Getting close to finding the gene
Getting even closer to finding this gene
For several years, scientists had been getting
close to finding the early-onset
dystonia gene using genetice mapping. In 1989, linkage analysis of
polymorphic DNA and protein markers helped to locate a gene responsible
for susceptibility to dystonia. This dystonia gene appeared, by multipoint
linkage analysis, to lie in the q32-q34 region of human chromosome 9 (see
Fig.1) between markers ABO and D9S26. Results also suggested that the GSN
(gelsolin) locus was also between these two markers and that there was
close linkage between the GSN and the ITD1 (DYT1) loci (Ozelius,
et al., 1989). Then in 1992, Ozelius, et al., used linkage disequilibrium
analysis and were able to pinpoint the dystonia related gene to a 6-cM
region bounded by loci AK1 and ASS (argino-succinate synthetase). Also
the DYT1 gene is centromeric to ASS (Ozelius,
et al., 1992). Fiurther more, this 6-cM region lies between the ABO
and GSN loci. Then in 1995, Risch, et al., used six polymorphic markers
to span a 3-cM region, including the ASS locus (centromere-D9S62a/b-D9S63-ASS-ABL-D9S64-telomere).
Their findings suggested that the DYT1 gene must have been between D9S62
and ASS, and that it must also have been in close proximity to D9S63 (Risch,
et al., 1995).
All
these previous findings enabled scientists to get
even closer to finding this gene. In May
of 1997, Ozelius, et al., were able to pinpoint this gene. A YAC
contig was created, with a new polymorphic locus, to span a 600-kb region
including the D9S62a marker, which had been found in their 1992 study
by linkage disequilibrium analysis. These results enabled refinement of
the locus the area to a 150-kb region between the loci D9S2161 and D9S63(
Ozelius, et al., 1997). Thus, by progressing from increasingly focused
genetic mapping to a physical map of the exact location was obtained for
the disease-related gene. In September of 1997, final analysis of this
refined region lead to the discovery of the DYT1 gene this refined region
was further analyzed, which lead to the discovery of this gene and the
protein it codes for.