A heterozygous intragenic duplication within the repeated area (CTGCAGCTG)×2 of the NR5A1 gene was found in a 15-year-old 46,XY DSD (disorders/differences of sex development) patient with micropenis and severe proximal hypospadias. This heterozygous duplication has already been described twice in boys with a similar phenotype, whereas a deletion of 3 amino acids at the same position in the protein SF-1 has been described in a 46,XX patient with primary ovarian failure and short stature. These data suggest that this region within the NR5A1 gene has an important role for SF-1 protein function in gonads and is a hotspot for intragenic rearrangements.

Achermann JC, Ito M, Ito M, Hindmarsh PC, Jameson JL: A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet 22:125-126 (1999).
Achermann JC, Ozisik G, Ito M, Orun UA, Harmanci K, et al: 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 (2002).
Ball EV, Stenson PD, Abeysinghe SS, Krawczak M, Cooper DN, Chuzhanova NA: Microdeletions and microinsertions causing human genetic disease: common mechanisms of mutagenesis and the role of local DNA sequence complexity. Hum Mutat 26:205-213 (2005).
Bashamboo A, Ferraz-de-Souza B, Lourenço D, Lin L, Sebire NJ, et al: Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1. Am J Hum Genet 87:505-512 (2010).
Biason-Lauber A, Schoenle EJ: Apparently normal ovarian differentiation in a prepubertal girl with transcriptionally inactive steroidogenic factor 1 (NR5A1/SF-1) and adrenocortical insufficiency. Am J Hum Genet 67:1563-1568 (2000).
Camats N, Pandey AV, Fernández-Cancio M, Andaluz P, Janner M, et al: Ten novel mutations in the NR5A1 gene cause disordered sex development in 46,XY and ovarian insufficiency in 46,XX individuals. J Clin Endocrinol Metab 97:E1294-1306 (2012).
Chen J-M, Cooper DN, Férec C: Local sequence determinants of two in-frame triplet deletion/duplication hotspots in the RHD/RHCE genes. Hum Genomics 6:8 (2012).
Eggers S, Ohnesorg T, Sinclair A: Genetic regulation of mammalian gonad development. Nat Rev Endocrinol 10:673-683 (2014).
El-Khairi R, Martinez-Aguayo A, Ferraz-de-Souza B, Lin L, Achermann JC: Role of DAX-1 (NR0B1) and steroidogenic factor-1 (NR5A1) in human adrenal function. Endocr Dev 20:38-46 (2011).
Hanley NA, Ball SG, Clement-Jones M, Hagan DM, Strachan T, et al: Expression of steroidogenic factor 1 and Wilms' tumour 1 during early human gonadal development and sex determination. Mech Dev 87:175-180 (1999).
Hiort O, Birnbaum W, Marshall L, Wünsch L, Werner R, et al: Management of disorders of sex development. Nat Rev Endocrinol 9:520-529 (2014).
Knower KC, Kelly S, Ludbrook LM, Bagheri-Fam S, Sim H, et al: Failure of SOX9 regulation in 46,XY disorders of sex development with SRY, SOX9 and SF1 mutations. PloS One 6:e17751 (2011).
Lourenço D, Brauner R, Lin L, De Perdigo A, Weryha G, et al: Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med 360:1200-1210 (2009).
Młynarczuk J, Rękawiecki R: The role of the orphan receptor SF-1 in the development and function of the ovary. Reprod Biol 10:177-193 (2010).
Oba K, Yanase T, Nomura M, Morohashi K, Takayanagi R, et al: Structural characterization of human Ad4bp (SF-1) gene. Biochem Biophys Res Commun 226:261-267 (1996).
Pedace L, Laino L, Preziosi N, Valentini MS, Scommegna S, et al: Longitudinal hormonal evaluation in a patient with disorder of sexual development, 46,XY karyotype and one NR5A1 mutation. Am J Med Genet A 164A: 2938-2946 (2014).
Philibert P, Zenaty D, Lin L, Soskin S, Audran F, et al: Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: a French collaborative study. Hum Reprod 22:3255-3261 (2007).
Sekido R, Lovell-Badge R: Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature 453:930-934 (2008).
Shen WH, Moore CC, Ikeda Y, Parker KL, Ingraham HA: Nuclear receptor steroidogenic factor 1 regulates the müllerian inhibiting substance gene: a link to the sex determination cascade. Cell 77:651-661 (1994).
Zare-Abdollahi D, Safari S, Mirfakhraie R, Movafagh A, Bastami M, et al: Mutational screening of the NR5A1 in azoospermia. Andrologia 47:395-401 (2015).
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.