The identification of variants in DHX37 as a cause of 46,XY DSD opens up the possibility that some forms of human sex-reversal are ribosomopathies. Pathogenic variants associated with a lack of testis-determination or, the inability to maintain testis identity are clustered within the functional RecA1 and RecA2 domains of the helicase and involve amino acids that are conserved through to yeast (Figure 2a). Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human, mouse and goat testis (Figure 2b).
Figure 2. (A) Schematic diagram of the RecA-like domains in DEAH-box RNA helicases. Alignment of human (top) and Saccharomyces cerevisiae (bottom) showing the positions of mutations causing 46,XY DSD. (B) DHX37 expression in somatic cells of mouse and human developing testis. Left panel, in human fetal testis (GW 10) DHX37 protein is observed in Sertoli cells (asterisk), but absent in gonocytes (arrows). Central panel, qRT-PCR analysis of Dhx37 in mouse gonads reveals no significant difference in expression between XX and XY. In situ hybridization reveals Dhx37 expression in XY gonad (left of dashed line). Signal is stronger towards the coelomic surface (left of dashed line) showing DHX37 (green), OCT4 (red, PGCs), and DAPI (blue). DHX37 protein is concentrated at the nuclear membrane in most cells, except germ cells (arrows). Right panel, box plot analysis depicting temporal (E10.5 to E16.5) cell-to-cell variations in gene expression for Dhx37 and selected SD genes.
The identification of DHX37 as a component of the mammalian SD pathway forces a paradigm shift from the prevalent transcription-factor centered view. The mechanism(s) of how a mutation in a widely expressed protein involved in a basic cellular function can generate a highly-specific human phenotype is unknown. We are currently assessing the impact of DHX37 mutations on human ribosome biogenesis and identifying functionally relevant partners (RNA and protein) for DHX37 that are involved in SD.