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Molecular Genetics of Disorders of Sex Development
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Molecular Genetics of Disorders of Sex Development

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

Deadline for manuscript submissions: closed (15 April 2023) | Viewed by 7208

Special Issue Editors

Dr. Silvano Bertelloni

E-Mail Website
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
Prof. Dr. Malgorzata Gabriela Wasniewska

E-Mail Website
Guest Editor
Department of Human Pathology of Adulthood and Childhood, University of Messina, 98124 Messina, Italy
Interests: thyroid pathology in pediatric age; thyroid alterations in genetic syndrome; thyroid cancer in pediatric age; pediatric and adolescent endocrinology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

In the embryo, sex development is a multi-step process that involves a complex network of genetic and hormonal factors. Usually, in the presence of an XY karyotype, the SRY (sex determining region on the Y chromosome) and related gene network promote the formation of a functional testis (sex determination). Then, the hormones produced by the testis guide the development of the male genital phenotype (sex differentiation). In XX foetuses, due to the absence of SRY, the pro-ovarian gene network determines the differentiation of the female gonad and the pro-testis gene downregulation. Since the ovary does not secrete AMH and androgens, female internal and external genitalia develop.

Disorders (or differences) of sex development (DSD) are congenital conditions characterized by the atypical development of genetic, gonadal or phenotypic sex. DSDs include a wide spectrum of conditions mostly due to genetic variants, altered hormonal secretion or abnormal peripheral sensitivity to gonadal hormones, which are all able to change the typical male or female foetal development. Today, the improvement of genetic and endocrinological technologies permits the etiological diagnosis in 50–80% of individuals with DSD. However, an exact diagnosis remains unknown in some patients, in whom variants of uncertain pathogenicity or endocrine data of uncertain significance are found. In addition, rare patients with new or unusual laboratory or clinical findings are observed in practice.

Dr. Silvano Bertelloni
Prof. Dr. Malgorzata Gabriela Wasniewska
Guest Editors

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Keywords

  • disorders of sex development
  • sex determination
  • sex differentiation
  • primordial gonad
  • testis
  • adrenal gland
  • ovary
  • sex steroids
  • adrenal steroids
  • molecular genetics
  • metabolomics
  • tandem mass spectrometry

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Published Papers (3 papers)

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17 pages, 2369 KiB  
Article
The Genotype-Phenotype Correlation in Human 5α-Reductase Type 2 Deficiency: Classified and Analyzed from a SRD5A2 Structural Perspective
by Jieun Seo, Saeam Shin, Sang-woon Kim, Su Jin Kim, Myeongseob Lee, Kyungchul Song, Junghwan Suh, Seung-Tae Lee, Yong Seung Lee, Hyun Wook Chae, Ho-Seong Kim, Jong Rak Choi, Sangwon Han and Ahreum Kwon
Int. J. Mol. Sci. 2023, 24(4), 3297; https://doi.org/10.3390/ijms24043297 - 7 Feb 2023
Cited by 6 | Viewed by 1965
Abstract
The phenotype of the 5α-reductase type 2 deficiency (5αRD2) by the SRD5A2 gene mutation varies, and although there have been many attempts, the genotype-phenotype correlation still has not yet been adequately evaluated. Recently, the crystal structure of the 5α-reductase type 2 isozyme (SRD5A2) [...] Read more.
The phenotype of the 5α-reductase type 2 deficiency (5αRD2) by the SRD5A2 gene mutation varies, and although there have been many attempts, the genotype-phenotype correlation still has not yet been adequately evaluated. Recently, the crystal structure of the 5α-reductase type 2 isozyme (SRD5A2) has been determined. Therefore, the present study retrospectively evaluated the genotype-phenotype correlation from a structural perspective in 19 Korean patients with 5αRD2. Additionally, variants were classified according to structural categories, and phenotypic severity was compared with previously published data. The p.R227Q variant, which belongs to the NADPH-binding residue mutation category, exhibited a more masculine phenotype (higher external masculinization score) than other variants. Furthermore, compound heterozygous mutations with p.R227Q mitigated phenotypic severity. Similarly, other mutations in this category showed mild to moderate phenotypes. Conversely, the variants categorized as structure-destabilizing and small to bulky residue mutations showed moderate to severe phenotypes, and those categorized as catalytic site and helix-breaking mutations exhibited severe phenotypes. Therefore, the SRD5A2 structural approach suggested that a genotype-phenotype correlation does exist in 5αRD2. Furthermore, the categorization of SRD5A2 gene variants according to the SRD5A2 structure facilitates the prediction of the severity of 5αRD2 and the management and genetic counseling of patients affected by it. Full article
(This article belongs to the Special Issue Molecular Genetics of Disorders of Sex Development)
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10 pages, 1177 KiB  
Communication
Disorder of Sex Development Due to 17-Beta-Hydroxysteroid Dehydrogenase Type 3 Deficiency: A Case Report and Review of 70 Different HSD17B3 Mutations Reported in 239 Patients
by Catarina I. Gonçalves, Josianne Carriço, Margarida Bastos and Manuel C. Lemos
Int. J. Mol. Sci. 2022, 23(17), 10026; https://doi.org/10.3390/ijms231710026 - 2 Sep 2022
Cited by 9 | Viewed by 2657
Abstract
The 17-beta-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) enzyme converts androstenedione to testosterone and is encoded by the HSD17B3 gene. Homozygous or compound heterozygous HSD17B3 mutations block the synthesis of testosterone in the fetal testis, resulting in a Disorder of Sex Development (DSD). We describe [...] Read more.
The 17-beta-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) enzyme converts androstenedione to testosterone and is encoded by the HSD17B3 gene. Homozygous or compound heterozygous HSD17B3 mutations block the synthesis of testosterone in the fetal testis, resulting in a Disorder of Sex Development (DSD). We describe a child raised as a female in whom the discovery of testes in the inguinal canals led to a genetic study by whole exome sequencing (WES) and to the identification of a compound heterozygous mutation of the HSD17B3 gene (c.608C>T, p.Ala203Val, and c.645A>T, p.Glu215Asp). Furthermore, we review all HSD17B3 mutations published so far in cases of 17-β-HSD3 deficiency. A total of 70 different HSD17B3 mutations have so far been reported in 239 patients from 187 families. A total of 118 families had homozygous mutations, 63 had compound heterozygous mutations and six had undetermined genotypes. Mutations occurred in all 11 exons and were missense (55%), splice-site (29%), small deletions and insertions (7%), nonsense (5%), and multiple exon deletions and duplications (2%). Several mutations were recurrent and missense mutations at codon 80 and the splice-site mutation c.277+4A>T each represented 17% of all mutated alleles. These findings may be useful to those involved in the clinical management and genetic diagnosis of this disorder. Full article
(This article belongs to the Special Issue Molecular Genetics of Disorders of Sex Development)
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Other

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6 pages, 1218 KiB  
Case Report
A Novel Look at Dosage-Sensitive Sex Locus Xp21.2 in a Case of 46,XY Partial Gonadal Dysgenesis without NR0B1 Duplication
by Ana Paula Francese-Santos, Jakob A. Meinel, Cristiane S. C. Piveta, Juliana G. R. Andrade, Beatriz A. Barros, Helena Fabbri-Scallet, Vera Lúcia Gil-da-Silva-Lopes, Gil Guerra-Junior, Axel Künstner, Hauke Busch, Olaf Hiort, Maricilda P. de Mello, Ralf Werner and Andréa T. Maciel-Guerra
Int. J. Mol. Sci. 2023, 24(1), 494; https://doi.org/10.3390/ijms24010494 - 28 Dec 2022
Cited by 4 | Viewed by 1882
Abstract
A region of 160 kb at Xp21.2 has been defined as dosage-sensitive sex reversal (DSS) and includes the NR0B1 gene, considered to be the candidate gene involved in XY gonadal dysgenesis if overexpressed. We describe a girl with 46,XY partial gonadal dysgenesis carrying [...] Read more.
A region of 160 kb at Xp21.2 has been defined as dosage-sensitive sex reversal (DSS) and includes the NR0B1 gene, considered to be the candidate gene involved in XY gonadal dysgenesis if overexpressed. We describe a girl with 46,XY partial gonadal dysgenesis carrying a 297 kb duplication at Xp21.2 upstream of NR0B1 initially detected by chromosomal microarray analysis. Fine mapping of the breakpoints by whole-genome sequencing showed a tandem duplication of TASL (CXorf21), GK and partially TAB3, upstream of NR0B1. This is the first description of an Xp21.2 duplication upstream of NR0B1 associated with 46,XY partial gonadal dysgenesis. Full article
(This article belongs to the Special Issue Molecular Genetics of Disorders of Sex Development)
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