Alteration of rRNA gene copy number and expression in patients with intellectual disability and heteromorphic acrocentric chromosomes

Background: Intellectual disability (ID) is an important medical and social problem that can be caused by different genetic and environmental factors. One such factor could be rDNA amplification and changes in rRNA expression and maturation. Aim of the study: The aim of the present study was to investigate rRNA levels in patients with heteromorphism of the p-arms of acrocentric chromosomes bearing nucleolus organizer regions compared to a healthy control group. Material and methods: Frequencies of p-arms enlargements in patients with ID and in healthy people were analyzed by G-banding screening. rRNA gene copy numbers on affected acrocentric chromosomes in peripheral blood lymphocytes were evaluated in ID patients and healthy bearers using FISH, and in immortalized lymphocytes of one patient – using FISH and real time PCR. Simultaneously, levels of 18S, 28S and 5,8S rRNA in both groups by means of qRT-PCR were investigated. Results: No difference in acrocentric chromosome heteromorphism frequency in patients versus the healthy group were found. However, we found an amplification of rDNA, a significant elevation in 28S and 5.8S rRNA expression and changes in the 28S/18S rRNA ratio in ID patients compared to healthy controls. At the same time, FISH appeared to be not reliable enough for copy number evaluation, but RT-PCR showed rDNA copy changes in heteromorphic cells compared to normal. Conclusion: Our findings indicate a loss of the correct regulation of rDNA activity and processing after amplification. This could disturb the ribosomal apparatus and thus lead to intellectual disability via at least two mechanisms. Keywords: Intellectual disability, Acrocentric chromosomes, Nucleolus organizer region – NOR, Ribosomal DNA – rDNA, Ribosomal RNA – rRNA