MAMLD1 (mastermind-like domain containing 1), previously 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 studies have shown that (1) the mouse homolog is transiently expressed in fetal Sertoli and Leydig cells around the critical period of sex development; (2) transient knockdown of Mamld1 results in significantly reduced testosterone production in murine Leydig tumor cells; (3) MAMLD1 protein shares homology to mastermind-like 2 (MAML2) protein that functions as a co-activator in canonical Notch signaling; (4) MAMLD1 localizes to the nuclear bodies and transactivates the promoter activity of a non-canonical Notch target gene hairy/enhancer of split 3 (Hes3), rather than the canonical Notch target genes such as Hes1 and Hes5, without demonstrable DNA-binding capacity, and (5) MAMLD1 is regulated by steroidogenic factor 1. These findings suggest that the MAMLD1 mutations cause hypospadias primarily because of compromised testosterone production around the critical period of sex development, and provide useful information for the molecular network involved in fetal testosterone production.

Keywords:
MAMLD1, CXorf6, Hypospadias, Testosterone
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2009
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