The lnc to clinical abnormalities in 22q11_2 deletion DiGeorge syndrome

Ut Southwestern Medical Center, Dallas TX

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Abstract

DESCRIPTION (provided by applicant): 22q11.2 deletion syndrome (22q11.2 S) is the most common chromosomal disorder affecting humans. Patients with this disorder have highly varied clinical phenotypes including a primary immune deficiency characterized by a T cell lymphopenia. The T cell lymphopenia results from abnormal thymus development during embryogenesis, which is also coupled to the low calcium levels resulting from hypoparathyroidism. The molecular mechanisms leading to the formation of these hypoplastic tissues are poorly understood. By profiling the hypoplastic thymii collected from 22q11.2 S patients, we discovered a striking deficiency in a novel long non-coding RNA termed MIR205HG. This lncRNA is highly conserved among all eutharians. In situ hybridizations with murine embryos revealed a remarkable spatial temporal expression pattern of the murine homolog of MIR205HG (MIR205.001) in the pharyngeal apparatus, nasal process, and telencephalon. The pharyngeal apparatus gives rise to several structures of the head and neck, with the 3rd pharyngeal pouch forming the thymus and parathyroid glands. At later developmental time points, MIR205.001 is restricted to the epithelium of the thymus and skin. Given these findings, the striking similarities with clinical features of 22q11.2 deletion syndrome and the embryonic lethality of a miR-205 KO mouse (encoded with the lncRNA), I hypothesize that a deficiency of MIR205.001 causes impaired thymic and parathyroid tissue specification. This question will be addressed with the following aims. Aim 1: Elucidate the functional contribution of MIR205.001 in the formation of the 3rd pharyngeal pouch leading to the specification of the thymus and parathyroid organs. Aim 2: Delineate the molecular activity of MIR205.001. With a better understanding of thymus development leading to thymopoiesis, more successful treatments can be created in which to treat patients undergoing chemoablative therapies and the elderly which have decrease thymic function.