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Sex Determination Mechanisms and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 26539

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Special Issue Editors

Dr. Jadwiga Jaruzelska

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Guest Editor

Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479 Poznan, Poland
Interests: sex determination; disorderes of sexual development – DSD; germ cells; posttrancriptional gene regulation – PTGR; RNA-binidng proteins – RBPs; 3’Utranslated region – 3’UTR
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Dr. Kamila Kusz-Zamelczyk

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Guest Editor

Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479 Poznan, Poland
Interests: mechanisms of mammalian sex-determination; genetics of disorders/differences of sexual development (DSD); germ cells development; genetics of infertility

Dr. Silvano Bertelloni

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Guest Editor

Pediatric and Adolescent Endocrinology, Division of Paediatrics, Azienda Ospedaliero Universitaria Pisana, 56126 Pisa, Italy
Interests: disorders/differences of sex development (DSD); children with DSD; testis function; puberty; bone health; hormonal substitutive therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Sex determination is one of the major developmental fate decisions that occur early in embryos by imposing male or female phenotypic sex on the whole individual; this process is critical especially in the context of frequent congenital sex development disorders/differences (DSD). These conditions are linked with several serious health and social problems from sex assignment at birth and trobles in pubertal development to infertility, increased susceptibility to testicular or ovarian cancer and bone health in adulthood. Albeit the molecular basis of DSD is only partially known, the advances in molecular biology permitt day-to-day discovery of new genes regulating sex determination and differentiation. The proposed Special Issue is focused on two main points. The first one is identification of novel genes which are involved in sex development and genomic mutations underlying the various phenotypes. The second point is to uncover roles of these novel genes and their functional relationship in the processes governing human sex development. Endocrynological aspects as well as any other topics related to sex development, DSD and their clinical managent through lifespan are welcome.

Dr. Jadwiga Jaruzelska
Dr. Kamila Kusz-Zamelczyk
Dr. Silvano Bertelloni
Guest Editors

Manuscript Submission Information

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Keywords

sex determination
disorders of sex development
sex ambiguity
gonadal development
endocrinology of sex development

Published Papers (7 papers)

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Research

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16 pages, 1771 KiB

Open AccessArticle

Identification of Small Regions of Overlap from Copy Number Variable Regions in Patients with Hypospadias

by Carter H. Scott and Ina E. Amarillo

Int. J. Mol. Sci. 2022, 23(8), 4246; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084246 - 12 Apr 2022

Cited by 3 | Viewed by 1779

Abstract

Hypospadias is a common form of congenital atypical sex development that is often associated with other congenital comorbidities. Many genes have been associated with the condition, most commonly single sequence variations. Further investigations of recurrent and overlapping copy number variations (CNVs) have resulted in the identification of genes and chromosome regions associated with various conditions, including differences of sex development (DSD). In this retrospective study, we investigated the DECIPHER database, as well as an internal institutional database, to identify small recurrent CNVs among individuals with isolated and syndromic hypospadias. We further investigated these overlapping recurrent CNVs to identify 75 smallest regions of overlap (SROs) on 18 chromosomes. Some of the genes within these SROs may be considered potential candidate genes for the etiology of hypospadias and, occasionally, additional comorbid phenotypes. This study also investigates for the first time additional common phenotypes among individuals with hypospadias and overlapping CNVs. This study provides data that may aid genetic counseling and management of individuals with hypospadias, as well as improve understanding of its underlying genetic etiology and human genital development overall. Full article

(This article belongs to the Special Issue Sex Determination Mechanisms and Disease)

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18 pages, 28566 KiB

Open AccessArticle

Oestrogen Activates the MAP3K1 Cascade and β-Catenin to Promote Granulosa-like Cell Fate in a Human Testis-Derived Cell Line

by Melanie K. Stewart, Pascal Bernard, Ching-Seng Ang, Deidre M. Mattiske and Andrew J. Pask

Int. J. Mol. Sci. 2021, 22(18), 10046; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810046 - 17 Sep 2021

Cited by 1 | Viewed by 1818

Abstract

Sex determination triggers the differentiation of the bi-potential gonad into either an ovary or testis. In non-mammalian vertebrates, the presence or absence of oestrogen dictates gonad differentiation, while in mammals, this mechanism has been supplanted by the testis-determining gene SRY. Exogenous oestrogen can override this genetic trigger to shift somatic cell fate in the gonad towards ovarian developmental pathways by limiting the bioavailability of the key testis factor SOX9 within somatic cells. Our previous work has implicated the MAPK pathway in mediating the rapid cellular response to oestrogen. We performed proteomic and phosphoproteomic analyses to investigate the precise mechanism through which oestrogen impacts these pathways to activate β-catenin—a factor essential for ovarian development. We show that oestrogen can activate β-catenin within 30 min, concomitant with the cytoplasmic retention of SOX9. This occurs through changes to the MAP3K1 cascade, suggesting this pathway is a mechanism through which oestrogen influences gonad somatic cell fate. We demonstrate that oestrogen can promote the shift from SOX9 pro-testis activity to β-catenin pro-ovary activity through activation of MAP3K1. Our findings define a previously unknown mechanism through which oestrogen can promote a switch in gonad somatic cell fate and provided novel insights into the impacts of exogenous oestrogen exposure on the testis. Full article

(This article belongs to the Special Issue Sex Determination Mechanisms and Disease)

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18 pages, 2681 KiB

Open AccessArticle

Identification and Characterization of the Masculinizing Function of the Helicoverpa armigera Masc Gene

by Zhongyuan Deng, Yakun Zhang, Yalu Li, Kaiyuan Huang, Xuewei Chen, Min Zhang, Jinyong Huang, Xinzhi Ni and Xianchun Li

Int. J. Mol. Sci. 2021, 22(16), 8650; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168650 - 11 Aug 2021

Cited by 4 | Viewed by 1942

Abstract

The Masculinizer (Masc) gene has been known to control sex development and dosage compensation in lepidopterans. However, it remains unclear whether its ortholog exists and plays the same roles in distantly related lepidopterans such as Helicoverpa armigera. To address this question, we cloned Masc from H. armigera (HaMasc), which contains all essential functional domains of BmMasc, albeit with less than 30% amino acid sequence identity with BmMasc. Genomic PCR and qPCR analyses showed that HaMasc is a Z chromosome-linked gene since its genomic content in males (ZZ) was two times greater than that in females (ZW). RT-PCR and RT-qPCR analyses revealed that HaMasc expression was sex- and stage-biased, with significantly more transcripts in males and eggs than in females and other stages. Transfection of a mixture of three siRNAs of HaMasc into a male embryonic cell line of H. armigera led to the appearance of female-specific mRNA splicing isoforms of H. armigeradoublesex (Hadsx), a downstream target gene of HaMasc in the H. armigera sex determination pathway. The knockdown of HaMasc, starting from the third instar larvae resulted in a shift of Hadsx splicing from male to female isoforms, smaller male pupa and testes, fewer but larger/longer spermatocytes and sperm bundles, delayed pupation and internal fusion of the testes and follicles. These data demonstrate that HaMasc functions as a masculinizing gene in the H. armigera sex-determination cascade. Full article

(This article belongs to the Special Issue Sex Determination Mechanisms and Disease)

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18 pages, 17659 KiB

Open AccessArticle

Gene Variant of Barrier to Autointegration Factor 2 (Banf2w) Is Concordant with Female Determination in Cichlids

by Arie Yehuda Curzon, Andrey Shirak, Ayana Benet-Perlberg, Alon Naor, Shai Israel Low-Tanne, Haled Sharkawi, Micha Ron and Eyal Seroussi

Int. J. Mol. Sci. 2021, 22(13), 7073; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137073 - 30 Jun 2021

Cited by 7 | Viewed by 2290

Abstract

Oreochromis fishes exhibit variability of sex-determination (SD) genes whose characterization contributes to understanding of the sex differentiation network, and to effective tilapia farming, which requires all-male culture. However, O. niloticus (On) amh is the only master-key regulator (MKR) of SD that has been mapped (XY/XX SD-system on LG23). In O. aureus (Oa), LG3 controls a WZ/ZZ SD-system that has recently been delimited to 9.2 Mbp, with an embedded interval rich with female-specific variation, harboring two paics genes and banf2. Developing genetic markers within this interval and using a hybrid Oa stock that demonstrates no recombination repression in LG3, we mapped the critical SD region to 235 Kbp on the orthologous On physical map (p < 1.5 × 10⁻²⁶). DNA-seq assembly and peak-proportion analysis of variation based on Sanger chromatograms allowed the characterization of copy-number variation (CNV) of banf2. Oa males had three exons capable of encoding 90-amino-acid polypeptides, yet in Oa females, we found an extra copy with an 89-amino-acid polypeptide and three non-conservative amino acid substitutions, designated as banf2w. CNV analysis suggested the existence of two to five copies of banf2 in diploidic Cichlidae. Disrupting the Hardy–Weinberg equilibrium (p < 4.2 × 10⁻³), banf2w was concordant with female determination in Oa and in three cichlids with LG3 WZ/ZZ SD-systems (O. tanganicae, O. hornorum and Pelmatolapia mariae). Furthermore, exclusive RNA-seq expression in Oa females strengthened the candidacy of banf2w as the long-sought LG3 SD MKR. As banf genes mediate nuclear assembly, chromatin organization, gene expression and gonad development, banf2w may play a fundamental role inducing female nucleus formation that is essential for WZ/ZZ SD. Full article

(This article belongs to the Special Issue Sex Determination Mechanisms and Disease)

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18 pages, 857 KiB

Open AccessArticle

Variants of STAR, AMH and ZFPM2/FOG2 May Contribute towards the Broad Phenotype Observed in 46,XY DSD Patients with Heterozygous Variants of NR5A1

by Idoia Martínez de LaPiscina, Rana AA Mahmoud, Kay-Sara Sauter, Isabel Esteva, Milagros Alonso, Ines Costa, Jose Manuel Rial-Rodriguez, Amaia Rodríguez-Estévez, Amaia Vela, Luis Castano and Christa E. Flück

Int. J. Mol. Sci. 2020, 21(22), 8554; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228554 - 13 Nov 2020

Cited by 11 | Viewed by 2356

Abstract

Variants of NR5A1 are often found in individuals with 46,XY disorders of sex development (DSD) and manifest with a very broad spectrum of clinical characteristics and variable sex hormone levels. Such complex phenotypic expression can be due to the inheritance of additional genetic hits in DSD-associated genes that modify sex determination, differentiation and organ function in patients with heterozygous NR5A1 variants. Here we describe the clinical, biochemical and genetic features of a series of seven patients harboring monoallelic variants in the NR5A1 gene. We tested the transactivation activity of novel NR5A1 variants. We additionally included six of these patients in a targeted diagnostic gene panel for DSD and identified a second genetic hit in known DSD-causing genes STAR, AMH and ZFPM2/FOG2 in three individuals. Our study increases the number of NR5A1 variants related to 46,XY DSD and supports the hypothesis that a digenic mode of inheritance may contribute towards the broad spectrum of phenotypes observed in individuals with a heterozygous NR5A1 variation. Full article

(This article belongs to the Special Issue Sex Determination Mechanisms and Disease)

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11 pages, 963 KiB

Open AccessCommunication

The FKBP4 Gene, Encoding a Regulator of the Androgen Receptor Signaling Pathway, Is a Novel Candidate Gene for Androgen Insensitivity Syndrome

by Erkut Ilaslan, Renata Markosyan, Patrick Sproll, Brian J. Stevenson, Malgorzata Sajek, Marcin P. Sajek, Hasmik Hayrapetyan, Tamara Sarkisian, Ludmila Livshits, Serge Nef, Jadwiga Jaruzelska and Kamila Kusz-Zamelczyk

Int. J. Mol. Sci. 2020, 21(21), 8403; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218403 - 09 Nov 2020

Cited by 7 | Viewed by 3161

Abstract

Androgen insensitivity syndrome (AIS), manifesting incomplete virilization in 46,XY individuals, is caused mostly by androgen receptor (AR) gene mutations. Therefore, a search for AR mutations is a routine approach in AIS diagnosis. However, some AIS patients lack AR mutations, which complicates the diagnosis. Here, we describe a patient suffering from partial androgen insensitivity syndrome (PAIS) and lacking AR mutations. The whole exome sequencing of the patient and his family members identified a heterozygous FKBP4 gene mutation, c.956T>C (p.Leu319Pro), inherited from the mother. The gene encodes FKBP prolyl isomerase 4, a positive regulator of the AR signaling pathway. This is the first report describing a FKBP4 gene mutation in association with a human disorder of sexual development (DSD). Importantly, the dysfunction of a homologous gene was previously reported in mice, resulting in a phenotype corresponding to PAIS. Moreover, the Leu319Pro amino acid substitution occurred in a highly conserved position of the FKBP4 region, responsible for interaction with other proteins that are crucial for the AR functional heterocomplex formation and therefore the substitution is predicted to cause the disease. We proposed the FKBP4 gene as a candidate AIS gene and suggest screening that gene for the molecular diagnosis of AIS patients lacking AR gene mutations. Full article

(This article belongs to the Special Issue Sex Determination Mechanisms and Disease)

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Review

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32 pages, 2314 KiB

Open AccessReview

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

by Martin A. Estermann and Craig A. Smith

Int. J. Mol. Sci. 2020, 21(18), 6614; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186614 - 10 Sep 2020

Cited by 17 | Viewed by 11008

Abstract

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. Full article

(This article belongs to the Special Issue Sex Determination Mechanisms and Disease)

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