Tricho-Dento-Osseus (TDO) Syndrome: Developing a Mouse Model

December 2007
By Maria I. Morasso, PhD, National Institute of Arthritis, Musculo-Skeletal and Skin, National Institutes of Health

The ectodermal dysplasias a large group of diseases, where more than 170 different pathological clinical conditions have been defined, all sharing in common anomalies of the hair, teeth, and nails. The anomalies affecting the epidermis and epidermal derivatives are extremely variable and clinical overlap is present among the majority of the ectodermal dysplasias. A recent clinical-genetic classification has been proposed where a defect in developmental regulation can be recognized on the basis of an identified causative gene, it’s putative or proven function and pattern of expression. A causative gene in this category that has been associated with Tricho-Dento-Osseus (TDO) syndrome is the DLX3 homeobox transcription regulator.

The Dlx homeobox family comprises a class of transcription factors that are crucial regulators of many developmental processes, ranging from organization of the body plan to differentiation of individual tissues. Transcription factors function by binding DNA and regulating the expression of other genes. Dlx genes are also involved in the processes of osteogenesis, hematopoiesis, epidermal stratification and placental development.

Dlx3 is a member of the Dlx vertebrate family that is comprised of six members (Dlx1-6). The Dlx3 gene is somewhat distinct in that it has not been detected in the mammalian central nervous system and has an essential role in epidermal and placental development. The Dlx3 gene is also broadly expressed in embryonic ectoderm, as well as in the tooth, hair follicle, limb bud, mammary gland and later has a role in the epidermis. Recently, evaluation of TDO patients has shown that besides the alteration in the intramembranous bone formation in the skull, DLX3 is important in bone formation and homeostasis of the appendicular skeleton.

Mutation of the DLX3 gene sequence has been linked to the human TDO syndrome that is characterized by defects in the development of hair, teeth, and increased bone density in the cranium with absence of overt limb malformations (Price et al., 1998). The mutation is due to a 4bp deletion immediately downstream of the DNA binding domain, resulting in a truncated DLX3 protein that can potentially still bind DNA but is functionally altered. In humans, the TDO mutation results in a dominant phenotype. Analysis of mouse models suggests that the dominant pattern of inheritance may be due to the formation of non-functional complexes involving the frame-shifted/truncated DLX3, that act either through a dominant–negative or a gain of function mechanism, as opposed to haploinsufficiency.

We seek to develop a mouse model for the TDO syndrome, that will help elucidate the role of Dlx3 in hair follicle, tooth and bone formation. Analysis of the development of these structures in the TDO mouse model will also enable us to understand at the molecular and biochemical level the effect of the specific mutation found in the TDO syndrome.

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