We propose to define further the molecular basis for the biological activity of the human androgen receptor. To reach this goal, we plan to detect and characterize the mutations of the androgen receptor in newborns with ambiguous genitalia due to a partial form of AIS and azoospermic individuals whose abnormality is related to a mild form of AIS. We will also explore the possibility that prostatic carcinoma cells, which have become resistant to the specific effects of suppression of androgen action, have become so due to somatic cell androgen receptor gene mutations causing a form of androgen insensitivity. In this application we will attempt to answer the following questions: 1) Can we expedite the diagnosis of AIS in newborns with ambiguous genitalia by testing for mutations of the androgen receptor gene? As a means of ruling out silent mutations, normal genetic variants of the androgen receptor gene of normal subjects will be identified. 2) Does the identification of a point mutation in the androgen receptor gene result in an abnormal biological activity? 3) Do some subjects with azoospermia present a mild form of AIS related to a point mutation of their androgen receptor gene? If so, what is the frequency of this abnormality and does it result in abnormal biological function? 4) In those subjects shown to have an abnormality in biological function of the androgen receptor associated with a point mutation in the androgen receptor gene, does immunocytochemical analysis of the androgen receptor in cultured genital skin fibroblasts demonstrate an effect on cytoplasmic/nuclear localization? 5) In some subjects with prostatic carcinoma, does resistance to hormonal therapy result from somatic cell mutations in the androgen receptor gene within a subpopulation of poorly differentiated cells from primary or metastatic lesions? The overall goal of our proposal is to establish structure/function correlates of naturally occurring androgen receptor gene mutations as a means to better understand the mechanisms of androgen action and to elucidate the causes for clinical conditions affecting human male sexual differentiation, fertility and prostatic carcinoma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK000180-40A1
Application #
3224231
Study Section
Reproductive Biology Study Section (REB)
Project Start
1976-01-01
Project End
1995-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
40
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Migeon, Claude J; Wisniewski, Amy B; Brown, Terry R et al. (2002) 46,XY intersex individuals: phenotypic and etiologic classification, knowledge of condition, and satisfaction with knowledge in adulthood. Pediatrics 110:e32
Migeon, Claude J; Wisniewski, Amy B; Gearhart, John P et al. (2002) Ambiguous genitalia with perineoscrotal hypospadias in 46,XY individuals: long-term medical, surgical, and psychosexual outcome. Pediatrics 110:e31
Sher, E S; Migeon, C J; Berkovitz, G D (1998) Evaluation of boys with marked breast development at puberty. Clin Pediatr (Phila) 37:367-71
Fuqua, J S; Sher, E S; Fechner, P Y et al. (1996) Linkage analysis of a kindred with inherited 46,XY partial gonadal dysgenesis. J Clin Endocrinol Metab 81:4479-83
Murono, K; Mendonca, B B; Arnhold, I J et al. (1995) Human androgen insensitivity due to point mutations encoding amino acid substitutions in the androgen receptor steroid-binding domain. Hum Mutat 6:152-62
Donohoue, P A; Guethlein, L; Collins, M M et al. (1995) The HLA-A3, Cw6,B47,DR7 extended haplotypes in salt losing 21-hydroxylase deficiency and in the Old Order Amish: identical class I antigens and class II alleles with at least two crossover sites in the class III region. Tissue Antigens 46:163-72
Turner, B; Fechner, P Y; Fuqua, J S et al. (1995) Combined Leydig cell and Sertoli cell dysfunction in 46,XX males lacking the sex determining region Y gene. Am J Med Genet 57:440-3
Fechner, P Y; Rosenberg, C; Stetten, G et al. (1994) Nonrandom inactivation of the Y-bearing X chromosome in a 46,XX individual: evidence for the etiology of 46,XX true hermaphroditism. Cytogenet Cell Genet 66:22-6
Marcantonio, S M; Fechner, P Y; Migeon, C J et al. (1994) Embryonic testicular regression sequence: a part of the clinical spectrum of 46,XY gonadal dysgenesis. Am J Med Genet 49:1-5
Fechner, P Y; Marcantonio, S M; Jaswaney, V et al. (1993) The role of the sex-determining region Y gene in the etiology of 46,XX maleness. J Clin Endocrinol Metab 76:690-5

Showing the most recent 10 out of 36 publications