MAMLD1 and 46,XY Disorders of Sex Development

Abstract MAMLD1 (mastermind-like domain containing 1) is a recently discovered causative gene for 46,XY disorders of sex development (DSD), with hypospadias as the salient clinical phenotype. To date, microdeletions involving MAMLD1 have been identified in six patients, and definitive mutations (nonsense and frameshift mutations that are predicted to undergo nonsense mediated mRNA decay [NMD]) have been found in six patients. In addition, specific MAMLD1 cSNP(s) and haplotype may constitute a susceptibility factor for hypospadias. Furthermore, in vitro studies have revealed that (1) the mouse homolog is expressed in fetal Sertoli and Leydig cells around the critical period for sex development; (2) transient Mamld1 knockdown results in significantly reduced testosterone production primarily because of compromised 17α-hydroxylation and Cyp17a1 expression in Murine Leydig tumor cells; (3) MAMLD1 localizes to the nuclear bodies and transactivates the promoter activity of a non-canonical Notch target gene hairy/enhancer of split 3, without demonstrable DNA-binding capacity; and (4) MAMLD1 is regulated by steroidogenic factor 1 (SF1). These findings suggest that the MAMLD1 mutations cause 46,XY DSD primarily because of compromised testosterone production around the critical period for sex development. Further studies will provide useful information for the molecular network involved in fetal testosterone production.

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