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DRPLA gene (atrophin-1) sequence and mRNA expression in human brain
R L Margolis1, S H Li, W S Young
1Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.
Brain Research. Molecular Brain Research
|March 1, 1996
Summary
Dentatorubral pallidoluysian atrophy (DRPLA) is linked to a CAG trinucleotide repeat expansion. The study found altered protein structure, not reduced mRNA, likely causes DRPLA pathology.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Dentatorubral pallidoluysian atrophy (DRPLA) is a neurodegenerative disorder caused by CAG trinucleotide repeat expansion.
- The atrophin-1 gene is implicated in DRPLA, with its glutamine repeat expansion being a key factor.
Purpose of the Study:
- To report the nucleic acid and deduced amino acid sequences of the open reading frame of the DRPLA gene.
- To investigate the expression patterns of atrophin-1 mRNA in DRPLA-affected and control brains.
Main Methods:
- Sequencing of independently isolated cDNA clones to determine gene sequences.
- Northern analysis and in situ hybridization to assess mRNA expression levels and localization.
Main Results:
- Identified eight nucleotide differences from the original sequence, leading to 34 amino acid changes, particularly in acidic/basic regions.
- Atrophin-1 mRNA is expressed in multiple brain regions.
- mRNA levels in DRPLA-diseased brains were indistinguishable from control brains.
Conclusions:
- The expanded allele in DRPLA does not cause significant mRNA loss.
- The pathology of DRPLA likely stems from altered structure and function of the abnormal atrophin-1 protein, rather than reduced gene expression.