Recent findings on the genetics of disorders of sex development

Kremen, Jessica; Chan, Yee-Ming; Swartz, Jonathan M.

doi:10.1097/mou.0000000000000353

Cited by 11 publications

(16 citation statements)

References 38 publications

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“…New genetic and genomic technologies such as array-comparative genomic hybridization (aCGH) and whole-exome sequencing revealed new causes of DSD and expanded our knowledge in the molecular mechanisms underlying gonadal development. However, the genetic etiology remains unidentified in the majority of DSD cases (3,4).…”

Section: Introductionmentioning

confidence: 99%

PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans

Güran

Yeşil²,

Turan

et al. 2019

European Journal of Endocrinology

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Context Most of the knowledge on the factors involved in human sexual development stems from studies of rare cases with disorders of sex development. Here, we have described a novel 46, XY complete gonadal dysgenesis syndrome caused by homozygous variants in PPP2R3C gene. This gene encodes B″gamma regulatory subunit of the protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase involved in the phospho-regulation processes of most mammalian cell types. PPP2R3C gene is most abundantly expressed in testis in humans, while its function was hitherto unknown. Patients and methods Four girls from four unrelated families with 46, XY complete gonadal dysgenesis were studied using exome or Sanger sequencing of PPP2R3C gene. In total, four patients and their heterozygous parents were investigated for clinical, laboratory, immunohistochemical and molecular characteristics. Results We have identified three different homozygous PPP2R3C variants, c.308T>C (p.L103P), c.578T>C (p.L193S) and c.1049T>C (p.F350S), in four girls with 46, XY complete gonadal dysgenesis. Patients also manifested a unique syndrome of extragonadal anomalies, including typical facial gestalt, low birth weight, myopathy, rod and cone dystrophy, anal atresia, omphalocele, sensorineural hearing loss, dry and scaly skin, skeletal abnormalities, renal agenesis and neuromotor delay. We have shown a decreased SOX9-Phospho protein expression in the dysgenetic gonads of the patients with homozygous PPP2R3C variants suggesting impaired SOX9 signaling in the pathogenesis of gonadal dysgenesis. Heterozygous males presented with abnormal sperm morphology and impaired fertility. Conclusion Our findings suggest that PPP2R3C protein is involved in the ontogeny of multiple organs, especially critical for testis development and spermatogenesis. PPPR3C provides insight into pathophysiology, as well as emerging as a potential therapeutic target for male infertility.

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Section: Introductionmentioning

confidence: 99%

PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans

Güran

Yeşil²,

Turan

et al. 2019

European Journal of Endocrinology

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“…To date, the combination of 78 XX (SRY‐negative) DSD, iEU and urinary incontinence have never been described in dogs although the embryologic development of urinary system and the genital system are intimately interwoven 1 . DSD represent a heterogeneous group of congenital conditions in which development of chromosomal, gonadal or anatomic sex is atypical 12 . The cytogenetic analysis from this dog, based on 98 observed metaphases, revealed a normal 78, XX karyotype.…”

Section: Discussionmentioning

confidence: 88%

Minimally invasive treatment of an intramural monolateral ectopic urether in a French bulldog with 78, XX (SRY‐negative) ovotesticular disorder of sexual development

Ferriani¹,

Moyano²,

Verde³

et al. 2021

Vet Record Case Reports

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A one‐year‐old phenotypically female French Bulldog was referred for urinary incontinence. Physical examination disclosed the presence of hypertrophic clitoris. Computer tomography highlighted the presence of a left intramural ectopic ureter, in presence of a fully constituted female reproductive tract. Retrograde cystoscopy confirmed the presence of the ectopic ureter that was treated with cystoscopic‐guided laser ablation although incontinence persisted. Ovariohysterectomy and clitoridectomy were performed and histopathology of gonads was consistent with ovotestis. The subject's karyotype was defined as XX SRY‐negative and the case was diagnosed with a 78 XX (SRY‐negative) disorder of sexual development. A treatment with phenylpropanolamine led to the resolution of the incontinence. The association of such disorder with ectopic ureter and urinary incontinence has never been reported in dogs. Our findings suggest that the displacement of the ureter might be related to an incorrect secretion of sexual hormones in fetal life due to the presence of ovotestis.

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“…Approximately 45% of 46,XY DSD at the gonadal level can be attributed to loss-of-function mutations in the testis-inducing genes, SRY [ 3 , 44 ], SOX9 [ 45 , 46 ] or upstream regulators of SRY , such as SF1, GATA4 and MAPK [ 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. However, around 55% of 46,XY DSD as the gonadal level cannot be explained by mutations in known genes [ 48 , 54 ]. The 46,XY DSDs are highly associated with the incidence of gonadal tumors and infertility [ 55 ].…”

Section: Disorders Of Sex Developmentmentioning

confidence: 99%

Applying Single-Cell Analysis to Gonadogenesis and DSDs (Disorders/Differences of Sex Development)

Estermann

Smith

2020

IJMS

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The gonads are unique among the body’s organs in having a developmental choice: testis or ovary formation. Gonadal sex differentiation involves common progenitor cells that form either Sertoli and Leydig cells in the testis or granulosa and thecal cells in the ovary. Single-cell analysis is now shedding new light on how these cell lineages are specified and how they interact with the germline. Such studies are also providing new information on gonadal maturation, ageing and the somatic-germ cell niche. Furthermore, they have the potential to improve our understanding and diagnosis of Disorders/Differences of Sex Development (DSDs). DSDs occur when chromosomal, gonadal or anatomical sex are atypical. Despite major advances in recent years, most cases of DSD still cannot be explained at the molecular level. This presents a major pediatric concern. The emergence of single-cell genomics and transcriptomics now presents a novel avenue for DSD analysis, for both diagnosis and for understanding the molecular genetic etiology. Such -omics datasets have the potential to enhance our understanding of the cellular origins and pathogenesis of DSDs, as well as infertility and gonadal diseases such as cancer.

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Recent findings on the genetics of disorders of sex development

Cited by 11 publications

References 38 publications

PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans

PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans

Minimally invasive treatment of an intramural monolateral ectopic urether in a French bulldog with 78, XX (SRY‐negative) ovotesticular disorder of sexual development

Applying Single-Cell Analysis to Gonadogenesis and DSDs (Disorders/Differences of Sex Development)

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