MAMLD1 (CXorf6) is a New Gene for Hypospadias

MAMLD1 (mastermind-like domain containing 1), previously known as CXorf6(chromosome X open reading frame 6), has been shown to be a causative gene forhypospadias. This is primarily based on the identification of nonsense mutations (E124X,Q197X, and R653X), which undergo nonsense mediated mRNA decay, in patients withpenoscrotal hypospadias. Subsequent molecular studies have shown that the mouse homolog istransiently expressed in fetal Sertoli and Leydig cells around the critical period for sexdevelopment, and that transient knockdown of Mamld1 results in significantly reducedtestosterone production in murine Leydig tumor cells. These findings suggest that theMAMLD1 mutations cause hypospadias primarily because of compromised testosteroneproduction around the critical period for sex development.