title: FGFR2 mutation in 46,XY sex reversal with craniosynostosis.
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 Fgfr2c(C342Y/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 Fgfr2c(C342Y/-) 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.
authors.affiliation: Centre for Reproductive Health, Hudson Institute of Medical Research, Melbourne, Australia, Department of Anatomy and Developmental Biology, vincent.harley@hudson.org.au stefan.bagheri-fam@hudson.org.au.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bagheri-Fam
authors.affiliation: Centre for Reproductive Health, Hudson Institute of Medical Research, Melbourne, Australia.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ono
authors.affiliation: Department of Orthopedics and Rehabilitation, Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Centre for Reproductive Health, Hudson Institute of Medical Research, Melbourne, Australia.
authors.forename: Janelle
authors.initials: J
authors.lastname: Ryan
authors.affiliation: Centre for Reproductive Health, Hudson Institute of Medical Research, Melbourne, Australia.
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
authors.affiliation: Department of Integrative Biology, University of California Berkeley, Berkeley, USA.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Katsura
authors.affiliation: Department of Anatomy and Developmental Biology, Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Rossello
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Koopman
authors.affiliation: Institute of Human Genetics, University of Freiburg, Freiburg, Germany and.
authors.forename: Gerd
authors.initials: G
authors.lastname: Scherer
authors.affiliation: Institute of Human Genetics, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bartsch
authors.affiliation: Department of Orthopedics and Rehabilitation, Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Jacob V P
authors.initials: JV
authors.lastname: Eswarakumar
authors.affiliation: Centre for Reproductive Health, Hudson Institute of Medical Research, Melbourne, Australia, Department of Anatomy and Developmental Biology, vincent.harley@hudson.org.au stefan.bagheri-fam@hudson.org.au.
authors.forename: Vincent R
authors.initials: VR
authors.lastname: Harley
mesh_terms: D000293:Adolescent; D000818:Animals; D003398:Craniosynostoses / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D013577:Syndrome
chemical_list: C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2