The thymic hypoplasia common to 22q11.2 deletion syndrome patients is linked to a deficiency of several novel RNA species (P4448)

Abstract

Abstract 22q11.2 deletion syndrome (22qDS) is the most frequent chromosomal microdeletion syndrome in humans (1 /4000 births). It arises from erroneous interchromosomal exchanges during meiosis, resulting in a hemizygous microdeletion of ~60 genes (3Mb) and 4 microRNAs on chromosome 22. Sixty percent of 22qDS patients have a thymic hypoplasia, resulting in a peripheral T cell lymphopenia. The thymic hypoplasia, hypoparathyroidism, and cardiac anomalies originate from defective pharyngeal pouch development during embryogenesis. The molecular causes remain unresolved. We profiled the RNA species in thymic tissues from normal and 22qDS patients. The miR-200 family and miR-205 were deficient in the 22qDS samples. MiR-205 is localized within a long intergenic non-coding RNA (lncRNA). This lncRNA and three transcription factors, Pax1, Foxn1, and Foxg1, were severely under-expressed in those 22qDS patients with a thymic hypoplasia. The functional role of these RNAs is being addressed with viral knockdown approaches in fetal thymic organ and pharyngeal pouch explant cultures. Preliminary findings suggest a role for several of these RNAs in thymic and parathyroid tissue specification. Results from our study could lead to better therapies for reconstituting T cell development in patients undergoing stem cell transplants and chemoablative therapies and for the elderly, who have a loss of thymic epithelial tissue with diminished T cell output.