Lindex #1906

Kwiatkowski DJ, Ozelius L, Kramer PL, Perman S, Schuback DE, Gusella JF, Fahn S, Breakefield XO

Torsion Dystonia Genes in Two Populations Confined to a Small Region on Chromosome 9q32-34

American Journal of Human Genetics

1991; 49:366-371

Torsion dystonia is a syndrome characterized by sustained, involuntary muscle contractions that will frequently cause its victim to have abnormal posturing with twisting and repetitive movements. The familial forms of Idiopathic Torsion Dystonia (ITD) are usually inherited as autosomal dominant with reduced penetrance. In the absence of either known disease or identifiable biochemical or pathologic disorder it is classified as ITD. This disease occurs most frequency among Askenazi Jews and is less common in non-Jewish populations. Onset in childhood leads usually to severe disability dystonia, while adult onset is frequently more restricted.

Findings from a previous study (Ozelius et. al., 1989) revealed a genetic linkage between a gene for dystonia and DNA markers in the chromosome 9q32-34 region. In the present study 12 Askenazi Jewish families and one large family of mixed non-Jewish ancestry were analyzed. Evaluation was performed by standardized neurologic examinations by neurologists experienced in evaluating dystonia. Videotape exams were reviewed by examiners blinded to the identity of the subject.

Blood was obtained and DNA was prepared for analysis by Southern blot technique. Two polymorphic marker probes on 9q were used: pMCT136 for random VNTR locus D9S10 and pAK1B3.25 for the adenylate kinase-1 locus. A linkage map of 9q32-34 was created using the markers GSN, AK1, ABL, ASS and D9S10 (MCT 136) and a panel of 56 venezuelan reference pedigrees containing 631 individuals. Two point linkage analysis was performed with an age correction incorporated. Autosomal dominant inheritance of a rare gene was assumed, and penetrance was estimated at .30 in the Jewish families and .75 in the non Jewish family.

Analysis of the 12 Jewish families indicated that there were five, one, zero, one and three likely crossover events between, respectively, the GSN, AK1, ABL, ASS and D9S10 markers and the dystonia trait in different family members.

Two sets of multipoint analyses were performed: (1) one with dystonia locus, GSN and AK1 and (2) a second with dystonia AK1, ASS and D9S10 for the Jewish and non-Jewish families. With respect to Jewish families the DYT1 gene is clearly excluded from the region spanning GSN to AK1. The most likely position of the DYT1 gene is midway between AK1 and ASS very close to ABL. The 1-lod-unit confidence interval has been reduced from 18cm to 6cm. Analyses in the non-Jewish family clearly reflect the fact that no recombinations were observed between the dystonia locus and GSN, AK1, or ASS.

These data provide strong evidence that, in the Jewish population studied, the dystonia gene is located within the 11 cm interval flanked by AK1 and D9S10 with odds of 21,878:1 that the gene actually lies near the center of the 6-Cm interval between AK1 and ASS. The results in this study are consistent with the same gene or two related genes linked to each other, causing the disease in these two groups. The difference in penetrance may be explained by the occurrence of distinct mutations in the same gene in the two populations.