A gene in the region of the autosomal dominant torsion dystonia locus on 9q34 contains SH3 signal transduction and binding motifs
- Harvard Medical School, Boston, MA (United States); and others
In a search to identify cytoskeletal proteins which might be involved in neuromuscular diseases, we identified an expressed tag (EST) that exhibited distant sequence homology to dystrophia and which mapped to 9q24-ter in somatic cell hybrids. A dinucleotide repeat polymorphism from a genomic clone of the EST showed complete co-segregation without recombination to the DYT1 locus on the 9q34 in families with autosomal dominant torsion dystonia. cDNAs were obtained from the brain cDNA libraries and these contained parts of trapped exons from the 9q34 region. Northern blotting reveals two distinct transcripts, 6-7 kb and 3 kb, which differ primarily in their 3{prime} untranslated regions. The transcripts are co-expressed at highest levels in brain and thymus, but are found in most other tissues as well. A comparison of cDNA sequences derived from this gene reveals a high degree of alternate processing in both the coding and 3{prime} untranslated regions. Antibodies raised against synthetic peptides from the ORF recognize a doublet of bands at approximately 50-55 kd in brain by Western blotting. In contrast to the Northern tissue distribution, the protein is detected only in small amounts in peripheral nerve and muscle and not at all in several other tissues, with the amount in thymus yet to be determined. A Genbank search of amino acid sequence homologies has revealed several interesting features, including: aN src homology 3 (SH3) domain that is a common feature of proteins involved in the tyrosine kinase signal transduction pathway and is found in some cytoskeletal proteins; a proline-rich region that may function as an intra- or intermolecular SH3 binding site; and weak homologies to the rod domains of dystrophin, myosin, and spectrin. These findings raise the possibility of a defect in signal transduction or the cytoskeleton as a cause of torsion dystonia. Mutation analysis of the gene and biochemical characterization of the protein are in progress.
- OSTI ID:
- 133826
- Report Number(s):
- CONF-941009--
- Journal Information:
- American Journal of Human Genetics, Journal Name: American Journal of Human Genetics Journal Issue: Suppl.3 Vol. 55; ISSN AJHGAG; ISSN 0002-9297
- Country of Publication:
- United States
- Language:
- English
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