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Dioxygenin binding

SOX9 expression in the testis during normal early embryonic development, as shown by binding of a dioxygenin labeled riboprobe to canine SOX9 mRNA.

Normal vs Abnormal External Genitalia of pup

A) Normal external genitalia of an XX female pup. B) Abnormal external genitalia of an XX DSD pup that developed ovotestes. Note that the cranial tip of the vulva (arrow) has the shape of a prepuce and is located farther cranial than is normal for a female, and farther caudally than is normal for an XY male.

Normal pup vs pup with testes

A) Normal XY male pup (left) and XX DSD pup that developed testes (right). The location of the umbilicus (arrowhead) and the opening to the urinary tract (arrow) indicate caudal displacement of the prepuce in the XX DSD pup. The prepuce is also pendulous. B) Abnormal external genitalia of the XX DSD pup as an adult. Note that the prepuce is still located farther caudally than is normal for a male, and the cranial opening is larger than normal (hypospadias). Not shown: A scrotum is absent and the testes are located within the abdomen (bilateral cryptorchidism).

Identification of XX DSD Mutations by RNA-seq and Comparative Genomics

Research on disorders of sexual development (DSD) has played a major role in understanding the genetic control of sex determination and the opposing pathways controlling gonadal development. In the testis pathway, SOX9 expression is critical to testis induction. Conversely, extinguishing SOX9 expression appears essential for normal ovarian development. For example, in XX DSD patients with SOX9 duplications, testes develop in XX individuals lacking the Y-linked testis-determining gene, SRY. Recent studies of the ovary pathway have not yet identified the long-sought mechanism by which SOX9 transcription is normally extinguished in XX gonads. This could be a key step in the ovary pathway that opposes the testis pathway.

Our goal is to identify a causative mutation in the subtype of XX DSD in which XX individuals develop testes while their XX siblings develop ovotestes. Studies in these patients have been impeded because the disorder is uncommon, family sizes are small, and there are no naturally occurring rodent models. The canine model is the only model of this XX DSD subtype. In the canine research pedigree, XX DSD is an autosomal recessive trait with expression limited to XX siblings, which develop testes or ovotestes. Early studies suggested that the testis pathway is incompletely suppressed or inappropriately activated in these gonads. Using genome-wide association studies, we have identified a region significantly associated with canine XX DSD in the model pedigree.

In search of candidate mutations, we are using a combined comparative genomics and bioinformatics approach, comparing our canine XX DSD model dataset to our collaborator’s dataset from human patients. In addition, we are comparing normal and affected gonadal gene expression during canine development.