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

Robertsonian translocation 13/14 associated with rRNA genes overexpression and intellectual disability

Background: The Robertsonian translocations inherited from parents with a normal phenotype are often discovered through children with pathogenesis. The exact causes of pathologies in children with clinical manifestations are often unknown and vary greatly in the reported cases: uniparental disomy, de novo rearrangements, changes in methylation patterns and gene expression, including ribosomal genes

Aim of the study: Molecular-cytogenetic investigation of a clinical case of intellectual disability

Material and methods: GTG-banding, Ag-NOR staining, fluorescent in situ hybridization, PCR, real-time PCR

Results: We describe a family case of a translocation rob [13; 14] and elevated rRNA expression in the proband with developmental delay and in his phenotypically normal mother. We show the loss of the p-arms of original chromosomes and the absence of NORs on the derived chromosome. The wholechromosome uniparental disomy is excluded

Conclusion: The translocated chromosome in the proband was most likely inherited from the mother and did not come about de novo with normal chromosomes 13 and 14 being obtained from the father. The cause of the pathogenesis in the proband still remains unknown. We hypothesize that it could be caused by impaired imprinting manifesting in altered methylation levels of loci on the derivative chromosome