Up‐regulation of SOX9 in human sex‐determining region on the Y chromosome (SRY)‐negative XX males

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Abstract
Summary: Background  In mammals, gonadal sex is normally determined by the presence or absence of the Y chromosome gene SRY. After expression of SRY in the sexually indifferent gonad, a number of genes encoding transcription factors and growth factors implicated in testis differentiation start to show male‐specific expression. However, in XX males, these genes must be up‐regulated in the absence of SRY, but the aetiology of SRY‐negative XX maleness remains unclear.Aim and methods  We examined the expression of representative gonad marker genes in SRY‐negative XX male testes.Results  RT‐PCR and immunohistochemical studies revealed that SOX9, DAX‐1, Ad4BP/SF‐1, WT‐1, GATA‐4 and MIS were expressed in testicular tissues of SRY‐negative XX males. Expression levels of SOX9 in testes of these patients averaged 1·9‐fold higher than in normal XY testes, while expression levels of Ad4BP/SF‐1, DAX‐1 and MIS were lower in the SRY‐negative XX testes than in XY testes. All XX patients were found to carry two copies of the SOX9 gene per diploid genome as do normal XX females and XY males. The XX male patients also carried two copies of the DAX‐1 gene as do normal XX females, while normal XY males carry a single DAX‐1 gene.Conclusions  Our data suggest that lesions affecting SOX9 expression are the key factor in sex determination in SRY‐negative XX males, and that the decreased expression of Ad4BP/SF‐1, DAX‐1 and MIS contribute to their clinical features.