Broad Phenotypes of Disorders/Differences of Sex Development in  MAMLD1  Patients Through Oligogenic Disease

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Abstract

Disorders/differences of sex development (DSD) are the result of a discordance between chromosomal, gonadal, and genital sex. DSD may be due to mutations in any of the genes involved in sex determination and development in general, as well as gonadal and/or genital development specifically. MAMLD1 is one of the recognized DSD genes. However, its role is controversial as some MAMLD1 variants are present in normal individuals, several MAMLD1 mutations have wild-type activity in functional studies, and the Mamld1-knockout male mouse presents with normal genitalia and reproduction. We previously tested nine MAMLD1 variants detected in nine 46,XY DSD patients with broad phenotypes for their functional activity, but none of the mutants, except truncated L210X, had diminished transcriptional activity on known target promoters CYP17A1 and HES3. In addition, protein expression of MAMLD1 variants was similar to wild-type, except for the truncated L210X. We hypothesized that MAMLD1 variants may not be sufficient to explain the phenotype in 46,XY DSD individuals, and that further genetic studies should be performed to search for additional hits explaining the broad phenotypes. We therefore performed whole exome sequencing (WES) in seven of these 46,XY patients with DSD and in one 46,XX patient with ovarian insufficiency, who all carried MAMLD1 variants. WES data were filtered by an algorithm including disease-tailored lists of MAMLD1-related and DSD-related genes. Fifty-five potentially deleterious variants in 41 genes were identified; 16/55 variants were reported in genes in association with hypospadias, 8/55 with cryptorchidism, 5/55 with micropenis, and 13/55 were described in relation with female sex development. Patients carried 1-16 variants in 1-16 genes together with their MAMLD1 variation. Network analysis of the identified genes revealed that 23 genes presented gene/protein interactions with MAMLD1. Thus, our study shows that the broad phenotypes of individual DSD might involve multiple genetic variations contributing towards the complex network of sexual development.

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Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system.

Thomas Carroll, Joo-Seop Park, Shigemi Hayashi … (2005)

The vertebrate urogenital system forms due to inductive interactions between the Wolffian duct, its derivative the ureteric bud, and their adjacent mesenchymes. These establish epithelial primordia within the mesonephric (embryonic) and metanephric (adult) kidneys and the Müllerian duct, the anlage of much of the female reproductive tract. We show that Wnt9b is expressed in the inductive epithelia and is essential for the development of mesonephric and metanephric tubules and caudal extension of the Müllerian duct. Wnt9b is required for the earliest inductive response in metanephric mesenchyme. Further, Wnt9b-expressing cells can functionally substitute for the ureteric bud in these interactions. Wnt9b acts upstream of another Wnt, Wnt4, in this process, and our data implicate canonical Wnt signaling as one of the major pathways in the organization of the mammalian urogenital system. Together these findings suggest that Wnt9b is a common organizing signal regulating diverse components of the mammalian urogenital system.

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PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.

Bruce Gelb, Christopher A. Patton, Dan L Musat … (2002)

Noonan syndrome (NS) is a developmental disorder characterized by facial dysmorphia, short stature, cardiac defects, and skeletal malformations. We recently demonstrated that mutations in PTPN11, the gene encoding the non-receptor-type protein tyrosine phosphatase SHP-2 (src homology region 2-domain phosphatase-2), cause NS, accounting for approximately 50% of cases of this genetically heterogeneous disorder in a small cohort. All mutations were missense changes and clustered at the interacting portions of the amino-terminal src-homology 2 (N-SH2) and protein tyrosine phosphatase (PTP) domains. A gain of function was postulated as a mechanism for the disease. Here, we report the spectrum and distribution of PTPN11 mutations in a large, well-characterized cohort with NS. Mutations were found in 54 of 119 (45%) unrelated individuals with sporadic or familial NS. There was a significantly higher prevalence of mutations among familial cases than among sporadic ones. All defects were missense, and several were recurrent. The vast majority of mutations altered amino acid residues located in or around the interacting surfaces of the N-SH2 and PTP domains, but defects also affected residues in the C-SH2 domain, as well as in the peptide linking the N-SH2 and C-SH2 domains. Genotype-phenotype analysis revealed that pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them (70.6% vs. 46.2%; P<.01), whereas hypertrophic cardiomyopathy was less prevalent among those with PTPN11 mutations (5.9% vs. 26.2%; P<.005). The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups. A PTPN11 mutation was identified in a family inheriting Noonan-like/multiple giant-cell lesion syndrome, extending the phenotypic range of disease associated with this gene.

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Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort

Stefanie Eggers, Simon Sadedin, Jocelyn van den Bergen … (2016)

Background Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. Results We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. Conclusions Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes. Electronic supplementary material The online version of this article (doi:10.1186/s13059-016-1105-y) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Christa E. Flück: URI : https://loop.frontiersin.org/people/13820

Kay-Sara Sauter: URI : https://loop.frontiersin.org/people/710292

Idoia Martinez de LaPiscina: URI : https://loop.frontiersin.org/people/514470

Núria Camats: URI : https://loop.frontiersin.org/people/210573

Journal

Journal ID (nlm-ta): Front Genet

Journal ID (iso-abbrev): Front Genet

Journal ID (publisher-id): Front. Genet.

Title: Frontiers in Genetics

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-8021

Publication date (Electronic): 29 August 2019

Publication date Collection: 2019

Volume: 10

Electronic Location Identifier: 746

Affiliations

[1] ¹Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics and Department of BioMedical Research, Bern University Hospital and University of Bern , Bern, Switzerland

[2] ²Growth and Development Research Unit, Vall d’Hebron Research Institute (VHIR), Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III , Barcelona, Spain

[3] ³Endocrinology and Diabetes Research Group, BioCruces Bizkaia Health Research Institute, Cruces University Hospital, CIBERDEM, CIBERER, University of the Basque Country (UPV-EHU) , Barakaldo, Spain

[4] ⁴Pediatric Endocrinology Section, Cruces University Hospital, Endocrinology and Diabetes Research Group, BioCruces Bizkaia Health Research Institute, CIBERDEM, CIBERER, University of the Basque Country (UPV-EHU) , Barakaldo, Spain

[5] ⁵Endocrinology Section, Gender Identity Unit, Regional University Hospital of Malaga , Málaga, Spain

Author notes

Edited by: Jeff Schwartz, Griffith University, Australia

Reviewed by: Maki Fukami, National Center for Child Health and Development (NCCHD), Japan; Vincent Russel Harley, Hudson Institute of Medical Research, Australia

*Correspondence: Núria Camats, nuria.camats@ 123456vhir.org

This article was submitted to Systems Endocrinology, a section of the journal Frontiers in Genetics

Article

DOI: 10.3389/fgene.2019.00746

PMC ID: 6726737

PubMed ID: 31555317

SO-VID: 4e7a263c-c177-4886-82f9-c4f7e4bd2756

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 21 March 2019

Date accepted : 16 July 2019

Page count

Figures: 2, Tables: 2, Equations: 0, References: 84, Pages: 17, Words: 7070

Funding

Funded by: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung 10.13039/501100001711

Funded by: Agència de Gestió d’Ajuts Universitaris i de Recerca 10.13039/501100003030

Broad Phenotypes of Disorders/Differences of Sex Development in MAMLD1 Patients Through Oligogenic Disease

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Most cited references 71

Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system.

PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.

Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort

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