ESPE Abstracts

Introduction: Complex and ordered intracellular signal pathways play a significant role in sex determination in mammals, mediating the balance of gonadal development. A major pathway involved in the regulation of the male development is mitogen-activated protein kinase (MAPK) signaling pathway. To date, mutations of MAP3K1 gene have been found to account for approximately 15%-20% of 46, XY gonadal dysgenesis (46, XY GD).

Objective: To determine and clarify the presence and functional consequence of the deleterious mutation in MAP3K1 gene of the patient with 46, XY complete gonadal dysgenesis (46, XY CGD).

Case presentation: Our patient, a 13-year-old girl, was first seen at our hospital because of undeveloped breasts and primary amenorrhea. On physical examination, her breasts development was B2 stage and pubic hair was PH1 stage without axillary hair. She had female external genitalia and small uterus. Endocrinological investigations revealed hypergonadotropic hypogonadism (FSH 107.10 IU/L, LH 32.89 IU/L, E2 11 ng/L, PRG 0.46 ug/L), and Cytogenetic studies showed a 46, XY karyotype. Owing to the possibility of gonad's deterioration, the patient underwent bilateral gonadectomy. Moreover, the older sister of the patient had a similar symptom but the detailed information was unknown

Methods and Materials: Whole-exome sequencing was performed in the patient and her family members. The MAP3K1 gene was PCR amplified and directly sequenced. The functional study was also performed to find out the interaction between the testis-development pathway and ovary-development pathway.

Results: We identified a heterozygous MAP3K1 gene mutation (c.556A>G, p.R249G) in the patient and her mother, which located in exon 2. Predicted results of prediction sites (Polyphen-2 and Mutation Taster) showed that the mutation was pathogenic. In vitro study showed a significantly increased phosphorylation of p38 and ERK1/2 and an obviously reduced expression of SRY gene, compared to the wild-type cells. Causing by the gain-of-function mutation, the stabilization of beta-catenin and degradation of SRY hinder the formation of the testis.

Conclusions: In our study, we describe one patient diagnosed with 46, XY CGD, carrying a novel mutation of MAP3K1 (c.556A>G). The results emphasize the role of MAP3K1 in human sex development and demonstrate MAPK pathway can tilt the balance of sex determination by regulating the expression of sex-related gene.