SNOMEDCT: 1220573009; ORPHA: 464440; DO: 0090050;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q37.3 | Dystonia 27 | 616411 | Autosomal recessive | 3 | COL6A3 | 120250 |
A number sign (#) is used with this entry because of evidence that dystonia-27 (DYT27) is caused by compound heterozygous mutation in the COL6A3 gene (120250) on chromosome 2q37.
Dystonia-27 (DYT27) is an autosomal recessive neurologic disorder characterized by onset of segmental isolated dystonia mainly affecting the craniocervical region and upper limbs in the first 2 decades of life (summary by Zech et al., 2015).
Zech et al. (2015) reported 2 German sibs, born of unrelated parents, with onset of segmental isolated dystonia involving the face, neck, bulbar muscles, and upper limbs at age 20 years. Symptoms included dystonic action and postural tremor, writer's cramp, oromandibular dystonia, and laryngeal dystonia. Three patients from 2 additional families were subsequently identified; all 3 had focal or segmental dystonia affecting the neck, oromandibular region, or upper limbs. Two sibs had onset at age 24 years and the third patient had onset at age 6 years.
The transmission pattern of DYT27 in the families reported by Zech et al. (2015) was consistent with autosomal recessive inheritance.
In affected members of 3 unrelated German families with autosomal recessive DYT27, Zech et al. (2015) identified compound heterozygous mutations in the COL6A3 gene (120250.0007-120250.0011) that segregated with the disorder in each family. The mutations in the first family were found by exome sequencing; mutations in the subsequent 2 families were found by sequencing exons 41 and 42 of the COL6A3 gene in 367 German cases with isolated dystonia. All patients carried mutations affecting the C terminus, and all had at least 1 mutation affecting exon 41. Patient fibroblasts showed normal distribution and organization of collagen VI. Functional studies of the variants were not performed, but selective knockdown of the zebrafish ortholog resulted in axonal targeting defects. Zech et al. (2015) hypothesized that perturbation of the brain extracellular matrix may underlie this form of dystonia.
Zech et al. (2015) found that morpholino knockdown of exon 42 of the zebrafish col6a3 gene, which corresponds to exon 41 of the human COL6A3 gene, caused dose-dependent motor neuron pathfinding, branching, and extension errors without overt collagen defects.
Zech, M., Lam, D. D., Francescatto, L., Schormair, B., Salminen, A. V., Jochim, A., Wieland, T., Lichtner, P., Peters, A., Gieger, C., Lochmuller, H., Strom, T. M., Haslinger, B., Katsanis, N., Winkelmann, J. Recessive mutations in the alpha-3 (VI) collagen gene COL6A3 cause early-onset isolated dystonia. Am. J. Hum. Genet. 96: 883-893, 2015. [PubMed: 26004199] [Full Text: https://doi.org/10.1016/j.ajhg.2015.04.010]