Failure of SOX9 Regulation in 46XY Disorders of Sex Development with SRY, SOX9 and SF1 Mutations

Knower, Kevin Christopher; Kelly, Sabine; Ludbrook, Louisa Mabel; Bagheri‐Fam, Stefan; Sim, Helena; Bernard, Pascal; Sekido, Ryohei; Lovell-Badge, Robin; Harley, Vincent R.

doi:10.1371/journal.pone.0017751

Cited by 65 publications

(71 citation statements)

References 78 publications

(111 reference statements)

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“…The AR gene mutation database summarized 800 types of cases in which AR mutations led to AIS, and reported research on 45 kinds of gene mutations and phenotypes (Knower et al, 2011). Mutation loci p.R841L, p.R856H, p.A871V and p.V890M, which were reported before, were also found in this study; in addition, it was reported that p.R841L could lead to PAIS.…”

Section: Discussionsupporting

confidence: 71%

Correlation of androgen receptor and SRD5A2 gene mutations with pediatric hypospadias in 46, XY DSD children

Zhang

2016

Genet. Mol. Res.

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ABSTRACT. We performed an exploratory study by analyzing the correlation of 46, XY disorders of sex development (46, XY DSD) with androgen receptor (AR) and steroid 5α-reductase-2 (SRD5A2) gene mutations and a safety analysis of dihydrotestosterone (DHT) gel treatment for pediatric micropenis. We collected samples from 76 pediatric patients with 46, XY DSD and 50 healthy adult men with normal fertility as the control group. The pediatric patients were treated with DHT gel (0.1-0.3 mg/kg/day) for three to six months. The extended penis length, testicular volume, and multiple blood parameters were collected before treatment and one, three, and six months after treatment. Of the 76 cases with 46, XY DSD, 31.58% had hypospadias with micropenis and 6.58% had male pseudohermaphroditism. Through AR gene screening, it was found that 14 patients had AR point mutations and 22 patients had SRD5A2 mutations. After treatment with DHT, the penis length of the patients significantly improved after one, three, and six months of treatment, with longer treatment times resulting in greater improvement. Before treatment with DHT, the average serum DHT value of patients with 46, XY DSD was 24.29 pg/mL. After one, three, and six months of treatment, this value increased to 430.71, 328.9, and 323.6 pg/mL, respectively. We conclude that for pediatric patients who have male hermaphroditism or hypospadias with micropenis, AR and SRD5A2 gene mutation detection should be performed. Local application of DHT gel can promote penis growth effectively without systemic adverse reactions.

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Section: Discussionsupporting

confidence: 71%

Correlation of androgen receptor and SRD5A2 gene mutations with pediatric hypospadias in 46, XY DSD children

Zhang

2016

Genet. Mol. Res.

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“…Inset shows the orientation of the R103 side chain, with the positive charge adjacent to the negatively charged DNA backbone. distinguishable in a previous study conducted with the human TES (hTES) element, most probably because SRY alone is sufficient for hTES activation (21).…”

Section: Resultsmentioning

confidence: 61%

Testicular differentiation factor SF-1 is required for human spleen development

Zangen¹,

Kaufman²,

Banne³

et al. 2014

J. Clin. Invest.

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The transcription factor steroidogenic factor 1 (SF-1; also known as NR5A1) is a crucial mediator of both steroidogenic and nonsteroidogenic tissue differentiation. Mutations within SF1 underlie different disorders of sexual development (DSD), including sex reversal, spermatogenic failure, ovarian insufficiency, and adrenocortical deficiency. Here, we identified a recessive mutation within SF1 that resulted in a substitution of arginine to glutamine at codon 103 (R103Q) in a child with both severe 46,XY-DSD and asplenia. The R103Q mutation decreased SF-1 transactivation of TLX1, a transcription factor that has been shown to be essential for murine spleen development. Additionally, the SF1 R103Q mutation impaired activation of steroidogenic genes, without affecting synergistic SF-1 and sex-determining region Y (SRY) coactivation of the testis development gene SOX9. Together, our data provide evidence that SF-1 is required for spleen development in humans via transactivation of TLX1 and that mutations that only impair steroidogenesis, without altering the SF1/SRY transactivation of SOX9, can lead to 46,XY-DSD.

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“…S5). The contribution of the murine glutaminerich domain to testicular differentiation in vivo (20) and to the gene regulatory activity of mSry in cell culture (present results) may resolve an apparent paradox posed by Swyer's mutations in hSRY that (akin to WT mSry) are proposed to impair its nuclear export (21).…”

Section: Discussionmentioning

confidence: 60%

“…Our previous study exploited this line as a model of the differentiating gonadal ridge (30). Impaired coupling is associated with an inherited form of Swyer's syndrome [(46), XY pure gonadal dysgenesis (49)] due to variable effects on hSRY-directed Sox9 expression (21).…”

Section: Discussionmentioning

confidence: 99%

“…Our investigation of mSry builds on studies of inherited mutations in hSRY at a functional threshold of gonadogenesis (6,21). Whereas glutamine-rich domains in other transcription factors flank conserved DNA-binding motifs without change in mutational clocks (22), the HMG boxes of mSry and its orthologs in Muroidea exhibit greater sequence variation (with respect to both synonymous and nonsynonymous base substitutions) than do Sry boxes in other mammalian orders (23,24).…”

mentioning

confidence: 99%

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Microsatellite-encoded domain in rodent Sry functions as a genetic capacitor to enable the rapid evolution of biological novelty

Chen¹,

Racca²,

Sequeira³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The male program of therian mammals is determined by Sry, a transcription factor encoded by the Y chromosome. Specific DNA binding is mediated by a high mobility group (HMG) box. Expression of Sry in the gonadal ridge activates a Sox9-dependent gene regulatory network leading to testis formation. A subset of Sry alleles in superfamily Muroidea (order Rodentia) is remarkable for insertion of an unstable DNA microsatellite, most commonly encoding (as in mice) a CAG repeat-associated glutamine-rich domain. We provide evidence, based on an embryonic pre-Sertoli cell line, that this domain functions at a threshold length as a genetic capacitor to facilitate accumulation of variation elsewhere in the protein, including the HMG box. The glutamine-rich domain compensates for otherwise deleterious substitutions in the box and absence of nonbox phosphorylation sites to ensure occupancy of DNA target sites. Such compensation enables activation of a male transcriptional program despite perturbations to the box. Whereas human SRY requires nucleocytoplasmic shuttling and coupled phosphorylation, mouse Sry contains a defective nuclear export signal analogous to a variant human SRY associated with inherited sex reversal. We propose that the rodent glutamine-rich domain has (i) fostered accumulation of cryptic intragenic variation and (ii) enabled unmasking of such variation due to DNA replicative slippage. This model highlights genomic contingency as a source of protein novelty at the edge of developmental ambiguity and may underlie emergence of nonSry-dependent sex determination in the radiation of Muroidea.nucleocytoplasmic trafficking | protein-DNA recognition | sexual dimorphism | transcriptional activation | triplet expansion

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Failure of SOX9 Regulation in 46XY Disorders of Sex Development with SRY, SOX9 and SF1 Mutations

Cited by 65 publications

References 78 publications

Correlation of androgen receptor and SRD5A2 gene mutations with pediatric hypospadias in 46, XY DSD children

Correlation of androgen receptor and SRD5A2 gene mutations with pediatric hypospadias in 46, XY DSD children

Testicular differentiation factor SF-1 is required for human spleen development

Microsatellite-encoded domain in rodent Sry functions as a genetic capacitor to enable the rapid evolution of biological novelty

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