FB2026_03 , released September 17, 2026
Human Disease Model Report: 46,XX sex reversal 4
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General Information
Name
46,XX sex reversal 4
FlyBase ID
FBhh0001297
Disease Ontology Term
Parent Disease
OMIM
46,XX SEX REVERSAL 4; SRXX4
Overview

This report describes 46,XX sex reversal 4 (SRXX4); SRXX4 exhibits autosomal dominant inheritance. The human gene implicated in this disease is NR5A1, which encodes a DNA-binding transcriptional activator known to be involved in sex determination. NR5A1 is also implicated in 46,XY sex reversal 3 (MIM:612965) and several other forms of gonadal dysgenesis or disfunction (see MIM:184757).

The Drosophila gene ftz-f1 is orthologous to both NR5A1 and NR5A2. Multiple genetic reagents including classical loss-of-functions mutations, RNAi-targeting constructs, overexpression constructs, and alleles caused by insertional mutagenesis have been generated for ftz-f1.

The human Hsap\NR5A1 gene has been introduced into flies and has been used to characterize a variant of NR5A1 associated with SRXX4; in at least one case, this variant has been implicated in SRXY3. Variant(s) implicated in human disease tested (as transgenic human gene, NR5A1): the R92W variant form of the human gene has been introduced into flies. High levels of expression of Hsap\NR5A1 during early development (using maternal drivers) results in severe developmental defects. The same levels of expression using the R92W variant result in much less severe or no developmental defects. These results support characterization of the R92W variant as a severe loss-of-function mutation, but not a complete null.

[updated Jan. 2021 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: 46,XX sex reversal 4
OMIM report

[46,XX SEX REVERSAL 4; SRXX4](https://omim.org/entry/617480)

Human gene(s) implicated

[NUCLEAR RECEPTOR SUBFAMILY 5, GROUP A, MEMBER 1; NR5A1](https://omim.org/entry/184757)

Symptoms and phenotype

A disorder of sex development (DSD) is a congenital condition in which development of chromosomal, gonadal, or anatomic sex is atypical. 46,XX DSD is a disorder of gonadal (ovarian) development, which may be complete or partial (Lee et al., 2006; pubmed:16882788)[from MIM:400045; 2021.01.05]

(OMIM, 2013-)

Ambiguous genitalia or ovotestes are typically observed in individuals diagnosed with SRXX4. [from MIM:617480; 2021.01.05]

(OMIM, 2013-)
Genetics

The NR5A1:p.Arg92Trp variant is been reported in multiple cases of 46,XX sex reversal; one case of 46,XY sex reversal (SRY-positive) is described (Bashamboo et al., 2016; pubmed:27378692).

(FlyBase Curators, 2013-)

46,XX sex reversal 4 is caused by heterozygous mutation in the NR5A1 gene. [from MIM:617480; 2021.01.05]

(OMIM, 2013-)
Cellular phenotype and pathology
Molecular information

NR5A1 encodes a DNA-binding transcriptional activator involved in sex determination. [Gene Cards, NR5A1; 2021.01.05]

(FlyBase Curators, 2013-)
External links
Disease synonyms
disorders of sex development, NR5A1-related
gonadal dysgenesis, NR5A1-related
SRXX4
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
Symbol / Name
NR5A1; nuclear receptor subfamily 5 group A member 1
D. melanogaster ortholog (based on DIOPT)
Dmel\ftz-f1
(DIOPT, 2013-)
Comments on ortholog(s)

Many to one: 2 human genes to 1 Drosophila gene.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Other Genes Used: Viral, Bacterial, Synthetic (0)
      Summary of Physical Interactions (18 groups)
      ftz-f1
      protein-protein
      Interacting group
      Assay
      References
      ftz-f1 - Ada2b
      anti tag coimmunoprecipitation, peptide massfingerprinting
      (Weake et al., 2011)
      ftz-f1 - Ant2
      anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
      (Rhee et al., 2014)
      ftz-f1 - Arp2
      anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
      (Rhee et al., 2014)
      ftz-f1 - βTub85D
      anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
      (Rhee et al., 2014)
      ftz-f1 - bon
      two hybrid, pull down, anti tag western blot
      (Beckstead et al., 2001)
      ftz-f1 - CG31955
      two hybrid array
      (Shokri et al., 2019)
      ftz-f1 - D
      electrophoretic mobility shift assay, autoradiography, electrophoretic mobility supershift assay, pull down, western blot
      (Liu et al., 2009)
      ftz-f1 - ftz
      nuclear magnetic resonance, predetermined participant, two hybrid, far western blotting, autoradiography, electrophoretic mobility shift assay, isothermal titration calorimetry, surface plasmon resonance, pull down, western blot, x-ray crystallography, anti bait coimmunoprecipitation
      (Daffern et al., 2018, Yoo et al., 2011, Liu et al., 2009, Schwartz et al., 2001, Suzuki et al., 2001, Yussa et al., 2001, Yu et al., 1999, Guichet et al., 1997, Yu et al., 1997)
      ftz-f1 - gce
      nuclear magnetic resonance, anti tag coimmunoprecipitation, anti tag western blot, two hybrid, pull down, western blot
      (Kolonko-Adamska et al., 2023, Kolonko et al., 2020, Bernardo and Dubrovsky, 2012, Dubrovsky et al., 2011)
      ftz-f1 - gro
      two hybrid array
      (Shokri et al., 2019)
      ftz-f1 - hkb
      pull down, tag visualisation
      (Kazemian et al., 2013)
      ftz-f1 - Met
      nuclear magnetic resonance, isothermal titration calorimetry, predetermined participant, pull down, western blot, anti tag western blot, two hybrid
      (Kolonko-Adamska et al., 2023, Bernardo and Dubrovsky, 2012, Dubrovsky et al., 2011)
      ftz-f1 - onecut
      two hybrid array
      (Shokri et al., 2019)
      ftz-f1 - Pgk
      anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
      (Rhee et al., 2014)
      ftz-f1 - Rel
      two hybrid array
      (Shokri et al., 2019)
      ftz-f1 - rig
      pull down, autoradiography
      (Gates et al., 2004)
      ftz-f1 - Sumo
      anti tag coimmunoprecipitation, western blot
      (Talamillo et al., 2013)
      ftz-f1 - Tsen34
      anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based
      (Rhee et al., 2014)
      Alleles Reported to Model Human Disease (Disease Ontology) (2 alleles)
      ftz-f1
      Models Based on Experimental Evidence ( 0 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 2 )
      Allele
      Disease
      Interaction
      References
      ftz-f1HMS00019
      ameliorates  Machado-Joseph disease
      modeled by Hsap\ATXN3tr.Q78.UAS.Tag:HA
      (Han et al., 2020)
      ftz-f1JF02738
      ameliorates  cancer
      modeled by Ras85DV12.UAS, scrib1
      (Külshammer et al., 2015)
      Alleles Representing Disease-Implicated Variants
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Related mammalian, viral, bacterial, or synthetic transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Hsap\NR5A1R92W.UAS
      P{UAS-hNR5A1.R92W}
      Hsap\NR5A1UAS.cSa
      P{UAS-hNR5A1.S}
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      ftz-f1RNAi.Sym.UAS
      P{UAS-ftz-f1.RNAi.Sym}
      ftz-f1RNAi.UAS.cSa
      P{UAS-ftz-f1.RNAi.S}
      ftz-f1RNAi.hs.cCa
      P{hs-ftz-f1.RNAi.C}
      ftz-f1GD1450
      P{GD1450}
      w1118; P{GD1450}v2959
      ftz-f1KK108995
      P{KK108995}
      P{KK108995}VIE-260B
      ftz-f1JF02738
      P{TRiP.JF02738}
      y1 v1; P{TRiP.JF02738}attP2
      ftz-f1HMS00019
      P{TRiP.HMS00019}
      y1 v1; P{TRiP.HMS00019}attP2/TM3, Sb1
      ftz-f1RNAi.UAS
      P{UAS-ftz-f1.RNAi}
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      ftz-f1282
      loss of function allele
      Delta2-3 transposase
      w*; ftz-f1282
      ftz-f1ex7
      loss of function allele
      P-element activity
      y1 w67c23; ftz-f1ex7 P{FRT(whs)}2A P{UAS-βftz-f1.B}1.4M/TM3, Sb1
      ftz-f119
      loss of function allele
      w1118; ftz-f119/TM6B, Tb+
      References (6)