By targeted high-throughput sequencing and Sanger sequencing of the candidate Welander distal myopathy (WDM; 604454) region on chromosome 2p13, Hackman et al. (2013) identified a heterozygous 1362G-A transition in exon 13 of the TIA1 gene, resulting in a glu384-to-lys (E384K; 603518.0001) substitution that segregated with the disorder in all 57 Swedish and Finnish patients studied. The same mutation was also found in 3 patients from Great Britain who had a partially shared haplotype with the Nordic patients, indicating common ancestry. The mutation was not found in 202 Finnish control samples. The E384K mutation occurred at a highly conserved residue in the RNA-binding domain of the protein at the C terminus, also known as the prion-related domain that is required for TIA1 aggregation in stress granules. Immunofluorescence microscopy of patient muscle showed diffuse TIA1-labeled cytoplasmic aggregates or granules in some atrophic fibers and fibers containing rimmed vacuoles. However, most fibers appeared normal and had normal TIA1 nuclear localization. Analysis of TIA1 splice isoforms and protein stability showed no consistent differences between WDM muscle and control muscle. Expression of the mutant protein in HeLa cells resulted in a mild increased (10-20%) of stress granule numbers compared to controls. The increased number was apparently due to a change in stress-granule dynamics resulting from a gain of function.
Klar et al. (2013) also restricted the WDM-associated haplotype and performed exome sequencing of 43 patients from 35 families with the disorder. They identified a heterozygous E384K mutation resulting from a 1150G-A transition in the TIA1 gene and occurring in a Q-rich domain. The mutation was not found in 800 control chromosomes. Patient muscle biopsies showed increased splicing of exon 7 of the SMN2 gene (601627), reflecting impaired TIA1 function. Klar et al. (2013) hypothesized that reduced activity of TIA1 may result in decreased response to cellular stress, such as oxidative stress, that may cause age-related cellular atrophy in patients carrying the mutation. The age of the mutation was estimated to be 1,050 years earlier, coinciding with the epoch of early seafaring across the Baltic Sea.
