Table 2. Mutations and variants in immune genes that cause or alter riskA for neurodegenertive disease.
Gene | Disease | Mutation/Variant |
---|---|---|
CSF1R | hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) | Numerous, more than 50 pathogenic variants, including missense, frameshift and non-sense mutations, but also deletions and splice-site mutations, all located in the intracellular tyrosine kinase domain, strongly support haploinsufficiency and partial loss of function in disease mechanism. Highly expressed on microglial cells and myeloid cells. |
GRN | frontotemporal dementia (FTD) | Numerous, heterozygous result in haploinsufficiency and thus partial loss of function through nonsense mediated RNA decay. Highly expressed by microglial cells. |
GRN | neuronal ceroid lipofuscinoses (NCL) | Numerous, homozygous or compound heterozygous mutations cause near complete loss of function |
TREM2 | Nasu-Hakola disease (NHD), also referred to as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also FTD | Numerous, homozygous or compound heterozygous mutations cause near complete loss of function. At least 11 mutations cause PLOSL/FTD. Not all mutation have been shown to have the osteodysplasia with the phenotype in those individuals largely FTD. Functionally mutations that cause PLOSL/FTD appear to be loss of function. Highly expressed on microglial cells. |
TYROBP | NHD/PLOSL | Multiple, homozygous or compound heterozygous mutations cause near complete loss of function. Mutations include deletions, insertions and frameshift, resulting in either no or truncated non-functional TYROB. Strongly expressed on Microglial Cells |
TREM2 | Increased Risk for AD | R47H and R62H TREM2 variants are associated with partial loss of function. Other variants may also be associated with altering AD risk, but studies showing these associations have not been as widely replicated |
ABI3 | Increased Risk for AD | S209F variants is associted with increased risk for AD. Expressed selectively on microglial cells, may function as part of the WAVE complex, implicated in regulation of cell migration. Little data on functional effects of variant. |
PLCG2 | Decreased risk for AD | P522R variant is associted with increased risk for AD. Initial data suggest that this variant slightly increases PLCG2 activity. Selectively expressed ion microglial cells in the brain and in many cells in the periphery. |
Numerous other variants in immune genes have been associated with AD, this table focuses only on the ones for which there is wide consensus in the field that these alter disease risk.