The lnc to clinical abnormalities in 22q11_2 deletion DiGeorge syndrome

描述（由申请人提供）：22q11.2缺失综合征（22q11.2 S）是影响人类最常见的染色体疾病。这种疾病的患者具有高度不同的临床表型，包括以T细胞淋巴细胞减少为特征的原发性免疫缺陷。T细胞淋巴细胞减少是由胚胎发育过程中胸腺发育异常引起的，这也与甲状旁腺功能低下引起的低钙水平有关。导致这些发育不良组织形成的分子机制尚不清楚。通过分析从22q11.2 S患者中收集的胸腺发育不全，我们发现了一种名为MIR205HG的新型长链非编码RNA的显著缺陷。这个lncRNA在所有的安乐死者中高度保守。小鼠胚胎原位杂交发现MIR205HG （MIR205.001）在小鼠咽器、鼻突和端脑中具有显著的时空表达模式。咽部器官产生头颈部的几个结构，第三咽袋形成胸腺和甲状旁腺。在较晚的发育时间点，MIR205.001仅限于胸腺上皮和皮肤。鉴于这些发现，与22q11.2缺失综合征的临床特征和miR-205 KO小鼠（用lncRNA编码）的胚胎致死性有着惊人的相似性，我假设MIR205.001的缺失导致胸腺和甲状旁腺组织规范受损。解决这个问题的目的如下。目的1：阐明MIR205.001在第三咽袋形成导致胸腺和甲状旁腺器官的功能贡献。目的2：描述MIR205.001的分子活性。随着对胸腺发育导致胸腺生成的更好理解，可以创造出更成功的治疗方法，用于治疗接受化疗治疗的患者和胸腺功能下降的老年人。

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.