Defining a role for GDD1/TMEM16E in the skeletal bone syndrome Gnathodiaphyseal Dysplasia

Gnathodiaphyseal dysplasia (GDD) is an inherited skeletal syndrome characterized by bone fragility, sclerosis of tubular bones and fibro-osseous lesions of the jawbones. Patients show facial deformity and begin to experience frequent bone fractures around puberty and are susceptible to inflammation in jawbones during adult life. GDD is caused by mutations in the GDD1 gene, also known as TMEM16E and Ano5, encoding a membrane protein of unknown function. Interestingly, the same gene is involved in different forms of muscular dystrophy, although there is no overlap with mutations associated to GDD. While some members of the TMEM16 family, in particular TMEM16A and B, have a clear plasma membrane localization and work as ion channels, by contrast, it is not clear which is the precise site of TMEM16E expression within the cell and whether it can function as ion transporter. The results obtained in this exploratory study are expected to clarify in which subcellular compartment TMEM16E is localized, whether it functions as an ion channel and what are the effects of disease-causing mutations on localization and function. These data are a prerequisite to advance hypotheses on its physiological role and the pathological mechanism leading to GDD disease. Additionally, although GDD and TMEM16E-related muscular dystrophies apparently do not show overlapping aspects, data on the functional activity of TMEM16E will be precious for the understanding of both diseases