Concomitant mutations in the P450 oxidoreductase and androgen receptor genes presenting with 46,XY disordered sex development and androgenization at adrenarche

Journal of Clinical Endocrinology and Metabolism

Volumn 95, Issue 7, 2010, Pages 3418-3427

  Idkowiak, Jan ^a   Malunowicz, Ewa M ^b   Dhir, Vivek ^a   Reisch, Nicole ^a   Szarras Czapnik, Maria ^b   Holmes, Donna M ^a   Shackleton, Cedric H L ^a   Davies, John D ^c   Hughes, Ieuan A ^c   Krone, Nils ^a   Arlt, Wiebke ^a  

^a UNIVERSITY OF BIRMINGHAM   (United Kingdom)

^b CHILDREN'S MEMORIAL HEALTH INSTITUTE   (Poland)

^c UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANDROGEN RECEPTOR; ANDROSTERONE; AROMATASE; CORTICOSTERONE DERIVATIVE; CYTOCHROME P450 17; CYTOCHROME P450 REDUCTASE; HYDROCORTISONE; HYDROXYPROGESTERONE; STEROID 21 MONOOXYGENASE; TESTOSTERONE; CYP17A1 PROTEIN, HUMAN; OXIDOREDUCTASE; STEROID 17ALPHA MONOOXYGENASE;

ADRENARCHE; ANDROGEN INSENSITIVITY SYNDROME; ANDROGEN SYNTHESIS; ARTICLE; CASE REPORT; CHILD; CLITORIS; ENZYME ACTIVITY; ENZYME INHIBITION; FEMALE; GAS CHROMATOGRAPHY; GENE EXPRESSION; GENE SEQUENCE; GENETIC ANALYSIS; GENETIC IDENTIFICATION; GONADECTOMY; HETEROZYGOSITY; HUMAN; HUMAN TISSUE; HYDROCORTISONE BLOOD LEVEL; KARYOTYPE 46,XY; MALE; MASS SPECTROMETRY; MICROSOME; MISSENSE MUTATION; NUCLEOTIDE SEQUENCE; PHENOTYPE; PRESCHOOL CHILD; PRIORITY JOURNAL; PROGESTERONE BLOOD LEVEL; SEXUAL DEVELOPMENT; STEROID ANALYSIS; STEROIDOGENESIS; TESTOSTERONE BLOOD LEVEL; URINALYSIS; GENETICS; GONADAL DISEASE; GONADAL DYSGENESIS; METABOLISM; MUTATION; WESTERN BLOTTING;

ADRENARCHE; BLOTTING, WESTERN; CHILD; FEMALE; GONADAL DYSGENESIS, 46,XY; HUMANS; MALE; MUTATION; OXIDOREDUCTASES; RECEPTORS, ANDROGEN; SEXUAL DEVELOPMENT; STEROID 17-ALPHA-HYDROXYLASE; VIRILISM;

EID: 77954910027     PISSN: 0021972X     EISSN: 0021972X     Source Type: Journal    
DOI: 10.1210/jc.2010-0058     Document Type: Article

References (40)

1. Mendonca BB, Domenice S, Arnhold IJ, Costa EM 2009 46,XY disorders of sex development (DSD). Clin Endocrinol (Oxf) 70:173-187
2. Hughes IA 2008 Disorders of sex development: a new definition and classification. Best Pract Res Clin Endocrinol Metab 22:119-134
3. Bevan CL, Brown BB, Davies HR, Evans BA, Hughes IA, Patterson MN 1996 Functional analysis of six androgen receptor mutations identified in patients with partial androgen insensitivity syndrome. Hum Mol Genet 5:265-273
4. Ghali SA, Gottlieb B, Lumbroso R, Beitel LK, Elhaji Y, Wu J, Pinsky L, Trifiro MA 2003 The use of androgen receptor amino/carboxylterminal interaction assays to investigate androgen receptor gene mutations in subjects with varying degrees of androgen insensitivity. J Clin Endocrinol Metab 88:2185-2193
5. Jääskeläinen J, Deeb A, Schwabe JW, Mongan NP, Martin H, Hughes IA 2006 Human androgen receptor gene ligand-binding-domain mutations leading to disrupted interaction between the N-and C-terminal domains. J Mol Endocrinol 36:361-368
6. Krone N, Dhir V, Ivison H, Arlt W 2007 Congenital adrenal hyperplasia and P450 oxidoreductase deficiency. Clin Endocrinol (Oxf) 66:162-172
7. Krone N, Arlt W 2009 Genetics of congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab 23:181-192
8. Arlt W, Walker EA, Draper N, Ivison HE, Ride JP, Hammer F, Chalder SM, Borucka-Mankiewicz M, Hauffa BP, Malunowicz EM, Stewart PM, Shackleton CHL 2004 Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study. Lancet 363:2128-2135
9. Flück C, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge C, Jabs EW, Mendonça BB, Fujieda K, Miller WL 2004 Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat Genet 36:228-230
10. Wilson JD, Auchus RJ, Leihy MW, Guryev OL, Estabrook RW, Osborn SM, Shaw G, Renfree MB 2003 5α-Androstane-3α,17β-diol is formed in tammar wallaby pouch young testes by a pathway involving 5α-pregnane- 3αa, 17α-diol-20-one as a key intermediate. Endocrinology 144:575-580
11. Shackleton C, Marcos J, Malunowicz EM, Szarras-Czapnik M, Jira P, Taylor NF, Murphy N, Crushell E, Gottschalk M, Hauffa B, Cragun DL, Hopkin RJ, Adachi M, Arlt W 2004 Biochemical diagnosis of Antley-Bixler syndrome by steroid analysis. Am J Med Genet A 128A:223-231
12. Batch JA, Williams DM, Davies HR, Brown BD, Evans BA, Hughes IA, Patterson MN 1992 Androgen receptor gene mutations identified by SSCP in fourteen subjects with androgen insensitivity syndrome. Hum Mol Genet 1:497-503
13. Dhir V, Ivison HE, Krone N, Shackleton CH, Doherty AJ, Stewart PM, Arlt W 2007 Differential inhibition of CYP17A1 and CYP21A2 activities by the P450 oxidoreductase mutant A287P. Mol Endocrinol 21:1958-1968
14. Quigley CA, De Bellis A, Marschke KB, el-Awady MK, Wilson EM, French FS 1995 Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev 16:271-321
15. Hiort O, Sinnecker GH, Holterhus PM, Nitsche EM, Kruse K 1996 The clinical and molecular spectrum of androgen insensitivity syndromes. Am J Med Genet 63:218-222
16. Thai HT, Kalbasi M, Lagerstedt K, Frisén L, Kockum I, Nordenskjöld A 2005 The valine allele of the V89L polymorphism in the 5α-reductase gene confers a reduced risk for hypospadias. J Clin Endocrinol Metab 90:6695-6698
17. Wang Q, Ghadessy FJ, Trounson A, de Kretser D, McLachlan R, Ng SC, Yong EL 1998 Azoospermia associated with a mutation in the ligand-binding domain of an androgen receptor displaying normal ligand binding, but defective trans-activation. J Clin Endocrinol Metab 83:4303-4309
18. Hiort O, Holterhus PM, Horter T, Schulze W, Kremke B, Bals-Pratsch M, Sinnecker GH, Kruse K 2000 Significance of mutations in the androgen receptor gene in males with idiopathic infertility. J Clin Endocrinol Metab 85:2810-2815
19. Ferlin A, Vinanzi C, Garolla A, Selice R, Zuccarello D, Cazzadore C, Foresta C 2006 Male infertility and androgen receptor gene mutations: clinical features and identification of seven novel mutations. Clin Endocrinol (Oxf) 65:606-610
20. Flück CE, Nicolo C, Pandey AV 2007 Clinical, structural and functional implications of mutations and polymorphisms in human NADPH P450 oxidoreductase. Fundam Clin Pharmacol 21:399-410
21. Agrawal V, Huang N, Miller WL 2008 Pharmacogenetics of P450 oxidoreductase: effect of sequence variants on activities of CYP1A2 and CYP2C19. Pharmacogenet Genomics 18:569-576
22. Huang N, Agrawal V, Giacomini KM, Miller WL 2008 Genetics of P450 oxidoreductase: sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations. Proc Natl Acad Sci USA 105:1733-1738
23. Homma K, Hasegawa T, Nagai T, Adachi M, Horikawa R, Fujiwara I, Tajima T, Takeda R, Fukami M, Ogata T 2006 Urine steroid hormone profile analysis in cytochrome P450 oxidoreductase deficiency: implication for the backdoor pathway to dihydrotestosterone. J Clin Endocrinol Metab 91:2643-2649
24. Counts DR, Pescovitz OH, Barnes KM, Hench KD, Chrousos GP, Sherins RJ, Comite F, Loriaux DL, Cutler Jr GB 1987 Dissociation of adrenarche and gonadarche in precocious puberty and in isolated hypogonadotropic hypogonadism. J Clin Endocrinol Metab 64:1174-1178
25. Sklar CA, Kaplan SL, Grumbach MM 1980 Evidence for dissociation between adrenarche and gonadarche: studies in patients with idiopathic precocious puberty, gonadal dysgenesis, isolated gonadotropin deficiency, and constitutionally delayed growth and adolescence. J Clin Endocrinol Metab 51:548-556
26. Hopper BR, Yen SS 1975 Circulating concentrations of dehydroepiandrosterone and dehydroepiandrosterone sulfate during puberty. J Clin Endocrinol Metab 40:458-461
27. Nakamura Y, Gang HX, Suzuki T, Sasano H, Rainey WE 2009 Adrenal changes associated with adrenarche. Rev Endocr Metab Disord 10:19-26
28. Suzuki T, Sasano H, Takeyama J, Kaneko C, Freije WA, Carr BR, Rainey WE 2000 Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies. Clin Endocrinol (Oxf) 53:739-747
29. Auchus R, Rainey W 2004 Adrenarche - physiology, biochemistry and human disease. Clin Endocrinol (Oxf) 60:288-296
30. Auchus RJ, Lee TC, Miller WL 1998 Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer. J Biol Chem 273:3158-3165
31. Wang M, Roberts DL, Paschke R, Shea TM, Masters BS, Kim JJ 1997 Three-dimensional structure of NADPH-cytochrome P450 reductase: prototype for FMN- and FAD-containing enzymes. Proc Natl Acad Sci USA 94:8411-8416
32. Wagner S, Kiupel M, Peterson 2nd RA, Heikinheimo M, Wilson DB 2008 Cytochrome b5 expression in gonadectomy-induced adrenocortical neoplasms of the domestic ferret (Mustela putorius furo). Vet Pathol 45:439-442
33. Beuschlein F, Looyenga BD, Bleasdale SE, Mutch C, Bavers DL, Parlow AF, Nilson JH, Hammer GD 2003 Activin induces x-zone apoptosis that inhibits luteinizing hormone-dependent adrenocortical tumor formation in inhibin-deficient mice. Mol Cell Biol 23:3951-3964
34. Rahman NA, Kiiveri S, Rivero-Müller A, Levallet J, Vierre S, Kero J, Wilson DB, Heikinheimo M, Huhtaniemi I 2004 Adrenocortical tumorigenesis in transgenic mice expressing the inhibin α-subunit promoter/simian virus 40 T-antigen transgene: relationship between ectopic expression of luteinizing hormone receptor and transcription factor GATA-4. Mol Endocrinol 18:2553-2569
35. Bernichtein S, Petretto E, Jamieson S, Goel A, Aitman TJ, Mangion JM, Huhtaniemi IT 2008 Adrenal gland tumorigenesis after gonadectomy in mice is a complex genetic trait driven by epistatic loci. Endocrinology 149:651-661
36. Lee PA, Houk CP 2004 Outcome studies among men with micropenis. J Pediatr Endocrinol Metab 17:1043-1053
37. Rösler A, Silverstein S, Abeliovich D 1996 A (R80Q) mutation in 17β-hydroxysteroid dehydrogenase type 3 gene among Arabs of Israel is associated with pseudohermaphroditism in males and normal asymptomatic females. J Clin Endocrinol Metab 81:1827-1831
38. Lee YS, Kirk JM, Stanhope RG, Johnston DI, Harland S, Auchus RJ, Andersson S, Hughes IA 2007 Phenotypic variability in 17β-hydroxysteroid dehydrogenase-3 deficiency and diagnostic pitfalls. Clin Endocrinol (Oxf) 67:20-28
39. Cohen-Kettenis PT 2005 Gender change in 46,XY persons with 5α-reductase-2 deficiency and 17β-hydroxysteroid dehydrogenase-3 deficiency. Arch Sex Behav 34:399-410
40. Metherell LA, Naville D, Halaby G, Begeot M, Huebner A, Nürnberg G, Nürnberg P, Green J, Tomlinson JW, Krone NP, Lin L, Racine M, Berney DM, Achermann JC, Arlt W, Clark AJ 2009 Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency. J Clin Endocrinol Metab 94:3865-3871