Familial frameshift SRY mutation inherited from a mosaic father with testicular dysgenesis syndrome
- PMID: 19531589
- DOI: 10.1210/jc.2009-0226
Familial frameshift SRY mutation inherited from a mosaic father with testicular dysgenesis syndrome
Abstract
Context: The SRY gene encodes a transcription factor responsible for initiating testis differentiation. Mutations in SRY almost always result in XY sex reversal with pure gonadal dysgenesis and an increased risk of gonadal tumor. Most of these mutations are de novo, affecting only one individual in a family. Only a small subset of mutations is shared between a phenotypically normal father and one or more of his affected children. Incomplete penetrance and somatic mosaicism are two hypotheses that may explain a normal phenotype in a father carrying a SRY mutation.
Patients and results: We describe a family with two sisters with XY sex reversal and pure gonadal dysgenesis and a phenotypically normal brother. A novel constitutional frameshift SRY mutation was identified in both sisters and was absent in the brother. The single base pair deletion (c.71delA) led to a premature stop codon in position 60 of the protein, removing entirely the high-mobility group domain and the DNA-binding domain of SRY. The father of the three children presented with hypospadias; cryptorchidism; testicular seminoma and oligoasthenozoospermia, an association termed testicular dysgenesis syndrome (TDS); and the SRY mutation in a mosaic state in the peripheral blood and the tumor.
Conclusions: This observation of somatic and germinal mosaicism for a SRY mutation may explain the variable penetrance in some familial gonadal dysgenesis. Importantly, the present report is the first one describing the association of SRY mutation in a male with TDS. This suggests that mutations in a sex-determining gene may contribute to the pathogenesis of TDS.
Similar articles
-
A SRY-HMG box frame shift mutation inherited from a mosaic father with a mild form of testicular dysgenesis syndrome in Turner syndrome patient.BMC Med Genet. 2010 Sep 19;11:131. doi: 10.1186/1471-2350-11-131. BMC Med Genet. 2010. PMID: 20849656 Free PMC article.
-
Novel mutations affecting SRY DNA-binding activity: the HMG box N65H associated with 46,XY pure gonadal dysgenesis and the familial non-HMG box R30I associated with variable phenotypes.J Mol Med (Berl). 2002 Dec;80(12):782-90. doi: 10.1007/s00109-002-0376-9. Epub 2002 Oct 1. J Mol Med (Berl). 2002. PMID: 12483463
-
Loss of sequences 3' to the testis-determining gene, SRY, including the Y pseudoautosomal boundary associated with partial testicular determination.Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8590-4. doi: 10.1073/pnas.93.16.8590. Proc Natl Acad Sci U S A. 1996. PMID: 8710915 Free PMC article.
-
Analysis of the SRY gene in two sex-reversed XY sisters identifies two new novel point mutations in the high mobility group box domain.Fertil Steril. 2008 Oct;90(4):1199.e1-8. doi: 10.1016/j.fertnstert.2007.11.062. Epub 2008 Mar 4. Fertil Steril. 2008. PMID: 18304538 Review.
-
Candidate genes in complete and partial XY sex reversal: mutation analysis of SRY, SRY-related genes and FTZ-F1.Mol Cell Endocrinol. 1998 May 25;140(1-2):51-8. doi: 10.1016/s0303-7207(98)00029-x. Mol Cell Endocrinol. 1998. PMID: 9722168 Review.
Cited by
-
Delayed Recognition of Disorders of Sex Development (DSD): A Missed Opportunity for Early Diagnosis of Malignant Germ Cell Tumors.Int J Endocrinol. 2012;2012:671209. doi: 10.1155/2012/671209. Epub 2012 Jan 19. Int J Endocrinol. 2012. PMID: 22315593 Free PMC article.
-
Three novel and two known androgen receptor gene mutations associated with androgen insensitivity syndrome in sex-reversed XY female patients.J Genet. 2016 Dec;95(4):911-921. doi: 10.1007/s12041-016-0716-0. J Genet. 2016. PMID: 27994190
-
A de novo frameshift mutation of the SRY gene leading to a patient with 46,XY complete gonadal dysgenesis.Asian J Androl. 2019 Sep-Oct;21(5):522-524. doi: 10.4103/aja.aja_123_18. Asian J Androl. 2019. PMID: 30785124 Free PMC article. No abstract available.
-
SRY mutation analysis by next generation (deep) sequencing in a cohort of chromosomal Disorders of Sex Development (DSD) patients with a mosaic karyotype.BMC Med Genet. 2012 Nov 16;13:108. doi: 10.1186/1471-2350-13-108. BMC Med Genet. 2012. PMID: 23157850 Free PMC article.
-
Possible fetal determinants of male infertility.Nat Rev Endocrinol. 2014 Sep;10(9):553-62. doi: 10.1038/nrendo.2014.97. Epub 2014 Jun 17. Nat Rev Endocrinol. 2014. PMID: 24935122 Review.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
