FGF9 variant in 46,XY DSD patient suggests a role for dimerization in sex determination.

Autor: Croft B; Hudson Institute of Medical Research, Monash Medical Centre, Melbourne, Australia.; Department of Molecular & Translational Science, Monash University, Melbourne, Australia.; Murdoch Children's Research Institute, Melbourne, Australia., Bird AD; Hudson Institute of Medical Research, Monash Medical Centre, Melbourne, Australia.; Department of Molecular & Translational Science, Monash University, Melbourne, Australia., Ono M; Hudson Institute of Medical Research, Monash Medical Centre, Melbourne, Australia.; Department of Paediatrics, Chiba Kaihin Municipal Hospital, Chiba, Japan., Eggers S; Murdoch Children's Research Institute, Melbourne, Australia., Bagheri-Fam S; Hudson Institute of Medical Research, Monash Medical Centre, Melbourne, Australia.; Department of Molecular & Translational Science, Monash University, Melbourne, Australia., Ryan JM; Hudson Institute of Medical Research, Monash Medical Centre, Melbourne, Australia., Reyes AP; Hudson Institute of Medical Research, Monash Medical Centre, Melbourne, Australia., van den Bergen J; Murdoch Children's Research Institute, Melbourne, Australia., Baxendale A; Department of Paediatrics, Chiba Kaihin Municipal Hospital, Chiba, Japan.; SA Clinical Genetics Service, Women's and Children's Hospital, Adelaide, Australia., Thompson EM; SA Clinical Genetics Service, Women's and Children's Hospital, Adelaide, Australia.; Adelaide Medical School, Faculty of Health Sciences, University of Adelaide, Adelaide, Australia., Kueh AJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Australia., Stanton P; Hudson Institute of Medical Research, Monash Medical Centre, Melbourne, Australia.; Department of Molecular & Translational Science, Monash University, Melbourne, Australia., Thomas T; The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Australia., Sinclair AH; Murdoch Children's Research Institute, Melbourne, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, Australia., Harley VR; Department of Molecular & Translational Science, Monash University, Melbourne, Australia.
Jazyk: angličtina
Zdroj: Clinical genetics [Clin Genet] 2023 Mar; Vol. 103 (3), pp. 277-287. Date of Electronic Publication: 2022 Nov 28.
DOI: 10.1111/cge.14261
Abstrakt: 46,XY gonadal dysgenesis (GD) is a Disorder/Difference of Sex Development (DSD) that can present with phenotypes ranging from ambiguous genitalia to complete male-to-female sex reversal. Around 50% of 46,XY DSD cases receive a molecular diagnosis. In mice, Fibroblast growth factor 9 (FGF9) is an important component of the male sex-determining pathway. Two FGF9 variants reported to date disrupt testis development in mice, but not in humans. Here, we describe a female patient with 46,XY GD harbouring the rare FGF9 variant (missense mutation), NM_002010.2:c.583G > A;p.(Asp195Asn) (D195N). By biochemical and cell-based approaches, the D195N variant disrupts FGF9 protein homodimerisation and FGF9-heparin-binding, and reduces both Sertoli cell proliferation and Wnt4 repression. XY Fgf9 D195N/D195N foetal mice show a transient disruption of testicular cord development, while XY Fgf9 D195N/- foetal mice show partial male-to-female gonadal sex reversal. In the general population, the D195N variant occurs at an allele frequency of 2.4 × 10 -5 , suggesting an oligogenic basis for the patient's DSD. Exome analysis of the patient reveals several known and novel variants in genes expressed in human foetal Sertoli cells at the time of sex determination. Taken together, our results indicate that disruption of FGF9 homodimerization impairs testis determination in mice and, potentially, also in humans in combination with other variants.
(© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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