Methylation Patterns of &lt;b&gt;&lt;i&gt;SOX3, SOX9&lt;/i&gt;&lt;/b&gt;, and &lt;b&gt;&lt;i&gt;WNT4&lt;/i&gt;&lt;/b&gt; Genes in Gonads of Dogs with XX (&lt;b&gt;&lt;i&gt;SRY&lt;/i&gt;&lt;/b&gt;-Negative) Disorder of Sexual Development

Salamon, Sylwia; Flisikowski, Krzysztof; Świtoński, M.

doi:10.1159/000466712

Cited by 7 publications

(6 citation statements)

References 43 publications

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“…Recently, significantly higher methylation of SOX3 gene [30] has been reported in both the ovotesticular and the testicular canine XX DSD. In mice, it has been shown that SOX3 can replace SRY and drive the differentiating gonad towards a female fate [63].…”

Section: Gain Of Function Of Sox9mentioning

confidence: 99%

“…Besides, as such loss of function would also enhance testosterone synthesis, the increased secretion of androgens could explain the partial masculinization of genital ducts, and the development of epididymides and deferens ducts in XX;SRY-negative individuals [67]. Studies on the methylation of WNT4 gene showed that methylation was similar in XX DSD and control dogs [30], suggesting that this may not be an adequate candidate gene for the XX DSD syndrome in dogs. Still, a decreased transcription of WNT4 was reported in XX DSD embryos using a genome wide association study and whole genome sequencing [13].…”

Section: Loss Of Function Of Wnt4/rspon1/-catenin and Foxl2 Pathwaysmentioning

confidence: 99%

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Disturbed Ovarian Differentiation in XX;SRY-Negative Dogs

Payan-Carreira¹

2018

obm genet

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In a mammal, at the beginning of its development, the gonad is bipotential. The shift into a male or female pathway is coordinated by the sex chromosomal complement, which triggers a series of genetic pathways signaling the developmental pattern of the gonadal anlage. Being mutually exclusive, the differentiated gonad should be either a testis or an ovary. In females, the absence of SRY, a testis-determining gene, drives the signaling cascades controlling the ovarian differentiation. Albeit rare, disorders of the gonadal differentiation may occur in men and domestic animals and may cause infertility or sterility. In dogs, the XX;SRY-negative disorder of sexual development (DSD) is the most frequent condition. The disorder typically presents a wide spectrum of developmental conditions of the gonad and variable virilization of the genital phenotype, that may be accompanied by hypospadias. This condition may be inherited as a sex-limited autosomal recessive trait; however, the mechanism explaining its occurrence remains poorly understood. This review intends to present an overview of the morphologic features of XX;SRY-negative syndrome in dogs, while addressing the current knowledge regarding the genetic mechanism underlying this condition.

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Section: Gain Of Function Of Sox9mentioning

confidence: 99%

Section: Loss Of Function Of Wnt4/rspon1/-catenin and Foxl2 Pathwaysmentioning

confidence: 99%

Disturbed Ovarian Differentiation in XX;SRY-Negative Dogs

Payan-Carreira¹

2018

obm genet

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“…Although until today, the molecular background of XX DSD (78, XX; SRY-negative) is not fully recognized, it is assumed to be linked to the copy number variation (CNV) in the region harbouring the SOX9 gene. Rossi et al (2014) and Switonski (2017) showed that methylation of SOX3 promoter region may play a role in canine XX DSD pathogenesis. As reported by Gonen et al (2018), the regulatory region of SOX9 is complex and that a single far-upstream 557-base pair element (Enhancer 13; Enh 13) is critical for up-regulating SOX9.…”

Section: Sequencing Resultsmentioning

confidence: 99%

“…The authors identified significant RSPO1 down‐regulation in embryonic gonads at risk of canine XX DSD, without significant up‐regulation of SOX9 or other known testis pathway genes supposing that molecular lesions acting upstream of RSPO1 induce epigenomic gonadal mosaicism. The results of Salamon, Flisikowski, and Switonski () showed that methylation of SOX3 promoter region may play a role in canine XX DSD pathogenesis. As reported by Gonen et al (), the regulatory region of SOX9 is complex and that a single far‐upstream 557‐base pair element (Enhancer 13; Enh 13) is critical for up‐regulating SOX9 .…”

Section: Discussionmentioning

confidence: 99%

A comprehensive study of disorder of sex development in Staffordshire bull terrier dog

Horňáková

Dianovský

Holečková

et al. 2019

Reprod Domestic Animals

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An 8‐month‐old female Staffordshire bull terrier was clinically examined because of external sexual organs abnormality—clitoral hypertrophy. As stated by the owner, the female dog had not been in heat yet. Serum profile of testosterone (3.39 ng/ml), as well as an anti‐Műllerian hormone (24.0 ng/ml), suggested the presence of testicular tissue. On the contrary, the estimated level of 17β‐oestradiol (24.6 pg/ml) was approximately two times higher when compared with the normal anoestrus values (5–10 pg/ml). A midline laparotomy was performed to detect the cranial parts of the genital system. Gonads resembling testicle or ovotestis (left) and hypoplastic testicle (right) was visible. Cranial portion of gonads was attached to structures indicative of bilateral epididymidis. The next tubular structures—oviducts were resected along with adherent parts of a hypoplastic uterus. Histological evaluation confirmed that the examined gonad samples were testicles with modified interstitial testicular tissue. Hypertrophy of interstitial space was predominantly formed by Leydig cells. Examination of a cross‐section through the head of suspected epididymidis confirmed their characteristic structures. In addition, the characteristic configuration of the oviducts was presented. The uterus consisted of three walls, in which the endometrium was hypoplastic with the presence of endometrial glands. No Y chromosome was detected by chromosomal analysis using CFA Y probe and the amplification of SRY‐gene coding region (813 bp) indicated genotype 78, XX; SRY‐negative. Sequencing of SOX9 gene exons 1–3 did not reveal any differences in exon 1 and 3. On the contrary, a few changes were determined in the SOX9 exon 2 sequences: G instead of A at position 103; C instead of reference T at position 115; GCG instead of reference CGC at position 138–140; T instead of reference C at positions 161, 164 and 167.

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“…Persistent abnormal hypermethylation of the Sry gene (resulting in down-regulated mRNA and protein expression) was established as the cause of ovotestis and female phenotype in cloned Sry-positive XY dogs generated through somatic cell nuclear transfer (Jeong et al, 2016). In another example involving XX DSD dogs with ovotestis or testis phenotype, candidate gene promoter methylation bisulfite sequencing revealed hypomethylation in Sox9, hypermethylation in Wnt4 and hypermethylation of the Sox3 promoter at levels similar to that of control XY male dogs (Salamon et al, 2017). Both these examples show that epigenetic promoter methylation of important sex determination genes can be determinants of DSD in mammals.…”

Section: Epigeneticsmentioning

confidence: 99%

Translating genomics to the clinical diagnosis of disorders/differences of sex development

Parivesh

Barseghyan

Délot

et al. 2019

Current Topics in Developmental Biology

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The medical and psychosocial challenges faced by patients living with Disorders/Differences of Sex Development (DSD) and their families can be alleviated by a rapid and accurate diagnostic process. Clinical diagnosis of DSD is limited by a lack of standardization of anatomical and endocrine phenotyping and genetic testing, as well as poor genotype/phenotype correlation. Historically, DSD genes have been identified through positional cloning of disease-associated variants segregating in families and validation of candidates in animal and in vitro modeling of variant pathogenicity. Owing to the complexity of conditions grouped under DSD, genome-wide scanning methods are better suited for identifying disease causing gene variant(s) and providing a clinical diagnosis. Here, we review a number of established genomic tools (karyotyping, chromosomal microarrays and exome sequencing) used in clinic for DSD diagnosis, as well as emerging genomic technologies such as whole-genome (short-read) sequencing, long-read sequencing, and optical mapping used for novel DSD gene discovery. These, together with gene expression and epigenetic studies can potentiate the clinical diagnosis of DSD diagnostic rates and enhance the outcomes for patients and families.

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Methylation Patterns of <b><i>SOX3, SOX9</i></b>, and <b><i>WNT4</i></b> Genes in Gonads of Dogs with XX (<b><i>SRY</i></b>-Negative) Disorder of Sexual Development

Cited by 7 publications

References 43 publications

Disturbed Ovarian Differentiation in XX;SRY-Negative Dogs

Disturbed Ovarian Differentiation in XX;SRY-Negative Dogs

A comprehensive study of disorder of sex development in Staffordshire bull terrier dog

Translating genomics to the clinical diagnosis of disorders/differences of sex development

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