MAMLD1 (mastermind-like domain containing 1), also known as CXorf6 (chromosome X open reading frame 6) has been shown to be a causative gene for hypospadias. This is primarily based on the identification of nonsense mutations (E124X, Q197X, and R653X) which undergo nonsense mediated mRNA decay in patients with penoscrotal hypospadias. Subsequent molecular studies have shown that (1) the mouse homolog is transiently expressed in fetal Sertoli and Leydig cells around the critical period for sex development; (2) CXorf6 protein shares homology to mastermind-like 2 (MAML2) protein that functions as a co-activator in canonical Notch signaling; (3) CXorf6 localizes to the nuclear bodies and transactivates the promoter activity of a non-canonical Notch target gene hairy/enhancer of split 3(Hes3) without demonstrable DNA binding capacity; (4) transient knockdown of CXorf6 results in significantly reduced testosterone production in murine Leydig tumor cells; and (5) CXorf6 can be regulated by steroidogenic factor 1 (SF-1). These findings suggest that the CXorf6 mutations cause hypospadias primarily because of testicular dysfunction and resultant compromised testosterone production around that period, and provide useful information for the molecular network involved in fetal testosterone production.
(c) 2008 S. Karger AG, Basel.