FGFR2 mutation in 46,XY sex reversal with craniosynostosis

Bagheri-Fam, Stefan, Ono, Makoto, Li, Li, Zhao, Liang, Ryan, Janelle, Lai, Raymond, Katsura, Yakako, Rosello, Fernando J., Koopman, Peter, Scherer, Gerd, Bartsch, Oliver, Eswarakumar, Jacob V. P. and Harley, Vincent R. (2015) FGFR2 mutation in 46,XY sex reversal with craniosynostosis. Human Molecular Genetics, 24 23: 6699-6710. doi:10.1093/hmg/ddv374

Author Bagheri-Fam, Stefan
Ono, Makoto
Li, Li
Zhao, Liang
Ryan, Janelle
Lai, Raymond
Katsura, Yakako
Rosello, Fernando J.
Koopman, Peter
Scherer, Gerd
Bartsch, Oliver
Eswarakumar, Jacob V. P.
Harley, Vincent R.
Title FGFR2 mutation in 46,XY sex reversal with craniosynostosis
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 1460-2083
Publication date 2015-09-11
Year available 2015
Sub-type Article (original research)
DOI 10.1093/hmg/ddv374
Open Access Status Not yet assessed
Volume 24
Issue 23
Start page 6699
End page 6710
Total pages 12
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 2016
Language eng
Formatted abstract
Patients with 46,XY gonadal dysgenesis (GD) exhibit genital anomalies, which range from hypospadias to complete male-to-female sex reversal. However, a molecular diagnosis is made in only 30% of cases. Heterozygous mutations in the human FGFR2 gene cause various craniosynostosis syndromes including Crouzon and Pfeiffer, but testicular defects were not reported. Here, we describe a patient whose features we would suggest represent a new FGFR2-related syndrome, craniosynostosis with XY male-to-female sex reversal or CSR. The craniosynostosis patient was chromosomally XY, but presented as a phenotypic female due to complete GD. DNA sequencing identified the FGFR2c heterozygous missense mutation, c.1025G>C (p.Cys342Ser). Substitution of Cys342 by Ser or other amino acids (Arg/Phe/Try/Tyr) has been previously reported in Crouzon and Pfeiffer syndrome. We show that the ‘knock-in’ Crouzon mouse model Fgfr2cC342Y/C342Y carrying a Cys342Tyr substitution displays XY gonadal sex reversal with variable expressivity. We also show that despite FGFR2c-Cys342Tyr being widely considered a gain-of-function mutation, Cys342Tyr substitution in the gonad leads to loss of function, as demonstrated by sex reversal in Fgfr2cC342Y/− mice carrying the knock-in allele on a null background. The rarity of our patient suggests the influence of modifier genes which exacerbated the testicular phenotype. Indeed, patient whole exome analysis revealed several potential modifiers expressed in Sertoli cells at the time of testis determination in mice. In summary, this study identifies the first FGFR2 mutation in a 46,XY GD patient. We conclude that, in certain rare genetic contexts, maintaining normal levels of FGFR2 signaling is important for human testis determination.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
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Created: Wed, 16 Dec 2015, 11:54:14 EST by Susan Allen on behalf of Institute for Molecular Bioscience