The SCA8 transcript is an antisense RNA to a brain-specific transcript encoding a novel actin-binding protein (KLHL1)

• Published in: Human molecular genetics Vol. 9; no. 10; pp. 1543 - 1551
• Main Authors: NEMES, J. P, BENZOW, K. A, KOOB, M. D
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 12-06-2000; Oxford Publishing Limited (England)
• Subjects: actin-binding protein; Alternative Splicing; Amino Acid Sequence; Animals; Biological and medical sciences; Blotting, Northern; Brain - metabolism; Carrier Proteins - chemistry; Carrier Proteins - genetics; Conserved Sequence; COS Cells; Cytoplasm - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA, Complementary - metabolism; Exons; Humans; Introns; Kelch gene; KLHL1 protein; Medical sciences; Mice; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Molecular Sequence Data; Neurology; Open Reading Frames; Plasmids; Promoter Regions, Genetic; RNA, Antisense; SCA8 gene; Sequence Homology, Amino Acid; Spinocerebellar ataxia; Spinocerebellar Ataxias - genetics; Tissue Distribution; Genome organization; Transcription; Chromosome D13; Homology; Gene; Microsatellite DNA; Degenerative disease; Human; Nervous system diseases; Translation; Splicing; Nucleotide sequence; Rodentia; Tissue specificity; Antisense RNA; Cerebral disorder; Genetic disease; Spinocerebellar heredodegeneration; Vertebrata; Mammalia; Complementary DNA; Mouse; Central nervous system disease; Spinal cord disease; Brain (vertebrata)
• DOI: 10.1093/hmg/9.10.1543
• EISSN: 1460-2083
• ISSN: 0964-6906; 1460-2083

Spinocerebellar ataxia type 8 (SCA8) is a neurodegenerative disorder caused by the expansion of a CTG trinucleotide repeat that is transcribed as part of an untranslated RNA. As a step towards understanding the molecular pathology of SCA8, we have defined the genomic organization of the SCA8 RNA transcripts and assembled a 166 kb segment of genomic sequence containing the repeat. The most striking feature of the SCA8 transcripts is that the most 5' exon is transcribed through the first exon of another gene that is transcribed in the opposite orientation. This gene arrangement suggests that the SCA8 transcript is an endogenous antisense RNA that overlaps the transcription and translation start sites as well as the first splice donor sequence of the sense gene. The sense transcript encodes a 748 amino acid protein with a predicted domain structure typical of a family of actin-organizing proteins related to the Drosophila Kelch gene, and so has been given the name Kelch-like 1 (KLHL1). We have identified the full-length cDNA sequence for both the human and mouse KLHLI genes, and have elucidated the general genomic organization of the human gene. The predicted open reading frame and promoter region are highly conserved, and both genes are primarily expressed in specific brain tissues, including the cerebellum, the tissue most affected by SCA8. Transfection studies with epitope-tagged KLHL1 demonstrate that the protein localizes to the cytoplasm, suggesting that it may play a role in organizing the actin cytoskeleton of the brain cells in which it is expressed.