Functional Aspects of a Mutation in the PLP2 Promoter Region of Patients with Non-Syndromic X-Linked Mental Retardation
Year: 2006
Type: other
Abstract: Mental retardation is defined by an overall intelligence quotient lower than 70 that is accompanied\nby functional deficits in adaptive behaviour. 1 – 3% of the population are\na ected by this disability. It can be caused by environmental and genetic factors. Environmental\nfactors can be found in e.g. malnutrition or exposure to toxins, whereas genetic\nfactors are represented by chromosomal rearrangements or single-gene mutations. In one\nthird of the cases, mental retardation is associated with other clinical features and is therefore\ncalled syndromic, as opposed to non-syndromic forms where mental retardation is the\nonly obvious sign.\nWhen screening a panel of patients with non-syndromic mental retardation for causative\nmutations, in 2.6% of the patients, a cytosine to adenine exchange was found 188 bp upstream\nof the translation start of the gene PLP2. This PLP2−188(A) genotype is not represented\nin the RefSeq. PLP2 codes for an integral membrane protein of the endoplasmic\nreticulum and was so far not implicated in mental retardation.\nAs the promoter region of a gene regulates its transcription, the cytosine to adenine\nchange might a ect gene expression. Thus, I investigated PLP2 expression on the mRNA\nlevel by Northern blotting and found that it was more than 2.7 fold reduced in nine carriers\nof PLP2−188(A) as compared to five controls with PLP2−188(C).\nIn parallel, I investigated the occurence of the PLP2 promoter change in control panels\ncontaining genetic material from blood donors that were not characterized for their intelligence\nquotient and from people that were selected to have at least an average intelligence\nquotient. In the male blood donors, the A-variant was found with a frequency of 2.6%,\nwhereas it was completely absent in people with at least average intelligence quotient.\nHowever, as the variation of the PLP2 promoter occurs with the frequency of a rare polymorphism,\nit cannot be an inevitable cause for mental retardation, but might still influence\nan individual’s susceptibility for being a ected by this disability. This is reflected in the\nconcept of genetic modifiers.\nSince regulation of transcription in eucaryotes mostly is achieved through modifying the\nassembly rate of the transcriptional pre-initiation complex by transcription factors binding\nto the promoter region of the regulated gene, I analyzed the consequences of the cytosine\nto adenine change of the promoter sequence by electrophoretic mobility shift assays. In\nsilico, I found that binding of the transcription factors REL and ETS1 was not predicted\nfor the A-variant in contrast to PLP2−188(C). In vitro, protein-binding was confirmed, but\nnot found to be di erential between both variants. However, this might have been due to\nlimitations of the electrophoretic mobility shift assay, for the large protein-DNA complex\nformed could not be analyzed well on the polyacrylamide and agarose gels used.\nIn conclusion, the absence of PLP2−188(A) in people with at least average intelligence\nquotient suggests a cognitive implication of this polymorphism. This is substantiated by\nthe finding that this promoter site contains a transcription factor binding site. However,\nas no di erence concerning protein binding could be found between both variants, future\nresearch is needed to elucidate the role of PLP2−188(A) in the etiology of mental retardation.
Source: MPG.PuRe (Max Planck Society)
Author: Achim Salamon
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W343551638