Organization of the SCA8 Gene

SCA8 transcripts are expressed at low levels in the d(CTG) direction with the d(CTG) repeat located at the 3' end of a highly alternatively spliced transcript (Fig. 2). In humans, low steady-state transcript levels are found throughout the CNS and in testis and kidney, but not in other tissues (Janzen et al. 1999; Koob et al. 1999). The SCA8 d(CTG) repeat tract is conserved in chimpanzees, gorillas, and orangutans, with humans having larger alleles than these other species (Andres et al. 2003, 2004). At the genomic level, the SCA8 gene overlaps the 5' end of a second gene, Kelch-like 1 (KLHL1), which encodes an actin binding protein that is transcribed in the opposite direction (Koob et al. 1999; Nemes et al. 2000). Although no functional relationship between the two transcripts has been demonstrated, the genomic organization of the two genes and the evolutionary conservation of a much shorter SCA8 mouse gene without the d(CTG) repeat (Benzow and Koob 2002) suggests the possibility that one normal function of the SCA8 transcript may be to regulate KLHL1 transcripts through an antisense mechanism (Koob et al. 1999; Nemes et al. 2000; Benzow and Koob 2002). Although reverse-transcription PCR shows that SCA8 is transcribed in the d(CTG) orientation and sequence analysis shows a short ORF with 41 amino acids plus the d(CTG) expansion, this ORF appeared unlikely to be translated because of the relatively large number of upstream start and stop codons, lead-

Fig. 2 SCA8 gene organization. Exons are shown as boxes and alternate splice forms are indicated by dashed lines. The SCA8 repeat tract is located in exon A at the 3' end of the gene and is transcribed in the CTG orientation. The region of the SCA8 gene that overlaps the 5' end of KLHL1 is shown. Various alternative splice forms of the SCA8 transcript are indicated. (Reproduced from Mosemiller et al. 2003, with permission from S. Karger AG, Basel)

Fig. 2 SCA8 gene organization. Exons are shown as boxes and alternate splice forms are indicated by dashed lines. The SCA8 repeat tract is located in exon A at the 3' end of the gene and is transcribed in the CTG orientation. The region of the SCA8 gene that overlaps the 5' end of KLHL1 is shown. Various alternative splice forms of the SCA8 transcript are indicated. (Reproduced from Mosemiller et al. 2003, with permission from S. Karger AG, Basel)

ing to our hypothesis that SCA8 is mediated by an RNA mechanism similar to DM1 (Mosemiller et al. 2003; Koob et al. 1999).

Was this article helpful?

0 0

Post a comment