In a recent study published by Cirulli et al (Science, 2015 Feb 19) whole exome sequencing of 2,874 ALS patients confirmed several known ALS genes and identified TBK1 as a novel ALS gene. TBK1 is known to be one of several proteins involved in autophagy, a degradation and recycling system for proteins within the cell. These observations support the second major paradigm shift in ALS research that came out of the Siddique laboratory with the identification of mutations in key components of the cellular protein recycling machinery, namely, p62 and ubiquilin2 (UBQLN2). Findings from the Siddique laboratory also show pathologic involvement of these proteins, as well as optineurin, in characteristic cellular inclusions of ALS not only in familial cases carrying mutations but also in the more common sporadic form of the disease. This implies that genes linked to rare familial cases may converge onto a unifying pathogenic pathway and thereby provide novel therapeutic targets common to a spectrum of diverse forms of ALS and ALS with dementia.
Whole exome sequencing (WES) is highly complex testing that sequences all (or nearly all) of the coding portions of the 22,000 human genes. It can be a valuable diagnostic tool for complex patients, and has become an important tool for gene-hunting in a research setting. Gene sequence information can be compared between patients to look for common areas of genetic changes that may cause disease. Dr. Siddique’s laboratory has been utilizing WES with our genetic database, and to date 193 exomes have been completed, leading to the identification of 10 genes that are associated with the progression of ALS. We have sequenced 75 sporadic ALS samples, 80 familial ALS samples, and 3 recessive ALS samples. Our laboratory staff have developed new pipelines and analytic tools to help identify mutations in these completed exomes as well as 121 new samples which are being sequenced in collaboration with Dr. Yongchao Ma of Lurie Children’s Hospital.