ALS Symposium: Session 8A GENETICS

The first talk in the GENETICS session was given by Roger Sher and demonstrated how the different genetic mouse backgrounds affect the survival of the human G93A SOD1 transgenic mice. In inbred lines, the B6 background extended life by 32 days whereas NOD, ALR and SJL backgrounds decreased the lifespan of the G93A SOD1 transgenic mice, but up to 52 days. This was not due to alterations in the expression of the transgene at either RNA or protein level. Sher and colleagues hypothesised that there were quantitative trait loci in the mice which conferred this advantage/disadvantage and identified region on chromosome 17, highly associated with this trait. Thirty-three genes have been identified in the region which have SNPs significantly associated either with a reduction in lifespan or onset of disease. Further analysis is ongoing. (The initial paper describing the effect of mouse background is available in Amyotroph Lateral Scler. 2011 12:79-86.)

The second talk, given by Xialou Liu, screened for ataxin 2 (ATXN2) expanded repeats in over 1000 Chinese ALS cases from across 30 of the 31 Chinese providences. CAG repeats were seen in 17 cases, though none were seen associated with the C9orf72 expansion. They proposed that whereas healthy controls can carry up to 27 pure CAG repeats and SCA2 is caused by 35-64 pure CAG repeats, expansions of CAG repeats with CAA interruptions of between 27 and 35 repeats cause ALS, whereas above 35 repeats are associates with Parkinsonism.

Isabella Fogh then presented recently published data on the identification of an ALS locus on Chr 17q11.2 using GWAS data from over 15,000 ALS cases originating from across Europe and the USA, all with European ancestry (Hum Mol Genet. 2013 E-pub). A second locus on Chr 18q11.2 was also discussed and work is ongoing to identify the causative genes.

Aaron Gitler then presented some unpublished data, rather than talk about the exome sequencing analysis of ALS trios which was recently published in Nature Neuroscience (2013, 16:851-5). They have been using yeast complementation assays to test the pathogenicity of profilin 1 (PFN1) mutations found in ALS patients and investigate the potential role of PFN1 in stress granules. The complementation assay can be done in 2 days and Aaron was happy to collaborate with anyone who has potential mutations to test their pathogenicity.

The final talk was given by Kevin Kenna, who discussed the use of public databases to establish if reported mutations are pathogenic (Hum Mutat. 2013, 34:836-41). With the increasing number of exome sequencing studies being completed, potential variants are screened out by establishing if they have already been reported in the 1000 genomes, dbSNP or Exome Sequencing Project (ESP) databases. However, of the 342 mutations reported on the ALSOD database, over 40% are found on one of these databases, and the majority of these are on dbSNP. Whilst some of these “mutations” may well be non-pathogenic, care should also be taken that true pathogenic mutations are not eliminated. Looking at the frequency of these nucleotide changes in the databases, compared to in ALS cases, is one way to evaluate the potential pathogenicity of these changes.