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To examine the genetic basis of disorders of sex determination (DSDs) and in particular to determine whether the disruption of MAP3K1 could be responsible for the DSDs in some patients.  

Two families were recruited with several members affected by DSDs, and additional sporadic cases were also examined. Some of the people participating in the study were women with apparently male karyotypes, and others were males who had abnormal sex development. The MAP3K1 gene from all participants was sequenced; this gene is a member of the MAP kinase signalling pathway and of interest because the mouse equivalent shows strong expression throughout the sex-determining stage of gonad development.

Affected members of the two families and two of the sporadic cases were found to have an alteration in their MAP3K1 gene. Several variants were identified but none previously reported as a known SNP. The mutations were shown to alter the regulation of the MAP3K1 gene in cultured lymphoblastoid cell lines.

Mutations in the MAP3K1 gene result in specific human DSDs with abnormal gonadal development. The results of the study suggest that the MAP kinase pathway may be involved in the balance of expression between the various genes involved in directing the undifferentiated gonad to become a testis or an ovary. 

These findings shed new light on the genetic causes of DSDs, which are often associated with fertility problems and emotional and social stress, and identify a potentially important biological switch in the process of sex determination during development. They could also improve the clinical management of DSDs patients as alterations in MAP3K1 can lead to the development of life-threatening tumors. Removal of the gonads early in life could therefore be an important preventative intervention.