scc: CDNA cloning, assignment of the gene to chromosome 15, and expression in the placenta". Proceedings of the National Academy of Sciences. 83 (23): 8962–6. Bibcode:1986PNAS...83.8962C. doi:10.1073/pnas.83.23.8962. PMC 387054. PMID 3024157.
  5. Zhang, L. H; Rodriguez, H; Ohno, S; Miller, W. L (1995). "Serine phosphorylation of human P450c17 increases 17,20-lyase activity: Implications for adrenarche and the polycystic ovary syndrome". Proceedings of the National Academy of Sciences. 92 (23): 10619–23. Bibcode:1995PNAS...9210619Z. doi:10.1073/pnas.92.23.10619. PMC 40663. PMID 7479852.
  6. Auchus, Richard J; Lee, Tim C; Miller, Walter L (1998). "Cytochromeb5Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer". Journal of Biological Chemistry. 273 (6): 3158–65. doi:10.1074/jbc.273.6.3158. PMID 9452426.
  7. Bristow, J; Tee, M. K; Gitelman, S. E; Mellon, S. H; Miller, W. L (1993). "Tenascin-X: A novel extracellular matrix protein encoded by the human XB gene overlapping P450c21B". The Journal of Cell Biology. 122 (1): 265–78. doi:10.1083/jcb.122.1.265. PMC 2119596. PMID 7686164.
  8. Burch, Grant H; Gong, Yan; Liu, Wenhui; Dettman, Robert W; Curry, Cynthia J; Smith, Lynne; Miller, Walter L; Bristow, James (1997). "Tenascin–X deficiency is associated with Ehlers–Danlos syndrome". Nature Genetics. 17 (1): 104–8. doi:10.1038/ng0997-104. PMID 9288108. S2CID 13224113.
  9. Schalkwijk, Joost; Zweers, Manon C; Steijlen, Peter M; Dean, Willow B; Taylor, Glen; Van Vlijmen, Ivonne M; Van Haren, Brigitte; Miller, Walter L; Bristow, James (2001). "A Recessive Form of the Ehlers–Danlos Syndrome Caused by Tenascin-X Deficiency" (PDF). New England Journal of Medicine. 345 (16): 1167–75. doi:10.1056/nejmoa002939. hdl:2066/185552. PMID 11642233. S2CID 42748708.
  10. Clark, B. J; Wells, J; King, S. R; Stocco, D. M (1994). "The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR)". The Journal of Biological Chemistry. 269 (45): 28314–22. doi:10.1016/S0021-9258(18)46930-X. PMID 7961770.
  11. Lin, D; Sugawara, T; Strauss, J; Clark, B; Stocco, D; Saenger, P; Rogol, A; Miller, W (1995). "Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis". Science. 267 (5205): 1828–31. Bibcode:1995Sci...267.1828L. doi:10.1126/science.7892608. PMID 7892608.
  12. Bose, Himangshu S; Sugawara, Teruo; Strauss, Jerome F; Miller, Walter L (1996). "The Pathophysiology and Genetics of Congenital Lipoid Adrenal Hyperplasia". New England Journal of Medicine. 335 (25): 1870–8. doi:10.1056/NEJM199612193352503. PMID 8948562.
  13. Bose, H. S; Whittal, R. M; Baldwin, M. A; Miller, W. L (1999). "The active form of the steroidogenic acute regulatory protein, StAR, appears to be a molten globule". Proceedings of the National Academy of Sciences. 96 (13): 7250–5. Bibcode:1999PNAS...96.7250B. doi:10.1073/pnas.96.13.7250. PMC 22068. PMID 10377400.
  14. Bose, Himangshu S; Lingappa, Vishwanath R; Miller, Walter L (2002). "Rapid regulation of steroidogenesis by mitochondrial protein import". Nature. 417 (6884): 87–91. Bibcode:2002Natur.417...87B. doi:10.1038/417087a. PMID 11986670. S2CID 4422166.
  15. Fu, G. K; Lin, D; Zhang, M. Y; Bikle, D. D; Shackleton, C. H; Miller, W. L; Portale, A. A (1997). "Cloning of Human 25-Hydroxyvitamin D-1 -Hydroxylase and Mutations Causing Vitamin D-Dependent Rickets Type 1". Molecular Endocrinology. 11 (13): 1961–70. CiteSeerX 10.1.1.320.3485. doi:10.1210/mend.11.13.0035. PMID 9415400.
  16. Wang, Jonathan T; Lin, Chin-Jia; Burridge, Sandra M; Fu, Glenn K; Labuda, Malgorzata; Portale, Anthony A; Miller, Walter L (1998). "Genetics of Vitamin D 1α-Hydroxylase Deficiency in 17 Families". The American Journal of Human Genetics. 63 (6): 1694–702. doi:10.1086/302156. PMC 1377641. PMID 9837822.
  17. Huang, Ningwu; Pandey, Amit V; Agrawal, Vishal; Reardon, William; Lapunzina, Pablo D; Mowat, David; Jabs, Ethylin Wang; Vliet, Guy Van; Sack, Joseph; Flück, Christa E; Miller, Walter L (2005). "Diversity and Function of Mutations in P450 Oxidoreductase in Patients with Antley-Bixler Syndrome and Disordered Steroidogenesis". The American Journal of Human Genetics. 76 (5): 729–49. doi:10.1086/429417. PMC 1199364. PMID 15793702.
  18. Flück, Christa E; Meyer-Böni, Monika; Pandey, Amit V; Kempná, Petra; Miller, Walter L; Schoenle, Eugen J; Biason-Lauber, Anna (2011). "Why Boys Will Be Boys: Two Pathways of Fetal Testicular Androgen Biosynthesis Are Needed for Male Sexual Differentiation". The American Journal of Human Genetics. 89 (2): 201–18. doi:10.1016/j.ajhg.2011.06.009. PMC 3155178. PMID 21802064.
  19. Seckl, J. R (1997). "How safe is long-term prenatal glucocorticoid treatment?". JAMA: The Journal of the American Medical Association. 277 (13): 1077–9. doi:10.1001/jama.277.13.1077. PMID 9091698.
  20. Miller, Walter L; Witchel, Selma Feldman (2013). "Prenatal treatment of congenital adrenal hyperplasia: Risks outweigh benefits". American Journal of Obstetrics and Gynecology. 208 (5): 354–9. doi:10.1016/j.ajog.2012.10.885. PMID 23123167.
  21. Speiser, Phyllis W; Azziz, Ricardo; Baskin, Laurence S; Ghizzoni, Lucia; Hensle, Terry W; Merke, Deborah P; Meyer-Bahlburg, Heino F. L; Miller, Walter L; Montori, Victor M; Oberfield, Sharon E; Ritzen, Martin; White, Perrin C (2010). "Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline". The Journal of Clinical Endocrinology & Metabolism. 95 (9): 4133–60. doi:10.1210/jc.2009-2631. PMC 2936060. PMID 20823466.
  22. "Abbott Nutrition Award in Research by a Young Investigator — Past Recipients". American Pediatric Society. Retrieved 21 May 2017.
  23. "Edwin B. Astwood Award Lecture". Endocrine Society. Retrieved 21 May 2017.
  24. "Henning Andersen Prizes". ESPE. Retrieved 21 May 2017.
  25. "Albion O. Bernstein, M.D. Award Recipients" (PDF). Medical Society NY. Retrieved 21 May 2017.
  26. Walter Miller, American Association for the Advancement of Science., 1994. Retrieved June 2, 2017.
  27. "Outstanding Clinical Investigator Award". Endocrine Society. Retrieved 21 May 2017.
  28. "Endocrine Society Honors Pediatric Professor". UC San Francisco. Retrieved 21 May 2017.
  29. "Academic Senate Names Miller Distinguished Clinical Research Lecturer". UC San Francisco. Retrieved 21 May 2017.
  30. "Walter Miller Receives Duke's Distinguished Alumnus Award". UC San Francisco. Retrieved 21 May 2017.
  31. Awards and Grants, Judson J. Van Wyk Prize, Pediatric Endocrine Society. Retrieved June 2, 2017.
  32. "Fred Conrad Koch Lifetime Achievement Award". Endocrine Society. Retrieved 21 May 2017.
  33. Baker, Mitzi. "Endocrine Society Awards Walter L. Miller Its Lifetime Achievement Award". UC San Francisco. Retrieved 21 May 2017.
  34. "Meet the 2017 Endocrine Society Laureate Award Winners". Endocrine News. 24 August 2016. Retrieved 21 May 2017.
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