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Functional Aspects of a Mutation in the PLP2 Promoter Region of Patients with Non-Syndromic X-Linked Mental Retardation


Salamon,  Achim
Max Planck Society;

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Salamon, A. (2006). Functional Aspects of a Mutation in the PLP2 Promoter Region of Patients with Non-Syndromic X-Linked Mental Retardation. Diploma Thesis, Technische Universität, Berlin.

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Mental retardation is defined by an overall intelligence quotient lower than 70 that is accompanied by functional deficits in adaptive behaviour. 1 – 3% of the population are a ected by this disability. It can be caused by environmental and genetic factors. Environmental factors can be found in e.g. malnutrition or exposure to toxins, whereas genetic factors are represented by chromosomal rearrangements or single-gene mutations. In one third of the cases, mental retardation is associated with other clinical features and is therefore called syndromic, as opposed to non-syndromic forms where mental retardation is the only obvious sign. When screening a panel of patients with non-syndromic mental retardation for causative mutations, in 2.6% of the patients, a cytosine to adenine exchange was found 188 bp upstream of the translation start of the gene PLP2. This PLP2−188(A) genotype is not represented in the RefSeq. PLP2 codes for an integral membrane protein of the endoplasmic reticulum and was so far not implicated in mental retardation. As the promoter region of a gene regulates its transcription, the cytosine to adenine change might a ect gene expression. Thus, I investigated PLP2 expression on the mRNA level by Northern blotting and found that it was more than 2.7 fold reduced in nine carriers of PLP2−188(A) as compared to five controls with PLP2−188(C). In parallel, I investigated the occurence of the PLP2 promoter change in control panels containing genetic material from blood donors that were not characterized for their intelligence quotient and from people that were selected to have at least an average intelligence quotient. In the male blood donors, the A-variant was found with a frequency of 2.6%, whereas it was completely absent in people with at least average intelligence quotient. However, as the variation of the PLP2 promoter occurs with the frequency of a rare polymorphism, it cannot be an inevitable cause for mental retardation, but might still influence an individual’s susceptibility for being a ected by this disability. This is reflected in the concept of genetic modifiers. Since regulation of transcription in eucaryotes mostly is achieved through modifying the assembly rate of the transcriptional pre-initiation complex by transcription factors binding to the promoter region of the regulated gene, I analyzed the consequences of the cytosine to adenine change of the promoter sequence by electrophoretic mobility shift assays. In silico, I found that binding of the transcription factors REL and ETS1 was not predicted for the A-variant in contrast to PLP2−188(C). In vitro, protein-binding was confirmed, but not found to be di erential between both variants. However, this might have been due to limitations of the electrophoretic mobility shift assay, for the large protein-DNA complex formed could not be analyzed well on the polyacrylamide and agarose gels used. In conclusion, the absence of PLP2−188(A) in people with at least average intelligence quotient suggests a cognitive implication of this polymorphism. This is substantiated by the finding that this promoter site contains a transcription factor binding site. However, as no di erence concerning protein binding could be found between both variants, future research is needed to elucidate the role of PLP2−188(A) in the etiology of mental retardation.