Dr. Alexandra Dumitrescu received her medical degree from the University of Medicine and Pharmacy Carol Davila in Romania. She subsequently earned a doctorate in Human Genetics from the University of Chicago, where she also completed residency in Internal Medicine and a fellowship in Endocrinology. Dr. Dumitrescu is now a physician-scientist in the Section of Endocrinology, Diabetes and Metabolism, who studies the pathophysiology of thyroid diseases both ways – from phenotype to genotype and back to phenotype. This bidirectional approach allows a rapid application of the acquired insights from research into clinics and vice versa.

 

She studies inherited thyroid disorders, and has discovered the genetic cause for two new human syndromes. She identified a defect in the X-linked monocarboxylate transporter 8 (MCT8) gene, a transmembrane transporter of thyroid hormone. This defect results in a severe psychomotor and development delay in males known as Allan Herndon Dudley syndrome. This is the first inherited disorder of the thyroid axis in humans that has been linked to thyroid hormone transport into cells. To study the mechanisms underlying the complex phenotype of MCT8 defect, she generated a Mct8KO mouse model, which has become a useful research tool for ongoing studies in different laboratories. Recent studies with this model have led to the novel finding that thyroid hormone secretion from the thyroid gland is partially regulated by Mct8. A thyroid hormone analog, DITPA, has been shown to bypass the Mct8 defect and to improve parameters of thyroid hormone action in brain. This analog is currently used in several patients with MCT8 gene mutations, as trials of thyroid hormone treatment did not produce clinical improvement.

 

Dr. Dumitrescu’s investigations on another novel thyroid phenotype led to the identification of mutations in the selenocysteine incorporation sequence binding protein 2 (SBP2). This is the first report of mutations within the selenoprotein synthesis machinery. A fundamental defect in selenoprotein synthesis such as SBP2 deficiency is expected to affect an entire class of proteins acting on multiple physiological pathways. Thus, patients manifest a complex phenotype with congenital myopathy, developmental delay, sensorineural hearing loss, infertility, a metabolic phenotype and immune deficits. This discovery has received particular attention in the scientific community, as it revealed that inherited selenoprotein synthesis defects have consequences on growth and thyroid function at young age. New families with SBP2 mutations were later identified based on the unusual thyroid phenotype she described.

 

In her quest to answer the many questions raised by the diagnosis of patients with SBP2 deficiency, she created a mouse model of global Sbp2 deficiency that replicates the human syndrome. To bypass the early lethality of complete Sbp2 deficiency, she used a Cre-ER /loxP approach to generate tamoxifen-inducible Sbp2 null mice. This mouse model has allowed her to elucidate the mechanisms of selenoprotein-mediated pathology that lead to the development of the pathognomonic thyroid phenotype. As importantly, the thyroid hormone status of specific tissues play regulatory roles in the observed metabolic and muscular phenotypes of this disease, and the implicated tissues such as liver, adipose tissue and muscle are at the interface of this intricate cross talk. Dr. Dumitrescu’s research on the global Sbp2 deficiency mouse model offers a unique opportunity for the advancement of our understanding of the role of selenoproteins in thyroid hormone homeostasis and cellular metabolisms that are in turn, relevant to fundamental physiologic pathways and functions. This knowledge can then be translated next into clinically relevant information that can potentially change patient outcomes.