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 molecular studies have shown that the mouse homolog is transiently expressed in fetal Sertoli and Leydig cells around the critical period for sex development, and that transient knockdown of Mamld1 results in significantly reduced testosterone production in murine Leydig tumor cells. These findings suggest that the MAMLD1 mutations cause hypospadias primarily because of compromised testosterone production around the critical period for sex development.
Keywords: CXorf6; MAMLD1; hypospadias; testosterone.