Understanding the Variability of 22q11.2 Deletion Syndrome: The Role of Epigenetic Factors

Abstract

Initially described as a triad of immunodeficiency, congenital heart defects and hypoparathyroidism, 22q11.2 deletion syndrome (22q11.2DS) now encompasses a great amount of abnormalities involving different systems. Approximately 85% of patients share a 3 Mb 22q11.2 region of hemizygous deletion in which 46 protein-coding genes are included. However, the hemizygosity of the genes of this region cannot fully explain the clinical phenotype and the phenotypic variability observed among patients. Additional mutations in genes located outside the deleted region, leading to "dual diagnosis", have been described in 1% of patients. In some cases, the hemizygosity of the 22q11.2 region unmasks autosomal recessive conditions due to additional mutations on the non-deleted allele. Some of the deleted genes play a crucial role in gene expression regulation pathways, involving the whole genome. Typical miRNA expression patterns have been identified in 22q11.2DS, due to an alteration in miRNA biogenesis, affecting the expression of several target genes. Also, a methylation epi-signature in CpG islands differentiating patients from controls has been defined. Herein, we summarize the evidence on the genetic and epigenetic mechanisms implicated in the pathogenesis of the clinical manifestations of 22q11.2 DS. The review of the literature confirms the hypothesis that the 22q11.2DS phenotype results from a network of interactions between deleted protein-coding genes and altered epigenetic regulation.

Keywords: 22q11.2 deletion syndrome; CpG islands; epigenetics; methylation; micro-RNAs.

Figure 1

Schematic representation of the 22q11.2 region, including the four low-copy repeats (LCRs) LCR22A-LCR22D. The 46 protein-coding genes are indicated in black. TBX1 (T-box 1) is highlighted in red, since it is considered the main genetic driver of 22q11.2 DS. The potential pathogenetic role of PRODH, HIRA, COMT, DGCR8, SNAP29 and CRKL genes (in the box) is discussed in the text. The 7 micro-RNAs are indicated in violet. The size and the localization of the different deletions are shown at the bottom of the figure. Mir, microRNA.

Figure 2

RNA: ribonucleic acid. RISC: RNA-induced silencing complex. DGCR8: DiGeorge syndrome critical region gene 8. The biogenesis of miRNA starts in the nucleus, where RNA polymerase II transcribes miRNA genes into long and capped RNA molecules, called primary miRNAs (pri-miRNAs). The pri-miRNAs can follow two pathways: the canonical and non-canonical pathways. In the canonical pathway, the pri-miRNAs are processed by a complex (microprocessor complex) composed of DGCR8, which works as the noncatalytic subunit, and Drosha, a type of double-stranded RNA-specific endoribonuclease. The microprocessor complex cleaves pri-miRNAs into premature miRNAs (pre-miRNA), which preserve a hairpin structure. In the non-canonical pathway, instead, pri-miRNA are processed by the spliceosome and cleaved into pre-miRNA. Pre-miRNAs are transported into the cytoplasm by Exportin 5. In the cytoplasm, Dicer, an RNase III enzyme, cleaves the hairpin loop and generates a mature miRNA duplex. Subsequently, the mature miRNA duplex separates into two single strands: one is degraded, and the other is incorporated into the RISC complex. In the RISC complex, the mature miRNAs recognize their specific mRNA targets through base pairing, fulfilling the function of transcription regulators. If the base pairing is complete, the mRNA target is degraded; if base pairing is incomplete, mRNA target translation is repressed.