Population-Based Study of Rare Coding Variants in /SF-1

Overview

Journal J Endocr Soc

Specialty Endocrinology

Date 2024 Oct 31

PMID 39479520

Authors

Chrysanthi Kouri

Raina Y Jia

Katherine A Kentistou

Eugene J Gardner

John R B Perry

Christa E Fluck

Ken K Ong

Affiliations

Soon will be listed here.

Abstract

Background: Steroidogenic Factor 1/Nuclear Receptor Subfamily 5 Group A Member 1 (SF-1/) is critical for the development and function of sex organs, influencing steroidogenesis and reproduction. While rare deleterious /SF-1 variants have been identified in individuals with various differences of sex development (DSD), primary ovarian insufficiency, and infertility, their impact on the general population remains unclear.

Methods: We analyzed health records and exome sequencing data from up to 420 162 individuals (227 858 women) from the UK Biobank study to assess the impact of rare (frequency < 0.1%) predicted deleterious /SF-1 variants on age at menopause and 26 other traits.

Results: No carriers of rare protein truncating variants in /SF-1 were identified. We found that the previously reported association of rare deleterious missense /SF-1 variants with earlier age at menopause is driven by variants in the DNA binding domain (DBD) and ligand binding domain (LBD) (combined test: beta = -2.36 years/allele, [95% CI: 3.21, -1.51], N = 107 carriers, = 4.6 × 10). Carriers also had a higher risk of adult obesity (OR = 1.061, [95% CI: 1.003, 1.104], N = 344, = .015), particularly among women (OR = 1.095 [95% CI: 1.034, 1.163, = 3.87 × 10], N = 176), but not men (OR = 1.019, [95% CI: 0.955, 1.088], = .57, N = 168).

Conclusion: Deleterious missense variants in the DBD and LBD likely disrupt /SF-1 function. This study broadens the relevance of deleterious /SF-1 variants beyond rare DSDs, suggesting the need for extended phenotyping and monitoring of affected individuals.

Citing Articles

Population-Based Study of Rare Coding Variants in /SF-1.

Kouri C, Jia R, Kentistou K, Gardner E, Perry J, Fluck C J Endocr Soc. 2024; 8(12):bvae178.

PMID: 39479520 PMC: 11521259. DOI: 10.1210/jendso/bvae178.

References

Loh P, Tucker G, Bulik-Sullivan B, Vilhjalmsson B, Finucane H, Salem R . Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat Genet. 2015; 47(3):284-90. PMC: 4342297. DOI: 10.1038/ng.3190. View

Zangen D, Kaufman Y, Banne E, Weinberg-Shukron A, Abulibdeh A, Garfinkel B . Testicular differentiation factor SF-1 is required for human spleen development. J Clin Invest. 2014; 124(5):2071-5. PMC: 4001552. DOI: 10.1172/JCI73186. View

Achermann J, Ito M, Hindmarsh P, Jameson J . A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet. 1999; 22(2):125-6. DOI: 10.1038/9629. View

Karczewski K, Francioli L, Tiao G, Cummings B, Alfoldi J, Wang Q . The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020; 581(7809):434-443. PMC: 7334197. DOI: 10.1038/s41586-020-2308-7. View

Ioannidis N, Rothstein J, Pejaver V, Middha S, McDonnell S, Baheti S . REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants. Am J Hum Genet. 2016; 99(4):877-885. PMC: 5065685. DOI: 10.1016/j.ajhg.2016.08.016. View

Meek T, Nelson J, Matsen M, Dorfman M, Guyenet S, Damian V . Functional identification of a neurocircuit regulating blood glucose. Proc Natl Acad Sci U S A. 2016; 113(14):E2073-82. PMC: 4833243. DOI: 10.1073/pnas.1521160113. View

Philibert P, Zenaty D, Lin L, Soskin S, Audran F, Leger J . Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: a French collaborative study. Hum Reprod. 2007; 22(12):3255-61. PMC: 2990861. DOI: 10.1093/humrep/dem278. View

Lourenco D, Brauner R, Lin L, De Perdigo A, Weryha G, Muresan M . Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med. 2009; 360(12):1200-10. PMC: 2778147. DOI: 10.1056/NEJMoa0806228. View

Camats N, Pandey A, Fernandez-Cancio M, Andaluz P, Janner M, Toran N . 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(7):E1294-306. DOI: 10.1210/jc.2011-3169. View

10.

Jaillard S, Sreenivasan R, Beaumont M, Robevska G, Dubourg C, Knarston I . Analysis of NR5A1 in 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility. Maturitas. 2019; 131:78-86. DOI: 10.1016/j.maturitas.2019.10.011. View

11.

Hu X, Li N, Xu Y, Li G, Yu T, Yao R . Proband-only medical exome sequencing as a cost-effective first-tier genetic diagnostic test for patients without prior molecular tests and clinical diagnosis in a developing country: the China experience. Genet Med. 2017; 20(9):1045-1053. DOI: 10.1038/gim.2017.195. View

12.

Suntharalingham J, Buonocore F, Duncan A, Achermann J . DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease. Best Pract Res Clin Endocrinol Metab. 2015; 29(4):607-19. PMC: 5159745. DOI: 10.1016/j.beem.2015.07.004. View

13.

Fosch A, Zagmutt S, Casals N, Rodriguez-Rodriguez R . New Insights of SF1 Neurons in Hypothalamic Regulation of Obesity and Diabetes. Int J Mol Sci. 2021; 22(12). PMC: 8229730. DOI: 10.3390/ijms22126186. View

14.

Tran L, Park S, Kim S, Lee J, Kim K, Kwon O . Hypothalamic control of energy expenditure and thermogenesis. Exp Mol Med. 2022; 54(4):358-369. PMC: 9076616. DOI: 10.1038/s12276-022-00741-z. View

15.

Ikeda Y, Luo X, Abbud R, Nilson J, Parker K . The nuclear receptor steroidogenic factor 1 is essential for the formation of the ventromedial hypothalamic nucleus. Mol Endocrinol. 1995; 9(4):478-86. DOI: 10.1210/mend.9.4.7659091. View

16.

Shekari S, Stankovic S, Gardner E, Hawkes G, Kentistou K, Beaumont R . Penetrance of pathogenic genetic variants associated with premature ovarian insufficiency. Nat Med. 2023; 29(7):1692-1699. DOI: 10.1038/s41591-023-02405-5. View

17.

Shinoda K, Lei H, Yoshii H, Nomura M, Nagano M, Shiba H . Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Dev Dyn. 1995; 204(1):22-9. DOI: 10.1002/aja.1002040104. View

18.

Kouri C, Jia R, Kentistou K, Gardner E, Perry J, Fluck C . Population-Based Study of Rare Coding Variants in /SF-1. J Endocr Soc. 2024; 8(12):bvae178. PMC: 11521259. DOI: 10.1210/jendso/bvae178. View

19.

Teoli J, Mallet D, Renault L, Gay C, Labrune E, Bretones P . Case Report: Longitudinal follow-up and testicular sperm extraction in a patient with a pathogenic (SF-1) frameshift variant: p.(Phe70Ser*5). Front Endocrinol (Lausanne). 2023; 14:1171822. PMC: 10319352. DOI: 10.3389/fendo.2023.1171822. View

20.

Salacki A, Wysokinski A . Reactive thrombocytosis resulting from frequent blood donations as an extremely rare cause of ST Segment Elevation Myocardial Infarction in the case of a 19-year-old male. Ann Agric Environ Med. 2018; 25(4):602-604. DOI: 10.26444/aaem/74196. View