Biomedical subjects

Gracjan Michlewski

Publications and source records attributed to Gracjan Michlewski.

4 recordsLinked to original sources

PubMed2005

Pathogenesis of spinocerebellar ataxias viewed from the RNA perspective.

The underlying cause of a number of autosomal dominant spinocerebellar ataxias is the expansion of various types of simple sequence repeats located in diverse functional regions of different single genes. The genetic heterogeneity of these diseases which contrasts with the similarity of their pathology sites and clinical symptoms justifies the search for the shared mechanism of pathogenesis. In this article we discuss the arguments which are in favor of the RNA-mediated pathomechanism.

Heterozygote↗

PubMed2004

Molecular architecture of CAG repeats in human disease related transcripts.

CAG repeats are present in numerous human transcripts but neither their structures nor physiological functions have been satisfactorily recognized. The expanded CAG repeats are present in transcripts from several mutant genes associated with hereditary neurodegenerative diseases but their contribution to pathogenesis has not been documented convincingly. Here, we show that the structures formed by the repeats and their natural flanking sequences in the spinocerebellar ataxia (SCA) type 3 and type 6, and dentatorubral-palidoluysian atrophy (DRPLA) transcripts have different molecular architectures which may have functional meaning. We provide evidence that the hairpin structure formed by CAG repeats in mRNA fragments is preserved in full-length mRNA. We also demonstrate that the single-nucleotide polymorphism (SNP) that is located immediately adjacent (3') to the repeats of the SCA3 transcript modulates the structures formed by these sequences, and may have functional significance, as only one of its variants is selected in human evolution.

Ataxin-3↗

PubMed2003

RNA structure of trinucleotide repeats associated with human neurological diseases.

The tandem repeats of trinucleotide sequences are present in many human genes and their expansion in specific genes causes a number of hereditary neurological disorders. The normal function of triplet repeats in transcripts is barely known and the role of expanded RNA repeats in the pathogenesis of Triplet Repeat Expansion Diseases needs to be more fully elucidated. Here we have described the structures formed by transcripts composed of AAG, CAG, CCG, CGG and CUG repeats, which were determined by chemical and enzymatic structure probing. With the exception of the repeated AAG motif, all studied repeats form hairpin structures and these hairpins show several alternative alignments. We have determined the molecular architectures of these co-existing hairpin structures by using transcripts with GC-clamps which imposed single alignments of hairpins. We have provided experimental evidence that CCUG repeats implicated in myotonic dystrophy type 2 also form hairpin structures with properties similar to that composed of the CUG repeats.

Base Sequence↗

PubMed2003

Structures of trinucleotide repeats in human transcripts and their functional implications.

Among the goals of RNA structural and functional genomics is determining structures and establishing the functions of a rich repertoire of simple sequence repeats in transcripts. These repeats are present in transcripts from their 'birth' in the nucleus to their 'death' in cytoplasm and have the potential of being involved in many steps of RNA regulation. The knowledge of their structural features and functional roles will also shed more light on the postulated mechanisms of RNA pathogenesis in a growing list of neurological diseases caused by simple sequence repeat expansions. Here, we discuss several different lines of research to support the hypothesis that the mechanism of RNA pathogenesis may be a more common phenomenon triggered or modulated also by abundant long normal repeats. We propose structures of the repeat regions in transcripts of genes involved in Triplet Repeat Expansion Diseases. We have classified the polymorphic repeat alleles of these genes according to their ability to form hairpin structures in transcripts, and describe the distribution of different structural forms of the repeats in the human population. We have also reported the results of a systematic survey of the human transcriptome to identify mRNAs containing triplet repeats and to classify them according to structural and functional criteria. Based on this knowledge, we discuss the putative wider role of triplet repeat RNA hairpins in human diseases. A hypothetical model is proposed in which long normal RNA hairpins formed by the repeats may also be involved in pathogenesis.

Alleles↗