Genetics of amyotrophic lateral sclerosis
Association between genetics and ALS / From Wikipedia, the free encyclopedia
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There are more than 25 genes known to be associated with amyotrophic lateral sclerosis (ALS) as of June 2018,[1] which collectively account for about 70% of cases of familial ALS (fALS) and 10% of cases of sporadic ALS (sALS).[2] About 5–10% of cases of ALS are directly inherited.[3] Overall, first-degree relatives of an individual with ALS have a 1% risk of developing ALS.[4][5] ALS has an oligogenic mode of inheritance, meaning that mutations in two or more genes are required to cause disease.[6]
C9orf72 is the most common gene associated with ALS, causing 40% of familial cases of ALS, as well as a small percentage of sporadic cases;[7] it also causes about 25% of familial cases of frontotemporal dementia.[6] The pathogenic mutation is a hexanucleotide repeat expansion (a series of six nucleotides repeated over and over); the more repeats in C9orf72, the more pathogenic the mutation. People without ALS tend to have fewer than 25 repeat units, while people with ALS due to a mutation in C9orf72 tend to have hundreds or thousands of repeat units. It is not clear exactly how many repeat units are needed to cause disease.[1]
SOD1, which codes for superoxide dismutase 1, is the second most common gene associated with ALS and causes about 12% of familial cases and about 2% of sporadic cases.[6] More than 150 mutations in SOD1 have been described, almost all of which have an autosomal dominant mode of inheritance.[8]
TARDBP, which codes for TAR DNA-binding protein (TDP-43), is associated with 1–5% of familial ALS and less than 1% of sporadic ALS.[6] While TARDBP mutations are somewhat rare in ALS, pathological aggregations of TDP-43 are seen in up to 97% of ALS patients and up to 50% of FTD patients.[1] TDP-43 is involved in the repair of DNA double-strand breaks. It is recruited to DNA damage sites and interacts with proteins involved in the repair process of non-homologous end joining.[9]
FUS, which codes for "Fused in sarcoma" protein, is associated with 1–5% of familial ALS and less than 1% of sporadic ALS. FUS is an RNA-binding protein with a similar function to TDP-43.[6]
Some people have both ALS and frontotemporal dementia (FTD–ALS). The four main genes associated with FTD–ALS are C9orf72, CHCHD10, SQSTM1, and TBK1.[8] C9orf72 repeat expansions explain about 40% of familial ALS and 25% of familial FTD; thus, C9orf72 provides a genetic explanation for most of the overlap between the two diseases.[6] While about half of the people with ALS have some degree of cognitive impairment, only 10-15% have cognitive impairment severe enough to meet the criteria for frontotemporal dementia (FTD). Additionally, about 15% of people with FTD have symptoms of motor neuron dysfunction that resemble ALS.[10] Mutations in TARDBP, FUS, C9orf72, and other genes can cause ALS as well as related forms of frontotemporal dementia (FTD–ALS). Proteins made by these genes appear to have prion-like activity and form inclusion bodies in some instances of ALS.[11][12]