ArticleHuman molecular genetics2015
FGFR2 mutation in 46,XY sex reversal with craniosynostosis.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
27 citing papers in PubMed, 79 citations in OpenAlex.
- Post-translational modification of proteins in the human testis development pathway.Human reproduction update · 2026Review
- Chromatin spatial analysis by METALoci unveils sex-determining 3D regulatory hubs.Nature structural & molecular biology · 2026Article
- Chromatin-Based Control of Mammalian Sex Determination: Integrating Epigenetic and Metabolic Mechanisms.Advances in experimental medicine and biology · 2026Review
- Differences of sex development.Nature reviews. Disease primers · 2025Review
- A novel CUL4B gene variant activating Wnt4/β-catenin signal pathway to karyotype 46, XY female with disorders of sex development.Biological research · 2025Article
- How relevant is the mouse model for understanding human sex determination?International journal of biological sciences · 2025Article
- Inhibition of WNT/β-catenin signalling during sex-specific gonadal differentiation is essential for normal human fetal testis development.Cell communication and signaling : CCS · 2024Article
- Genetic control of typical and atypical sex development.Nature reviews. Urology · 2023Review
- Cytogenomic Investigation of Syndromic Brazilian Patients with Differences of Sexual Development.Diagnostics (Basel, Switzerland) · 2023Article
- Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects.Nature communications · 2023Article
- FGF9 variant in 46,XY DSD patient suggests a role for dimerization in sex determination.Clinical genetics · 2023Article
- Case Report: Novel Compound Heterozygotic Variants inFrontiers in genetics · 2022Article
- Deciphering Sex-Specific Differentiation of Human Fetal Gonads: Insight From Experimental Models.Frontiers in cell and developmental biology · 2022Review
- Exogenous Oestrogen Impacts Cell Fate Decision in the Developing Gonads: A Potential Cause of Declining Human Reproductive Health.International journal of molecular sciences · 2020Review
- Disorders of Sex Development-Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation.International journal of molecular sciences · 2020Review
- Dysregulation of FGFR signalling by a selective inhibitor reduces germ cell survival in human fetal gonads of both sexes and alters the somatic niche in fetal testes.Human reproduction (Oxford, England) · 2019Article
- Article
- PIN1 is a new therapeutic target of craniosynostosis.Human molecular genetics · 2018Article
- Overexpression ofDisease models & mechanisms · 2018Article
- DMRT1 repression using a novel approach to genetic manipulation induces testicular dysgenesis in human fetal gonads.Human reproduction (Oxford, England) · 2018Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 7 institutions in 3 countries.
Funding
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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.