Top

Published in:

Open Access 01-12-2010 | Research

Steroidogenic factor-1 (SF-1) gene mutation as a frequent cause of primary amenorrhea in 46,XY female adolescents with low testosterone concentration

Authors: Pascal Philibert, Elodie Leprieur, Delphine Zenaty, Elisabeth Thibaud, Michel Polak, Anne-Marie Frances, James Lespinasse, Isabelle Raingeard, Nadège Servant, Françoise Audran, Françoise Paris, Charles Sultan

Published in: Reproductive Biology and Endocrinology | Issue 1/2010

Abstract

Background

Primary amenorrhea due to 46,XY disorders of sex differentiation (DSD) is a frequent reason for consultation in endocrine and gynecology clinics. Among the genetic causes of low-testosterone primary amenorrhea due to 46,XY DSD, SRY gene is reported to be frequently involved, but other genes, such as SF1 and WT1, have never been studied for their prevalence.

Methods

We directly sequenced SRY, SF1 and WT1 genes in 15 adolescent girls with primary amenorrhea, low testosterone concentration, and XY karyotype, to determine the prevalence of mutations. We also analyzed the LH receptor gene in patients with high LH and normal FSH concentrations.

Results

Among the 15 adolescents with primary amenorrhea and low testosterone concentration, we identified two new SRY mutations, five new SF1 mutations and one new LH receptor gene mutation. Our study confirms the 10-15% prevalence of SRY mutations and shows the high prevalence (33%) of SF1 abnormalities in primary amenorrhea due to 46,XY DSD with low plasma testosterone concentration.

Conclusions

The genetic analysis of low-testosterone primary amenorrhea is complex as several factors may be involved. This work underlines the need to systematically analyze the SF1 sequence in girls with primary amenorrhea due to 46,XY DSD and low testosterone, as well as in newborns with 46,XY DSD.

Available only for authorised users

Christin-Maitre S, Braham R: [General mechanisms of premature ovarian failure and clinical check-up]. Gynecol Obstet Fertil. 2008, 36 (9): 857-861. 10.1016/j.gyobfe.2008.07.003.CrossRefPubMed

Mendonca BB, Domenice S, Arnhold IJ, Costa EM: 46,XY disorders of sex development (DSD). Clin Endocrinol (Oxf). 2009, 70 (2): 173-187.

Michala L, Creighton SM: The XY Female. Best Pract Res Clin Endocrinol Metab. 2009, (doi:10.1016/j.bpobgyn.2009.09.009)

Hughes IA: Disorders of sex development: a new definition and classification. Best Pract Res Clin Endocrinol Metab. 2008, 22 (1): 119-134. 10.1016/j.beem.2007.11.001.CrossRefPubMed

MacLaughlin DT, Donahoe PK: Sex determination and differentiation. N Engl J Med. 2004, 350 (4): 367-378. 10.1056/NEJMra022784.CrossRefPubMed

Philibert P, Zenaty D, Lin L, Soskin S, Audran F, Leger J, Achermann JC, Sultan C: Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: a French collaborative study. Hum Reprod. 2007, 22 (12): 3255-3261. 10.1093/humrep/dem278.PubMedCentralCrossRefPubMed

Paris F, Philibert P, Lumbroso S, Baldet P, Charvet JP, Galifer RB, Sultan C: Primary amenorrhea in a 46,XY adolescent girl with partial gonadal dysgenesis: identification of a new SRY gene mutation. Fertil Steril. 2007, 88 (5): 1437-10.1016/j.fertnstert.2007.01.048. e1421-1435CrossRefPubMed

Kohler B, Pienkowski C, Audran F, Delsol M, Tauber M, Paris F, Sultan C, Lumbroso S: An N-terminal WT1 mutation (P181S) in an XY patient with ambiguous genitalia, normal testosterone production, absence of kidney disease and associated heart defect: enlarging the phenotypic spectrum of WT1 defects. Eur J Endocrinol. 2004, 150 (6): 825-830. 10.1530/eje.0.1500825.CrossRefPubMed

Ramensky V, Bork P, Sunyaev S: Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 2002, 30 (17): 3894-3900. 10.1093/nar/gkf493.PubMedCentralCrossRefPubMed

10.

Ng PC, Henikoff S: SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003, 31 (13): 3812-3814. 10.1093/nar/gkg509.PubMedCentralCrossRefPubMed

11.

PolyPhen: prediction of functional effect of human nsSNPs. [http://genetics.bwh.harvard.edu/pph/index.html]

12.

The SIFT Software. [http://sift.jcvi.org/]

13.

Michala L, Goswami D, Creighton SM, Conway GS: Swyer syndrome: presentation and outcomes. BJOG. 2008, 115 (6): 737-741. 10.1111/j.1471-0528.2008.01703.x.CrossRefPubMed

14.

Brennan J, Capel B: One tissue, two fates: molecular genetic events that underlie testis versus ovary development. Nat Rev Genet. 2004, 5 (7): 509-521. 10.1038/nrg1381.CrossRefPubMed

15.

Lourenco D, Brauner R, Lin L, De Perdigo A, Weryha G, Muresan M, Boudjenah R, Guerra-Junior G, Maciel-Guerra AT, Achermann JC, McElreavey K, Bashamboo A: Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med. 2009, 360 (12): 1200-1210. 10.1056/NEJMoa0806228.PubMedCentralCrossRefPubMed

16.

Mallet D, Bretones P, Michel-Calemard L, Dijoud F, David M, Morel Y: Gonadal dysgenesis without adrenal insufficiency in a 46, XY patient heterozygous for the nonsense C16X mutation: a case of SF1 haploinsufficiency. J Clin Endocrinol Metab. 2004, 89 (10): 4829-4832. 10.1210/jc.2004-0670.CrossRefPubMed

17.

Hasegawa T, Fukami M, Sato N, Katsumata N, Sasaki G, Fukutani K, Morohashi K, Ogata T: Testicular dysgenesis without adrenal insufficiency in a 46,XY patient with a heterozygous inactive mutation of steroidogenic factor-1. J Clin Endocrinol Metab. 2004, 89 (12): 5930-5935. 10.1210/jc.2004-0935.CrossRefPubMed

18.

Lin L, Philibert P, Ferraz-de-Souza B, Kelberman D, Homfray T, Albanese A, Molini V, Sebire NJ, Einaudi S, Conway GS, Hughes IA, Jameson JL, Sultan C, Dattani MT, Achermann JC: Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function. J Clin Endocrinol Metab. 2007, 92 (3): 991-999. 10.1210/jc.2006-1672.PubMedCentralCrossRefPubMed

19.

Piersma D, Verhoef-Post M, Berns EM, Themmen AP: LH receptor gene mutations and polymorphisms: an overview. Mol Cell Endocrinol. 2007, 260-262: 282-286. 10.1016/j.mce.2005.11.048.CrossRefPubMed

Title: Steroidogenic factor-1 (SF-1) gene mutation as a frequent cause of primary amenorrhea in 46,XY female adolescents with low testosterone concentration
Authors: Pascal Philibert
Elodie Leprieur
Delphine Zenaty
Elisabeth Thibaud
Michel Polak
Anne-Marie Frances
James Lespinasse
Isabelle Raingeard
Nadège Servant
Françoise Audran
Françoise Paris
Charles Sultan
Publication date: 01-12-2010
Publisher: BioMed Central
Published in: Reproductive Biology and Endocrinology / Issue 1/2010
Electronic ISSN: 1477-7827
DOI: https://doi.org/10.1186/1477-7827-8-28

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Steroidogenic factor-1 (SF-1) gene mutation as a frequent cause of primary amenorrhea in 46,XY female adolescents with low testosterone concentration

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2010

Amifostine reduces the seminiferous epithelium damage in doxorubicin-treated prepubertal rats without improving the fertility status

Metabolic abnormalities in adolescents with polycystic ovary syndrome in south china

Adiponectin promotes syncytialisation of BeWo cell line and primary trophoblast cells

Quantitative analysis of mRNA translation in mammalian spermatogenic cells with sucrose and Nycodenz gradients

Health implications resulting from the timing of elective cesarean delivery

Genetic evidence that SMAD2 is not required for gonadal tumor development in inhibin-deficient mice