An intron 9 CYP19 Gene Variant (IVS9+5G>A), present in an aromatase-deficient girl, affects normal splicing and is also present in normal human steroidogenic tissues

Hormone Research in Paediatrics

Volumn 84, Issue 4, 2015, Pages 275-282

  Saraco, Nora ^a   Nesi Franca, Suzana ^b   Sainz, Romina ^a   Marino, Roxana ^a   Marques Pereira, Rosana ^b   La Pastina, Julia ^b   Garrido, Natalia Perez ^a   Sandrini, Romolo ^b   Rivarola, Marco Aurelio ^a   De Lacerda, Luiz ^b   Belgorosky, Alicia ^a  

^a HOSPITAL DE PEDIATRÍA PROF DR JUAN P GARRAHAN   (Argentina)

^b FEDERAL UNIVERSITY OF PARANÁ   (Brazil)

Author keywords

Aromatase deficiency; CYP19A1; Mutation; Splicing; Steroidogenic tissues

Indexed keywords

ACTIN; AROMATASE; ESTRADIOL; ESTROGEN; FLUDROCORTISONE; FOLLITROPIN; GLUCOCORTICOID; LUTEINIZING HORMONE; MESSENGER RNA; ORAL CONTRACEPTIVE AGENT; CYP19A1 PROTEIN, HUMAN;

ADOLESCENT; AROMATASE DEFICIENCY; ARTICLE; BONE AGE; BONE DENSITY; CASE REPORT; CLITOROMEGALY; ENZYME ACTIVITY; ENZYME ANALYSIS; ESTROGEN BLOOD LEVEL; EXON; FEEDBACK SYSTEM; FEMALE; FOLLICLE CYST; FOLLITROPIN BLOOD LEVEL; GENE; GENE MUTATION; GENETIC VARIABILITY; GONADOTROPIN RELEASE; HETEROZYGOSITY; HOMOZYGOTE; HUMAN; INTRON; INTRON 9 CYP19 GENE; KARYOTYPE 46,XX; LABORATORY; LUTEINIZING HORMONE BLOOD LEVEL; MENARCHE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PUBERTY; RNA SPLICING; URETHRA; ADRENAL GLAND; AMENORRHEA; ANIMAL; CELL LINE; CHLOROCEBUS AETHIOPS; COS 1 CELL LINE; DEFICIENCY; GENETICS; MALE; METABOLISM; MOUSE; MUTATION; PHENOTYPE; PLACENTA; PREGNANCY; PROTEIN SPLICING; TESTIS;

ADOLESCENT; ADRENAL GLANDS; AMENORRHEA; ANIMALS; AROMATASE; CELL LINE; CERCOPITHECUS AETHIOPS; COS CELLS; FEMALE; HUMANS; MALE; MICE; MUTATION; PHENOTYPE; PLACENTA; PREGNANCY; PROTEIN SPLICING; TESTIS;

EID: 84947495042     PISSN: 16632818     EISSN: 16632826     Source Type: Journal    
DOI: 10.1159/000437142     Document Type: Article

References (32)

1. Means GD, Mahendroo MS, Corbin CJ, Mathis JM, Powell FE, Mendelson CR, Simpson ER. Structural analysis of the gene encoding human aromatase cytochrome P-450, the enzyme responsible for estrogen biosynthesis. J Biol Chem 1989; 264: 19385-19391
2. Santen RJ, Brodie H, Simpson ER, Siiteri PK, Brodie A. History of aromatase: saga of an important biological mediator and therapeutic target. Endocr Rev 2009; 30: 343-375
3. Bulun SE, Sebastian S, Takayama K, Suzuki T, Sasano H, Shozu M. The human CYP19 (aromatase P450) gene: update on physiologic roles and genomic organization of promoters. J Steroid Biochem Mol Biol 2003; 86: 219-224
4. Shozu M, Akasofu K, Harada T, Kubota Y. A new cause of female pseudohermaphroditism: placental aromatase deficiency. J Clin Endocrinol Metab 1991; 72: 560-566
5. Belgorosky A, Guercio G, Pepe C, Saraco N, Rivarola MA. Genetic and clinical spectrum of aromatase deficiency in infancy, childhood and adolescence. Horm Res 2009; 72: 321-330
6. Hauri-Hohl A, Meyer-Boni M, Lang-Muritano M, Hauri-Hohl M, Schoenle EJ, Biason-Lauber A. Aromatase deficiency owing to a functional variant in the placenta promoter and a novel missense mutation in the CYP-19A1 gene. Clin Endocrinol (Oxf) 2011; 75: 39-43
7. Verma N, Jain V, Birla S, Jain R, Sharma A. Growth and hormonal profile from birth to adolescence of a girl with aromatase deficiency. J Pediatr Endocrinol Metab 2012; 25: 1185-1190
8. Ludwikowski B, Heger S, Datz N, Richter-Unruh A, Gonzalez R. Aromatase deficiency: rare cause of virilization. Eur J Pediatr Surg 2013; 23: 418-422
9. Baykan EK, Erdoʇan M, Ozen S, Darcan Ş, Saygili LF. Aromatase deficiency, a rare syndrome: case report. J Clin Res Pediatr Endocrinol 2013; 5: 129-132, erratum in J Clin Res Pediatr Endocrinol 2013; 5: 216
10. Gagliardi L, Scott HS, Feng J, Torpy DJ. A case of aromatase deficiency due to a novel CYP19A1 mutation. BMC Endocr Disord 2014; 14: 16
11. Bouchoucha N, Samara-Boustani D, Pandey AV, Bony-Trifunovic H, Hofer G, Aigrain Y, Polak M, Fluck CE. Characterization of a novel CYP19A1 (aromatase) R192H mutation causing virilization of a 46, XX newborn, undervirilization of the 46, XY brother, but no virilization of the mother during pregnancies. Mol Cell Endocrinol 2014; 390: 8-17
12. Yamada-Mouri N, Hirata S, Kato J, Hoshi K. Expression and distribution of cortical type aromatase mRNA variant in the adult rat brain. J Steroid Biochem Mol Biol 1997; 60: 325-329
13. Roselli CE, Abdelgadir SE, Ronnekleiv OK, Klosterman SA. Anatomic distribution and regulation of aromatase gene expression in the rat brain. Biol Reprod 1998; 58: 79-87
14. Levallet J, Mittre H, Delarue B, Carreau S. Alternative splicing events in the coding region of the cytochrome P450 aromatase gene in male rat germ cells. J Mol Endocrinol 1998; 20: 305-312
15. Delarue B, Breard E, Mittre H, Leymarie P. Expression of two aromatase cDNAs in various rabbit tissues. J Steroid Biochem Mol Biol 1998; 64: 113-119
16. Abdelgadir SE, Roselli CE, Choate JV, Resko JA. Distribution of aromatase cytochrome P450 messenger ribonucleic acid in adult rhesus monkey brains. Biol Reprod 1997; 57: 772-777
17. Pereyra-Martinez AC, Roselli CE, Stadelman HL, Resko JA. Cytochrome P450 aromatase in testis and epididymis of male rhesus monkeys. Endocrine 2001; 16: 15-19
18. Lephart ED, Peterson KG, Noble JF, George FW, McPhaul MJ. The structure of cDNA clones encoding the aromatase P-450 isolated from a rat Leydig cell tumor line demonstrates differential processing of aromatase mRNA in rat ovary and a neoplastic cell line. Mol Cell Endocrinol 1990; 70: 31-40
19. Fukada S, Tanaka M, Matsuyama M, Kobayashi D, Nagahama Y. Isolation, characterization, and expression of cDNAs encoding the Medaka (Oryzias latipes) ovarian follicle cytochrome P-450 aromatase. Mol Reprod Dev 1996; 45: 285-290
20. Hanoux V, Bouraima H, Mittre H, Feral C, Benhaim A. Differential regulation of two 3 ' end variants of P450 aromatase transcripts and of a new truncated aromatase protein in rabbit preovulatory granulosa cells. Endocrinology 2003; 144: 4790-4798
21. Pepe CM, Saraco NI, Baquedano MS, Guercio G, Vaiani E, Marino R, Pandey AV, Fluck CE, Rivarola MA, Belgorosky A. The cytochrome P450 aromatase lacking exon 5 is associated with a phenotype of nonclassic aromatase deficiency and is also present in normal human steroidogenic tissues. Clin Endocrinol (Oxf) 2007; 67: 698-705
22. Greulich WW, Pyle SI. Radiographic Atlas of Skeletal Development of the Hand and Wrist. Stanford, Stanford University Press, 1959
23. Belgorosky A, Pepe C, Marino R, Guercio G, Saraco N, Vaiani E, Rivarola MA. Hypothalamic-pituitary-ovarian axis during infancy, early and late prepuberty in an aromatase-deficient girl who is a compound heterocygote for two new point mutations of the CYP19 gene. J Clin Endocrinol Metab 2003; 88: 5127-5131
24. Tools for Prediction and Analysis of Protein-Coding Gene Structure. Istituto di Tecnologie Biomediche Avanzate. http://bioinfo4.itb. cnr.it/webgene/wwwspliceview.html
25. Yeo G, Burge CB. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals; in Vingron M, Istrail S, Pevzner P, Waterman M (eds): RECOMB 2003: Proceedings of the Seventh Annual International Conference on Research in Computational Molecular Biology. New York, ACM, 2003, pp 322-331
26. Brunak S, Engelbrecht J, Knudsen S. Prediction of human mRNA donor and acceptor sites from the DNA sequence. J Mol Biol 1991; 220: 49-65
27. Reese MG, Eeckman FH, Kulp D, et al. Improved splice site detection in Genie. J Comput Biol 1997; 4: 311-323
28. Cartegni L, Wang J, Zhu Z, et al. ESEfinder: a web resource to identify exonic splicing enhancers. Nucleic Acids Res 2003; 31: 3568-3571
29. Harada N, Ogawa H, Shozu M, Yamada K. Genetic studies to characterize the origin of the mutation in placental aromatase deficiency. Am J Hum Genet 1992; 51: 666-672
30. Mullis PE, Yoshimura N, Kuhlmann B, Lippuner K, Jaeger P, Harada H. Aromatase deficiency in a female who is compound heterozygote for two new point mutations in the P450arom gene: impact of estrogens on hypergonadotropic hypogonadism, multicystic ovaries, and bone densitometry in childhood. J Clin Endocrinol Metab 1997; 82: 1739-1745
31. Guercio G, Di Palma MI, Pepe C, Saraco NI, Prieto M, Saure C, Mazza C, Rivarola MA, Belgorosky A. Metformin, estrogen replacement therapy and gonadotropin inhibition fail to improve insulin sensitivity in a girl with aromatase deficiency. Horm Res 2009; 72: 370-376
32. Burckhardt MA, Obmann V, Wolf R, Janner M, Fluck CE, Mullis PE. Ovarian and uterine development and hormonal feedback mechanism in a 46 XX patient with CYP19A1 deficiency under low dose estrogen replacement. Gynecol Endocrinol 2015; 14: 1-6