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dc.contributorVall d'Hebron Barcelona Hospital Campus
dc.contributor.authorFlück, Christa E.
dc.contributor.authorAudí Parera, Laura
dc.contributor.authorFernández Cancio, Mónica
dc.contributor.authorSauter, Kay-Sara
dc.contributor.authorMartinez de LaPiscina, Idoia
dc.contributor.authorCastaño, Luis
dc.contributor.authorCamats Tarruella, Nuria
dc.date.accessioned2020-07-28T08:53:40Z
dc.date.available2020-07-28T08:53:40Z
dc.date.issued2019-08-29
dc.identifier.citationFlück CE, Audí L, Fernández-Cancio M, Sauter KS, Martinez de LaPiscina I, Castaño L, et al. Broad phenotypes of disorders/differences of sex development in MAMLD1 patients through oligogenic disease. Front Genet. 2019 Aug 29;10:746.
dc.identifier.issn1664-8021
dc.identifier.urihttp://hdl.handle.net/11351/5110
dc.descriptionMAMLD1; Disorders/differences of sex development; Hypospadias
dc.description.abstractDisorders/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.
dc.language.isoeng
dc.publisherFrontiers Media
dc.relation.ispartofseriesFrontiers in Genetics;10
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceScientia
dc.subjectCromosomes sexuals - Anomalies
dc.subjectGenètica - Tècnica
dc.subject.meshGenetic Techniques
dc.subject.meshSex Chromosome Disorders of Sex Development
dc.titleBroad phenotypes of disorders/differences of sex development in MAMLD1 patients through oligogenic disease
dc.typeinfo:eu-repo/semantics/article
dc.identifier.doi10.3389/fgene.2019.00746
dc.subject.decstécnicas genéticas
dc.subject.decstrastornos de los cromosomas sexuales del desarrollo sexual
dc.relation.publishversionhttps://www.frontiersin.org/articles/10.3389/fgene.2019.00746/full
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.audienceProfessionals
dc.contributor.authoraffiliation[Flück CE, Sauter KS] Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics and Department of BioMedical Research, Bern University Hospital and University of Bern, Bern, Switzerland. [Audí L, Fernández-Cancio M, Camats N] Grup de Recerca en Creixement i Desenvolupament, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. [Martinez de LaPiscina I] Endocrinology and Diabetes Research Group, BioCruces Bizkaia Health Research Institute, Cruces University Hospital, CIBERDEM, CIBERER, University of the Basque Country (UPV-EHU), Barakaldo, Spain. [Castaño L] Pediatric 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
dc.identifier.pmid31555317
dc.identifier.wos000483038400001
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess


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