ESPE Abstracts (2015) 84 FC6.2

aUniversity of Minnesota, Minneapolis, Minnesota, USA; bInstitut Pasteur, Paris, France; cCentre Hospitalier de Dunkerque, Dunkerque, France; dCornell University, Chicago, Illinois, USA

Background: DMRT transcription factors are highly conserved regulators of metazoan sexual development. The role of DMRT1 in human primary sex-determination is unclear. Chromosome 9p deletions that remove one copy of DMRT1 are associated with 46,XY feminization and gonadal dysgenesis. While they suggest that DMRT1 is haploinsufficient for testicular development, these deletions usually remove other genes, including DMRT2 and DMRT3. Also, most 9p deletions cause incomplete gonadal dysgenesis so it has been unclear whether loss of DMRT1 alone can cause full sex reversal.

Objective and hypotheses: Using an exome sequencing approach on a large cohort of 46,XY individuals with gonadal dysgenesis, we predicted that mutations in DMRT1 should occur if it is a primary sex-determining gene.

Method: Exome sequencing was performed on >100 cases of 46,XY complete gonadal dysgenesis using the Illumina HiSeq2000 System at ×50 average coverage. In vitro DNA-binding and transient transfection assays were performed using the WT and mutated DMRT1 proteins.

Results: We identified a de novo missense mutation (p.R111G) in a sporadic case of 46,XY complete gonadal dysgenesis. This mutation was absent in 200 ancestry-matched controls as well as the publicly available SNP databases. The mutation affects an arginine residue that located in DM-domain and which is conserved in both Caenorhabditis elegans and Drosophila. The DMRT1p.R111G protein shows reduced DNA-affinity and altered sequence specificity indicating a loss-of-function. Moreover the mutant protein showed a dominant disruption of WT DMRT1 binding stoichiometry at some DMRT1 binding sites. This combination of haploinsufficiency and dominant disruption may explain the severe phenotype caused by the DMRT1R111G mutation.

Conclusion: This is the first amino acid change described in human DMRT1, which results in a complete absence of testis-determination. This indicates that in the human DMRT1 plays a role in primary sex-determination.

Funding: This work was funded by the US National Institutes of Health (GM59152, GM50399, AI087098, and GM095558), COST Action DSDnet BM1303 and Program Blanc Assistance Publique-Institut Pasteur.

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