A Case of Two Sisters Suffering from 46,XY Gonadal Dysgenesis and Carrying a Mutation of a Novel Candidate Sex-Determining Gene &lt;b&gt;&lt;i&gt;STARD8&lt;/i&gt;&lt;/b&gt; on the X Chromosome

Ilaslan, Erkut; Nowak, D.; Szarras‐Czapnik, Maria; Słowikowska-Hilczer, Jolanta; Spik, Anna; Sararols, Pauline; Nef, Serge; Jaruzelska, Jadwiga; Kusz-Zamelczyk, Kamila

doi:10.1159/000489692

Cited by 13 publications

(18 citation statements)

References 13 publications

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“…The mutation was present in the heterozygous carrier mother (Fig. 1 A ) and in the two 46,XY dysgenic patients but not in their 46,XY healthy sibling (Ilaslan et al ., 2018). However, despite this strong correlation, no direct evidence linking DLC3 to gonadal dysgenesis was provided.…”

Section: Resultsmentioning

confidence: 97%

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DLC3/Cv-c function in testis development in humans and Drosophila: implication for variants of sex development

Sotillos

Decken

Mercadé

et al. 2022

Preprint

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Identifying genes affecting gonad development is essential to understand the mechanisms causing Variants/Differences in Sex Development. Recently, a DLC3 mutation was associated with male gonadal dysgenesis in 46,XY DSD patients. We show that Cv-c, the Drosophila ortholog of DLC3, is also required to maintain testis integrity during fly development. We found that Cv-c and human DLC3 can perform the same function in fly embryos, as flies with wild type but not mutated DLC3 rescue gonadal dysgenesis, suggesting a functional conservation. Expression of different Cv-c protein variants demonstrated that the StART domain mediates the Cv-c function in the male gonad, independently from the GAP domain activity. This work demonstrates a role for DLC3/Cv-c in male gonadogenesis and highlights a novel StART-mediated function required for gonadal mesoderm-germ cell interaction during testis development.

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Section: Resultsmentioning

confidence: 97%

“…Recently, the human X-linked DLC3 human gene (also known as STARD8 ) has been implicated in a case of 46,XY gonadal dysgenesis in two patients carrying a variant in the StART domain (Ilaslan et al , 2018). The Deleted in Liver Cancer (DLC) proteins belong to the RhoGAP family of small GTPase regulators.…”

Section: Introductionmentioning

confidence: 99%

DLC3/Cv-c function in testis development in humans and Drosophila: implication for variants of sex development

Sotillos

Decken

Mercadé

et al. 2022

Preprint

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“…Swyer syndrome is a relatively uncommon condition, and only few familial cases have been reported. [245] It can be inherited as Y-linked, X-linked, and autosomal dominant or recessive disorder. [6] The most commonly accepted mechanism is that a protein produced by sex-determining region Y (SRY) gene present on Y chromosome is responsible for differentiation of primitive gonad into testes.…”

Section: Discussionmentioning

confidence: 99%

“…[7] In other cases, role of genes located on autosomes or X chromosome which affects sex differentiation has been suggested. [4]…”

Section: Discussionmentioning

confidence: 99%

A rare case of swyer syndrome in two sisters with successful pregnancy outcome in both

Gupta¹,

Bajaj²,

Jindal³

2019

J Hum Reprod Sci

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Swyer syndrome is a disorder of sex development characterized by gonadal dysgenesis in a phenotypic female with normally developed Mullerian structures but a 46XY karyotype resulting from failure of testicular development in the early embryogenesis. It can have X-linked, Y-linked, or autosomal inheritance. We had a case of two sisters who presented with primary amenorrhea and primary infertility. On investigation, both had hypergonadotropic hypogonadism, 46XY karyotype, and streak gonads. They conceived following in vitro fertilization (IVF) with ovum donation. Prophylactic gonadectomy has been done in one and advised in other due to the increased risk of gonadoblastoma which is as high as 15%–35%. Such patients should be counseled that despite hypoplastic uterus, successful pregnancy can be achieved through IVF and ovum donation.

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“…Recently, the human X-linked DLC3 gene (also known as STARD8 ) has been implicated in a case of 46,XY gonadal dysgenesis in two patients carrying a variant in the StART domain ( Ilaslan et al, 2018 ). The Deleted in Liver Cancer (DLC) proteins belong to the RhoGAP family of small GTPase regulators.…”

Section: Introductionmentioning

confidence: 99%

A conserved function of Human DLC3 and Drosophila Cv-c in testis development

Sotillos

Decken

Mercadé

et al. 2022

eLife

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Background: The identification of genes affecting gonad development is essential to understand the mechanisms causing Variations/Differences in Sex Development. Recently, a DLC3 mutation was associated with male gonadal dysgenesis in 46,XY DSD patients.Methods: We have studied the requirement of cv-c, the Drosophila ortholog of DLC3, for Drosophila gonad development as well as the functional capacity of DLC3 human variants to rescue cv-c gonad defects. We show that Cv-c is required to maintain testis integrity during fly development.Results: We find that Cv-c and human DLC3 can perform the same function in fly embryos, as flies carrying wild type but not patient DLC3 variations can rescue gonadal dysgenesis, suggesting a functional conservation. Expression of different Cv-c protein variants demonstrate that the StART domain mediates Cv-c's function in the male gonad independently from the GAP domain's activity.Conclusions: This work demonstrates a role for DLC3/Cv-c in male gonadogenesis and highlights a novel StART domain mediated function required to organize the gonadal mesoderm and maintain its interaction with the germ cells during testis development.Funding: María de Maeztu Unit excellence grants MDM-2016-0687 and CEX-2020-001088-M. Ministerio de Ciencia e Innovación grant PID2019-104656GB-I00 cofunded by the European Regional Development Fund (FEDER). Swiss National Science Foundation (PP00P3_194807). Swiss National Supercomputing Centre under project ID s1132. European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement no. 803952). Swiss National Science Foundation's Grant 320030-184807.Swiss National Science Foundation (grant number SCOPES IZ73Z0_152347/1) and National Academy of Sciences of Ukraine, project 'Molecular-Genetic Mechanisms of Human Disorders of Sexual Development' [0121U110054].

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A Case of Two Sisters Suffering from 46,XY Gonadal Dysgenesis and Carrying a Mutation of a Novel Candidate Sex-Determining Gene <b><i>STARD8</i></b> on the X Chromosome

Cited by 13 publications

References 13 publications

DLC3/Cv-c function in testis development in humans and Drosophila: implication for variants of sex development

DLC3/Cv-c function in testis development in humans and Drosophila: implication for variants of sex development

A rare case of swyer syndrome in two sisters with successful pregnancy outcome in both

A conserved function of Human DLC3 and Drosophila Cv-c in testis development

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