Long noncoding RNAs and their contribution to 22q11.2 deletion syndrome

Ut Southwestern Medical Center, Dallas TX

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Abstract

? DESCRIPTION (provided by applicant): 22q11.2 deletion syndrome is one of the most common microdeletion syndromes in humans. The deletions result in a haploinsufficiency of over 60 genes, 4 microRNAs, and a group of uncharacterized long noncoding RNAs. Individuals with 22q11.2 deletion syndrome can present with many clinical complications including three that are commonly linked, thymic hypoplasia, hypocalcemia related to the parathyroid hypoplasia, and cardiac anomalies. Additional clinical manifestations include growth delay, facial dysmorphology, learning disorders, and/or schizophrenia. Those patients with a hypoplastic thymus have reduced thymopoiesis. This causes a peripheral T cell lymphopenia, with fewer effector and regulatory T cells present in these individuals. Insufficient numbers of such T cells increases the severity and duration of infections and autoimmune disorders. The thymus hypoplasia, the hypoparathyroidism, and defects in the outflow tracts of the heart, result from impaired tissue specification of the pharyngeal apparatus. We characterized human thymic tissues from normal and 22q11.2 deletion syndrome patients with a combination of histology, immunohistochemistry, flow cytometry, microRNA (miR) arrays, RT-PCR, and RNA sequencing. Preliminary findings reveal a deficiency of miR-205 and the surrounding long noncoding RNA (lncRNA, MIR205HG) in the hypoplastic tissues from a subset of 22q11.2 deletion syndrome patients. We have generated conditional knockout mice for the murine homolog of the lncRNA and have miR-205 conditional knockout lines. Preliminary findings indicate that miR-205 is required for T cell output during normal and stress situations. A complete deficiency of lncRNA results in a growth delay in the mice. By using diverse conditional knockout mice, and comparing the phenotypes in these mice to those reported for chromosome 22q11.2 deletion syndrome, we will determine how the novel RNA species result in poor T cell output and developmental delays. The studies will include a comparative analysis of human thymii from normal and 22q11.2 deletion syndrome patients.