Endocrine Abstracts (2011) 26 PL1

Disorders of sex development: recent progress

Tsutomu Ogata & Maki Fukami


Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.


Disorders of sex development (DSD) can occur as a single gene disorder, a multifactorial disorder, and an imprinting/epigenetic disorder. Here, I will report our recent progress on two causative genes for DSD.

MAMLD1: Mastermind domain containing gene 1

We have reported that MAMLD1 is a causative gene for hypospadias, a mild form of 46,XY DSD. This is primarily based on the identification of several pathologic mutations of MAMLD1 in patients with hypospadias. The murine homolog was specifically expressed in fetal Sertoli and Leydig cells around the critical period for sex development, and transient knockdown experiments showed significantly reduced testosterone production and Cyp17a1 expression in murine Leydig tumor cells. We also found that MAMLD1 was controlled by SF1 and transactivated the non-canonical Notch target gene Hes3 in nuclear bodies. Notably, Mamld1 knockout mice had no abnormal genitalia but exhibited metabolic syndrome.

POR: P450 Oxidoreductase

POR deficiency (PORD) is a rare autosomal recessive disorder characterized by skeletal dysplasia referred to as Antley–Bixler syndrome, adrenal dysfunction, 46,XY and 46,XX DSD, and maternal virilization during pregnancy. We have studied 38 patients with POR, and classified them into two major groups: group A, homozygosity for R457H with low residual POR activity; and group B, compound heterozygosity for R457H and one apparently null mutation. Phenotypic comparison between group A and group B suggest that the residual POR activity reflected by the R457H dosage constitutes the underlying factor for clinical variability in some features but not in other features, probably due to the simplicity and complexity of POR dependent metabolic pathways relevant to each phenotype. Notably, PORD is almost invariably associated with 46,XX DSD, and this is primarily explained by placenta-derived testosterone exposure and backdoor pathway (fetal adrenal)-derived dihydrotestosterone exposure. Furthermore, we have identified the promoter region of POR gene by analyzing three patients with apparently heterozygous mutations.

Conclusions: Although DSD is a highly heterogeneous condition with many unknown underlying factors, the black box is gradually shrinking with progress in molecular endocrinology.

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