Identical NR5A1 Missense Mutations in Two Unrelated 46,XX Individuals with Testicular Tissues

Human Mutation

Volumn 38, Issue 1, 2017, Pages 39-42

  Igarashi, Maki ^a   Takasawa, Kei ^b   Hakoda, Akiko ^c   Kanno, Junko ^c   Takada, Shuji ^a   Miyado, Mami ^a   Baba, Takashi ^d   Morohashi, Ken Ichirou ^d   Tajima, Toshihiro ^e   Hata, Kenichiro ^a   Nakabayashi, Kazuhiko ^a   Matsubara, Yoichi ^a   Sekido, Ryohei ^f   Ogata, Tsutomu ^a,g   Kashimada, Kenichi ^b   Fukami, Maki ^a  

^a NATIONAL RESEARCH INSTITUTE FOR CHILD HEALTH AND DEVELOPMENT   (Japan)

^b TOKYO MEDICAL AND DENTAL UNIVERSITY   (Japan)

^c MIYAGI CHILDREN S HOSPITAL   (Japan)

^d KYUSHU UNIVERSITY   (Japan)

^e HOKKAIDO UNIVERSITY   (Japan)

^f UNIVERSITY OF ABERDEEN   (United Kingdom)

^g HAMAMATSU UNIVERSITY SCHOOL OF MEDICINE   (Japan)

Author keywords

46,XX ovotesticular DSD; 46,XX testicular DSD; NR0B1; NR5A1; SOX9

Indexed keywords

CELL NUCLEUS RECEPTOR; NUCLEAR RECEPTOR DAX 1; NUCLEAR RECEPTOR SUBFAMILY 5 GROUP A MEMBER 1; TRANSCRIPTION FACTOR SOX9; UNCLASSIFIED DRUG; BIOLOGICAL MARKER; STEROIDOGENIC FACTOR 1;

ARTICLE; CASE REPORT; COMPUTER MODEL; CONTROLLED STUDY; DISEASE MARKER; DISORDER OF SEX DEVELOPMENT; ENHANCER REGION; FEMALE; GENE IDENTIFICATION; GENETIC ASSOCIATION; GENETIC VARIABILITY; HUMAN; HUMAN TISSUE; IN VITRO STUDY; INFANT; JAPANESE (PEOPLE); MALE; MISSENSE MUTATION; NEWBORN; PHENOTYPE; PRIORITY JOURNAL; TESTIS; TESTIS DEVELOPMENT; ABNORMALITIES; ALLELE; AMINO ACID SUBSTITUTION; CHEMISTRY; DNA MUTATIONAL ANALYSIS; GENETICS; GENOTYPE; GONAD; KARYOTYPE; METABOLISM; MOLECULAR MODEL; PROTEIN CONFORMATION;

ALLELES; AMINO ACID SUBSTITUTION; BIOMARKERS; DISORDERS OF SEX DEVELOPMENT; DNA MUTATIONAL ANALYSIS; FEMALE; GENOTYPE; GONADS; HUMANS; INFANT; KARYOTYPE; MALE; MODELS, MOLECULAR; MUTATION, MISSENSE; PHENOTYPE; PROTEIN CONFORMATION; STEROIDOGENIC FACTOR 1; TESTIS;

EID: 85003706947     PISSN: 10597794     EISSN: 10981004     Source Type: Journal    
DOI: 10.1002/humu.23116     Document Type: Article

References (27)

1. Achermann JC, Ozisik G, Ito M, Orun UA, Harmanci K, Gurakan B, Jameson JL. 2002. Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner. J Clin Endocrinol Metab 87:1829–1833.
2. Bashamboo A, McElreavey K. 2013. Gene mutations associated with anomalies of human gonad formation. Sex Dev 7:126–146.
3. Baxter RM, Arboleda VA, Lee H, Barseghyan H, Adam MP, Fechner PY, Bargman R, Keegan C, Travers S, Schelley S, Hudgins L, Mathew RP et al. 2015. Exome sequencing for the diagnosis of 46,XY disorders of sex development. J Clin Endcrinol Metab 100:333–344.
4. Combes AN, Spiller CM, Harley VR, Sinclair AH, Dunwoodie SL, Wilhelm D, Koopman P. 2010. Gonadal defects in Cited2-mutant mice indicate a role for SF1 in both testis and ovary differentiation. Int J Dev Biol 54:683–689.
5. De Baere E, Lemercier B, Christin-Maitre S, Durval D, Messiaen L, Fellous M, Veitia R. 2002. FOXL2 mutation screening in a large panel of POF patients and XX males. J Med Genet 39:e43.
6. Eggers S, Ohnesorg T, Sinclair A. 2014. Genetic regulation of mammalian gonad development. Nat Rev Endocrinol 10:673–683.
7. Ferraz-de-Souza B, Lin L, Achermann JC. 2011. Steroidogenic factor-1 (SF-1, NR5A1) and human disease. Mol Cell Endocrinol 336:198–205.
8. Flück CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF, 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.
9. Guran T, Buonocore F, Saka N, Ozbek MN, Aycan Z, Bereket A, Bas F, Darcan S, Bideci A, Guven A, Demir K, Akinci A, et al. 2016. Rare causes of primary adrenal insufficiency: genetic and clinical characterization of a large nationwide cohort. J Clin Endocrinol Metab 101:284–292.
10. Hanley NA, Ball SG, Clement-Jones M, Hagan DM, Strachan T, Lindsay S, Robson S, Ostrer H, Parker KL, Wilson DI. 1999. Expression of steroidogenic factor 1 and Wilms' tumour 1 during early human gonadal development and sex determination. Mech Dev 87:175–180.
11. Hanley NA, Hagan DM, Clement-Jones M, Ball SG, Strachan T, Salas-Cortés L, McElreavey K, Lindsay S, Robson S, Bullen P, Ostrer H, Wilson DI. 2000. SRY, SOX9, and DAX1 expression patterns during human sex determination and gonadal development. Mech Dev 91:403–407.
12. Jameson JL, Achermann JC, Ozisik G, Meeks JJ. 2003. Battle of the sexes: new insights into genetic pathways of gonadal development. Trans Am Clin Climatol Assoc 114:51–65.
13. Kawabe K, Shikayama T, Tsuboi H, Oka S, Oba K, Yanase T, Nawata H, Morohashi K. 1999. Dax-1 as one of the target genes of Ad4BP/SF-1. Mol Endocrinol 13:1267–1284.
14. Kim GJ, Sock E, Buchberger A, Just W, Denzer F, Hoepffner W, German J, Cole T, Mann J, Seguin JH, Zipf W, Costigan C, et al. 2015. Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development. J Med Genet 52:240–247.
15. Kousta E, Papathanasiou A, Skordis N. 2010. Sex determination and disorders of sex development according to the revised nomenclature and classification in 46,XX individuals. Hormones 9:218–231.
16. López M, Torres L, Méndez JP, Cervantes A, Pérez-Palacios G, Erickson RP, Alfaro G, Kofman-Alfaro S. 1995. Clinical traits and molecular findings in 46, XX males. Clin Genet 48:29–34.
17. Ludbrook LM, Bernard P, Bagheri-Fam S, Ryan J, Sekido R, Wilhelm D, Lovell-Badge R, Harley VR. 2012. Excess DAX1 leads to XY ovotesticular disorder of sex development (DSD) in mice by inhibiting steroidogenic factor-1 (SF1) activation of the testis enhancer of SRY-box-9 (Sox9). Endocrinology 153:1948–1958.
18. Mandel H, Shemer R, Borochowitz ZU, Okopnik M, Knopf C, Indelman M, Drugan A, Tiosano D, Gershoni-Baruch R, Choder M, Sprecher E. 2008. SERKAL syndrome: an autosomal-recessive disorder caused by a loss-of-function mutation in WNT4. Am J Hum Genet 82:39–47.
19. Morohashi K, Omura T. 1996. Ad4BP/SF-1, a transcription factor essential for the transcription of steroidogenic cytochrome P450 genes and for the establishment of the reproductive function. FASEB J 10:1569–1577.
20. Okuhara K, Abe S, Kondo T, Fujita K, Koda N, Mochizuki H, Fujieda K, Tajima T. 2008. Four Japanese patients with adrenal hypoplasia congenita and hypogonadotropic hypogonadism caused by DAX-1 gene mutations: mutant DAX-1 failed to repress steroidogenic acute regulatory protein (StAR) and luteinizing hormone β-subunit gene promoter activity. Endocr J 55:97–103.
21. Ono M, Harley VR. 2013. Disorders of sex development: new genes, new concepts. Nat Rev Endocrinol 9:79–91.
22. Park M, Shin E, Won M, Kim JH, Go H, Kim HL, Ko JJ, Lee K, Bae J. 2010. FOXL2 interacts with steroidogenic factor-1 (SF-1) and represses SF-1-induced CYP17 transcription in granulosa cells. Mol Endocrinol 24:1024–1036.
23. Sekido R, Lovell-Badge R. 2008. Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature 453:930–934.
24. Takasawa K, Kashimada K, Pelosi E, Takagi M, Morio T, Asahara H, Schlessinger D, Mizutani S, Koopman P. 2014. FOXL2 transcriptionally represses Sf1 expression by antagonizing WT1 during ovarian development in mice. FASEB J 28:2020–2028.
25. Tomaselli S, Megiorni F, De Bernardo C, Felici A, Marrocco G, Maggiulli G, Grammatico B, Remotti D, Saccucci P, Valentini F, Mazzilli MC, Majore S et al. 2008. Syndromic true hermaphroditism due to an R-spondin 1 (RSPO1) homozygous mutation. Hum Mutat 29:220–226.
26. Vetro A, Dehghani MR, Kraoua L, Giorda R, Beri S, Cardarelli L, Merico M, Manolakos E, Bustamante AP, Castro A, Radi O, Camerino G, et al. 2015. Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3. Eur J Hum Genet 8:1025–1032.
27. Voican A, Bachelot A, Bouligand J, Francou B, Dulon J, Lombès M, Touraine P, Guiochon-Mantel A. 2013. NR5A1 (SF-1) mutations are not a major cause of primary ovarian insufficiency. J Clin Endocrinol Metab 98:1017–1021.