Camats, NúriaFernández-Cancio, MónicaAudí, LauraMullis, Primus EMoreno, FranciscaGonzález Casado, IsabelLópez-Siguero, Juan PedroCorripio, RaquelBermúdez de la Vega, José AntonioBlanco, José AntonioFlück, Christa E2016-06-232016-06-232015-11-16Camats N, Fernández-Cancio M, Audí L, Mullis PE, Moreno F, González Casado I, et al. Human MAMLD1 Gene Variations Seem Not Sufficient to Explain a 46,XY DSD Phenotype. PLoS ONE. 2015; 10(11):e0142831http://hdl.handle.net/10668/2222Journal Article; Research Support, Non-U.S. Gov't;MAMLD1 is thought to cause disordered sex development in 46,XY patients. But its role is controversial because some MAMLD1 variants are also detected in normal individuals, several MAMLD1 mutations have wild-type activity in functional tests, and the male Mamld1-knockout mouse has normal genitalia and reproduction. Our aim was to search for MAMLD1 variations in 108 46,XY patients with disordered sex development, and to test them functionally. We detected MAMDL1 variations and compared SNP frequencies in controls and patients. We tested MAMLD1 transcriptional activity on promoters involved in sex development and assessed the effect of MAMLD1 on androgen production. MAMLD1 expression in normal steroid-producing tissues and mutant MAMLD1 protein expression were also assessed. Nine MAMLD1 mutations (7 novel) were characterized. In vitro, most MAMLD1 variants acted similarly to wild type. Only the L210X mutation showed loss of function in all tests. We detected no effect of wild-type or MAMLD1 variants on CYP17A1 enzyme activity in our cell experiments, and Western blots revealed no significant differences for MAMLD1 protein expression. MAMLD1 was expressed in human adult testes and adrenals. In conclusion, our data support the notion that MAMLD1 sequence variations may not suffice to explain the phenotype in carriers and that MAMLD1 may also have a role in adult life.enInmunotransferencia WesternTrastornos del desarrollo sexual 46XYHeterocigotoRatonesRatones noqueadosProteínas mutantesMutaciónFenotipoDesarrollo sexualEsteroide 17-alfa-hidroxilasaMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Molecular Probe Techniques::Blotting, WesternMedical Subject Headings::Diseases::Endocrine System Diseases::Gonadal Disorders::Disorders of Sex Development::46, XY Disorders of Sex DevelopmentMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genotype::HeterozygoteMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Transgenic::Mice, KnockoutMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Mutant ProteinsMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::MutationMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::PhenotypeMedical Subject Headings::Phenomena and Processes::Reproductive and Urinary Physiological Phenomena::Reproductive Physiological Phenomena::Reproductive Physiological Processes::Sexual DevelopmentMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Hemeproteins::Cytochromes::Cytochrome P-450 Enzyme System::Steroid Hydroxylases::Steroid 17-alpha-Hydroxylaseresearch article26580071open access10.1371/journal.pone.01428311932-6203PMC4646284