Novel Mutation of NR5A1 in A Case of 46,XY Disorder of Sexual Development: A Case Report
Keywords:
Disorder of sexual development, NR5A1, SF1Abstract
46,XY disorder of sexual differentiation (DSD) is a type of sexual ambiguity which a patient with male chromosome does not completely developed male sex phenotype. Although the condition is known as androgen insensitivity syndrome, its pathophysiology is not always such unresponsiveness to androgen. Defective androgen production caused by molecular pathology on steroidogenic hormone regulating genes explain the phenotypes in a number of cases. Herein, we report a case of 46,XY DSD with gonadal dysgenesis who had a heterozygous germline mutation of NR5A1 at the position 9:124500710. The mutation is predicted to result in a substitution of Arginine with Cysteine at the codon 84 (p.R84C) of NR5A1, which encodes for a DNA binding domain of the transcription factor SF1. On familial study, the mutation was found derived from the maternal side who also carried a heterozygous p.R84C. With this novel mutation, our evidence was consistent with previous studies which have suggested that mutations within NR5A1 are associated with 46,XY DSD and primary ovarian insufficiency.
References
1. MacLaughlin DT, Donahoe PK. Sex determination and differentiation. N Engl J Med. 2004;350:367-78.
2. Achermann JC, Ozisik G, Meeks JJ, et al. Genetic causes of human reproductive disease. J Clin Endocrinol Metab. 2002;87:2447-54.
3. Parker KL, Schimmer BP. Genes essential for early events in gonadal development. Ann Med. 2002;34:171-8.
4. Parker KL, Rice DA, Lala DS, et al. Steroidogenic factor 1: an essential mediator of endocrine development. Recent Prog Horm Res. 2002;57:19-36.
5. Buaas FW, Gardiner JR, Clayton S, et al. In vivo evidence for the crucial role of SF1 in steroid-producing cells of the testis, ovary and adrenal gland. Development. 2012;139:4561-70.
6. Camats N, Pandey AV, Fernandez-Cancio 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. 2012;97:E1294-306.
7. Gomes NL, Lerario AM, Machado AZ, et al. Long-term outcomes and molecular analysis of a large cohort of patients with 46,XY disorder of sex development due to partial gonadal dysgenesis. Clin Endocrinol (Oxf). 2018.
8. Kohler B, Lin L, Ferraz-de-Souza B, et al. Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency. Hum Mutat. 2008;29:59-64.
9. Wang H, Zhang L, Wang N, et al. Next-generation sequencing reveals genetic landscape in 46, XY disorders of sexual development patients with variable phenotypes. Hum Genet. 2018;137:265-77.
10. Luo X, Ikeda Y, Parker KL. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell. 1994;77:481-90.
11. Hussain S, Amar A, Najeeb MN, et al. Two novel mutations in the NR5A1 gene as a cause of disorders of sex development in a Pakistani cohort of 46,XY patients. Andrologia. 2016;48:509-17.
12. Achermann JC, Ito M, Hindmarsh PC, et al. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet. 1999;22:125-6.
13. Achermann JC, Ozisik G, Ito M, 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. 2002;87:1829-33.
14. Philibert P, Polak M, Colmenares A, et al. Predominant Sertoli cell deficiency in a 46,XY disorders of sex development patient with a new NR5A1/SF-1 mutation transmitted by his unaffected father. Fertil Steril. 2011;95:1788 e5-9.
15. Ciaccio M, Costanzo M, Guercio G, et al. Preserved fertility in a patient with a 46,XY disorder of sex development due to a new heterozygous mutation in the NR5A1/SF-1 gene: evidence of 46,XY and 46,XX gonadal dysgenesis phenotype variability in multiple members of an affected kindred. Horm Res Paediatr. 2012;78:119-26.
16. Fabbri HC, de Andrade JG, Soardi FC, et al. The novel p.Cys65Tyr mutation in NR5A1 gene in three 46,XY siblings with normal testosterone levels and their
mother with primary ovarian insufficiency. BMC Med Genet. 2014;15:7.
17. Gabriel Ribeiro de Andrade J, Marques-de-Faria AP, Fabbri HC, et al. Long-Term Follow-Up of Patients with 46,XY Partial Gonadal Dysgenesis Reared as Males. Int J Endocrinol. 2014;2014:480724.
18. Tantawy S, Mazen I, Soliman H, et al. Analysis of the gene coding for steroidogenic factor 1 (SF1, NR5A1) in a cohort of 50 Egyptian patients with 46,XY disorders of sex development. Eur J Endocrinol. 2014;170:759-67.
19. Fabbri HC, Ribeiro de Andrade JG, Maciel-Guerra AT, et al. NR5A1 Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three Novel Mutations. Sex Dev. 2016;10:191-9.
20. Rehkamper J, Tewes AC, Horvath J, et al. Four Novel NR5A1 Mutations in 46,XY Gonadal Dysgenesis Patients Including Frameshift Mutations with Altered Subcellular SF-1 Localization. Sex Dev. 2017;11:248-53.
21. Rocca MS, Ortolano R, Menabo S, et al. Mutational and functional studies on NR5A1 gene in 46,XY disorders of sex development: identification of six novel loss of function mutations. Fertil Steril. 2018;109:1105-13.
22. Domenice S, Machado AZ, Ferreira FM, et al. Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals. Birth Defects Res C Embryo Today. 2016;108:309-20.
23. Kohler B, Lin L, Mazen I, et al. The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46,XY males without adrenal insufficiency. Eur J Endocrinol. 2009;161:237-42.
24. Ropke A, Tewes AC, Gromoll J, et al. Comprehensive sequence analysis of the NR5A1 gene encoding steroidogenic factor 1 in a large group of infertile males. Eur J Hum Genet. 2013;21:1012-5.
25. 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. 2000;67:1563-8.
26. Bashamboo A, Donohoue PA, Vilain E, et al. A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development. Hum Mol Genet. 2016;25:5286.
27. Grinspon RP, Rey RA. Disorders of Sex Development with Testicular Differentiation in SRY-Negative 46,XX Individuals: Clinical and Genetic Aspects. Sex Dev. 2016;10:1-11.
28. Saito-Hakoda A, Kanno J, Suzuki D, et al. A Follow-Up from Infancy to Puberty in a Japanese Male with SRY-Negative 46,XX Testicular Disorder of Sex Development Carrying a p.Arg92Trp Mutation in NR5A1. Sex Dev. 2019.
29. Warman DM, Costanzo M, Marino R, et al. Three new SF-1 (NR5A1) gene mutations in two unrelated families with multiple affected members: within-family variability in 46,XY subjects and low ovarian reserve in fertile 46,XX subjects. Horm Res Paediatr. 2011;75:70-7.
30. Woo KH, Cheon B, Kim JH, et al. Novel Heterozygous Mutations of NR5A1 and Their Functional Characteristics in Patients with 46,XY Disorders of Sex Development without Adrenal Insufficiency. Horm Res Paediatr. 2015;84:116-23.
2. Achermann JC, Ozisik G, Meeks JJ, et al. Genetic causes of human reproductive disease. J Clin Endocrinol Metab. 2002;87:2447-54.
3. Parker KL, Schimmer BP. Genes essential for early events in gonadal development. Ann Med. 2002;34:171-8.
4. Parker KL, Rice DA, Lala DS, et al. Steroidogenic factor 1: an essential mediator of endocrine development. Recent Prog Horm Res. 2002;57:19-36.
5. Buaas FW, Gardiner JR, Clayton S, et al. In vivo evidence for the crucial role of SF1 in steroid-producing cells of the testis, ovary and adrenal gland. Development. 2012;139:4561-70.
6. Camats N, Pandey AV, Fernandez-Cancio 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. 2012;97:E1294-306.
7. Gomes NL, Lerario AM, Machado AZ, et al. Long-term outcomes and molecular analysis of a large cohort of patients with 46,XY disorder of sex development due to partial gonadal dysgenesis. Clin Endocrinol (Oxf). 2018.
8. Kohler B, Lin L, Ferraz-de-Souza B, et al. Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency. Hum Mutat. 2008;29:59-64.
9. Wang H, Zhang L, Wang N, et al. Next-generation sequencing reveals genetic landscape in 46, XY disorders of sexual development patients with variable phenotypes. Hum Genet. 2018;137:265-77.
10. Luo X, Ikeda Y, Parker KL. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell. 1994;77:481-90.
11. Hussain S, Amar A, Najeeb MN, et al. Two novel mutations in the NR5A1 gene as a cause of disorders of sex development in a Pakistani cohort of 46,XY patients. Andrologia. 2016;48:509-17.
12. Achermann JC, Ito M, Hindmarsh PC, et al. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet. 1999;22:125-6.
13. Achermann JC, Ozisik G, Ito M, 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. 2002;87:1829-33.
14. Philibert P, Polak M, Colmenares A, et al. Predominant Sertoli cell deficiency in a 46,XY disorders of sex development patient with a new NR5A1/SF-1 mutation transmitted by his unaffected father. Fertil Steril. 2011;95:1788 e5-9.
15. Ciaccio M, Costanzo M, Guercio G, et al. Preserved fertility in a patient with a 46,XY disorder of sex development due to a new heterozygous mutation in the NR5A1/SF-1 gene: evidence of 46,XY and 46,XX gonadal dysgenesis phenotype variability in multiple members of an affected kindred. Horm Res Paediatr. 2012;78:119-26.
16. Fabbri HC, de Andrade JG, Soardi FC, et al. The novel p.Cys65Tyr mutation in NR5A1 gene in three 46,XY siblings with normal testosterone levels and their
mother with primary ovarian insufficiency. BMC Med Genet. 2014;15:7.
17. Gabriel Ribeiro de Andrade J, Marques-de-Faria AP, Fabbri HC, et al. Long-Term Follow-Up of Patients with 46,XY Partial Gonadal Dysgenesis Reared as Males. Int J Endocrinol. 2014;2014:480724.
18. Tantawy S, Mazen I, Soliman H, et al. Analysis of the gene coding for steroidogenic factor 1 (SF1, NR5A1) in a cohort of 50 Egyptian patients with 46,XY disorders of sex development. Eur J Endocrinol. 2014;170:759-67.
19. Fabbri HC, Ribeiro de Andrade JG, Maciel-Guerra AT, et al. NR5A1 Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three Novel Mutations. Sex Dev. 2016;10:191-9.
20. Rehkamper J, Tewes AC, Horvath J, et al. Four Novel NR5A1 Mutations in 46,XY Gonadal Dysgenesis Patients Including Frameshift Mutations with Altered Subcellular SF-1 Localization. Sex Dev. 2017;11:248-53.
21. Rocca MS, Ortolano R, Menabo S, et al. Mutational and functional studies on NR5A1 gene in 46,XY disorders of sex development: identification of six novel loss of function mutations. Fertil Steril. 2018;109:1105-13.
22. Domenice S, Machado AZ, Ferreira FM, et al. Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals. Birth Defects Res C Embryo Today. 2016;108:309-20.
23. Kohler B, Lin L, Mazen I, et al. The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46,XY males without adrenal insufficiency. Eur J Endocrinol. 2009;161:237-42.
24. Ropke A, Tewes AC, Gromoll J, et al. Comprehensive sequence analysis of the NR5A1 gene encoding steroidogenic factor 1 in a large group of infertile males. Eur J Hum Genet. 2013;21:1012-5.
25. 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. 2000;67:1563-8.
26. Bashamboo A, Donohoue PA, Vilain E, et al. A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development. Hum Mol Genet. 2016;25:5286.
27. Grinspon RP, Rey RA. Disorders of Sex Development with Testicular Differentiation in SRY-Negative 46,XX Individuals: Clinical and Genetic Aspects. Sex Dev. 2016;10:1-11.
28. Saito-Hakoda A, Kanno J, Suzuki D, et al. A Follow-Up from Infancy to Puberty in a Japanese Male with SRY-Negative 46,XX Testicular Disorder of Sex Development Carrying a p.Arg92Trp Mutation in NR5A1. Sex Dev. 2019.
29. Warman DM, Costanzo M, Marino R, et al. Three new SF-1 (NR5A1) gene mutations in two unrelated families with multiple affected members: within-family variability in 46,XY subjects and low ovarian reserve in fertile 46,XX subjects. Horm Res Paediatr. 2011;75:70-7.
30. Woo KH, Cheon B, Kim JH, et al. Novel Heterozygous Mutations of NR5A1 and Their Functional Characteristics in Patients with 46,XY Disorders of Sex Development without Adrenal Insufficiency. Horm Res Paediatr. 2015;84:116-23.
Downloads
Published
2019-09-30
How to Cite
1.
Attawettayanon W, Laochareonsuk W, Jaruratanasirikul S, Maneechay W, Sangkhathat S. Novel Mutation of NR5A1 in A Case of 46,XY Disorder of Sexual Development: A Case Report. Thai J Surg [Internet]. 2019 Sep. 30 [cited 2024 Jul. 18];40(3):65-70. Available from: https://he02.tci-thaijo.org/index.php/ThaiJSurg/article/view/243919
Issue
Section
Case Reports
License
Articles must be contributed solely to The Thai Journal of Surgery and when published become the property of the Royal College of Surgeons of Thailand. The Royal College of Surgeons of Thailand reserves copyright on all published materials and such materials may not be reproduced in any form without the written permission.
