 Hi, my name is Niklas Dahl, I'm a professor of clinical genetics at Uppsala University in Sweden. My main interest is to identify gene variants behind genetic disorders, and in this particular project we have identified the genetic background to the London distilled myopathy. This map of Scandinavia with Sweden in the middle indicates the distribution of the disorder, mainly in the middle part of Sweden and western part of Finland. The geographical distribution and the fact that the disorder is not described elsewhere in the world suggests a founder effect for the London distilled myopathy and a very strong such founder effect. We will now introduce you to the phenotype in the London distilled myopathy. This patient is 55 years old and she started to have symptoms from age 40, about first in the hands, later from the feet. Here is a typical finding, unequal power of different extensors, index finger and thumb, weaker for extension. Noticeable is atrophy in the first dorsal enterosis region between thumb and index finger. Noticeable, cleaner eminence is quite flat with muscle atrophy. And there is weakness for abduction of the thumb, but there is good power for flexion of the fingers. The patient has difficulties with fine motor skills, like zippers. Hi, my name is Joakim Kjar, I'm a researcher. I'm working with the genetic analysis of patients with the London distilled myopathy. Although linkage was established to chromosome 2 already in 1999, no candidate gene could be identified. By using microsatellite markers and segregation analysis, we were able to identify a shared haplotype in all affected individuals. The haplotype is specific to this patient group as we could not find it in any of the controlled chromosomes studied. The haplotype spans approximately 1.5 megabases and contains a little over 30 known genes. We performed exome sequencing on two individuals and were able to identify a single shared heterozygous variant within the chromosome 2 region. The variant was also excluded from 300 in-house exomes available. It could be seen to segregate within the families and was confirmed in all patients. The variant is a G to A transition in the T1 gene. The T1 gene encodes the RNA binding protein T cell intracellular antigen 1. As shown in A, T1 protein contains four functional domains, three RNA recognition motifs and a Q-rich domain known to interact with the U1C of the spliceosome as shown in figure B. The mutation is situated within this Q-rich domain. We hypothesized that this would lead to a reduced interaction of T1 to the U1C. One known target of T1 is the SMN2 transcript. And as shown in C, we show that the mutation leads to an increased alternative splicing, which includes a skipping of X and 7. Since T1 interacts with a very large number of different transcripts, we believe that these mutations results in a general defect of transcription and translation leading to cellular stress.