ESPE Abstracts

Background: Recently, eight MAP3K1 mutations have been identified in patients with 46,XY disorder of sex development (DSD), although detailed clinical findings of the mutation-positive patients remain to be investigated.

Objective and hypotheses: To clarify the frequency and clinical consequences of MAP3K1 mutations.

Method: Mutation screening of MAP3K1 were performed for 37 patients with 46,XY DSD. Phenotypic analysis was preformed for a patient with a MAP3K1 variant.

Results: We identified a heterozygous nucleotide change (c.745C>T, p.R249C) in a patient. He had no mutations in other 46,XY DSD-causative genes including AR, DMRT1, NR5A1, SOX9, SRD5A2, and SRY. Sequence analysis of the parental samples indicated maternal origin of the MAP3K1 variant. The p.R249C variant has previously been submitted to the 1000 genome database as a rare polymorphism (rs200234617, allele frequency: 0.001, detected only in a female). The arginine residue at the 249th codon is conserved among species. In silico analysis using PloyPhen-2 and SIFT revealed that p.R249C is a probably damaging mutation. Salient clinical features of the patient were hypospadias and bifid scrotum. He had normal penile length (2.5 cm) and testicular volumes (1 ml). Abdominal ultrasound analysis detected no abnormalities. GnRH stimulation test revealed slightly elevated gonadotropin levels, and hCG stimulation test showed normal levels of testosterone.

Conclusion: The results indicate a possible association between the p.R249C variant and hypospadias, together with the rarity of MAP3K1 mutations in patients with 46,XY DSD. Endocrine data of the patient suggest that MAP3K1 mutations permit apparently normal testicular function after birth.