ESPE Abstracts (2015) 84 P-2-308

MAP3K1 Mutation in a Patient with Complete XY Gonadal Dysgenesis

Birgit Köhlera, Nicole Gehrmannb, Annette Grüters-Kieslichc, Joelle Bignon-Topalovicd, Kenneth McElreaveyd & Anu Bashambood

aInsitute of Experimental Paediatric Endocrinology, Charité Universitätsmedizin, Berlin, Germany; bDepartment of Gynaecology, Charite Universitätsmedizin, Berlin, Germany; cDepartment of Paediatric Endocrinology, Diabetes and Obesity, Charite Universitätsmedizin, Berlin, Germany; dHuman Developmental Genetics, Institut Pasteur, Paris, France

Background: 49,XY gonadal dysgenesis (GD) is a very rare disorder of testes development with an incidence of 1:50–100 000. MAP3K1 is a MAPK that mainly regulates the MAPK pathways. High Map3k1 expression was found in female and male mice gonads at 13.5 dpc. In 2010, MAP3K1 mutations were identified in two families with complete and partial XY GD and in two unrelated sporadic cases with complete XY GD (Pearlman 2010 AJMG). Recently, four additional mutations (four out of 40) in XY GD (Baxter 2015 J Clin Endocrinol Metab) were identified.

The patient: Clinical signs: 16 years, primary amenorrhea, height 177 cm, weight 60 kg. B1, P3. Hormones: FSH 86 U/l, LH 36 U/l, estradiol <5.0 pg/ml, and testosterone 0.13 ng/ml. Ultrasound: infantile uterus, no gonads. Karyotype 46,XY. The diagnosis complete XY GD was made. The patient reported female gender identity and the wish for further female development. Estradiolvalerate therapy was started. Gonadectomy was performed at the age of 17 years of age.

Methods and results: We have detected the same heterozygous mutation (exon 2, c.566T>C, p.Leu189Pro) as previously reported in a sporadic case with complete XY GD by exome sequencing. The mutation is located in the conserved focal adhesion kinase (FAK) binding site. The mutation was not found in the 1000 Genomes Project. In cultured primary lymphoblastoid cells, this mutation was previously found to increase phosphorylation of the downstream target p38, ERK1 (MAPK3)/ERK2 (MAPK1) compared to WT.

Conclusion: MAP3K1 is a novel important regulator of testis development. Exome sequencing is an appropriate tool to reveal the genetic cause in the rare cases of XY GD.

Funding: Institut Pasteur core funding.

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