Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Probable Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr6:41127579 G>T
dbSNP ID: rs766647311
Mutation Type: Point, Missense
Codon Change: GGG to TGG
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 3
This variant was identified in a patient from a nonconsanguineous Portuguese family with a history of dementia. The proband was diagnosed with early onset probable Alzheimer’s-type dementia at age 57, and was described as showing signs of primary progressive aphasia and posterior cortical atrophy. She began experiencing symptoms at age 53, including forgetfulness and difficulty locating objects in familiar environments. Her disease rapidly progressed, and she was unable to live independently two years after symptom onset. MRI at this time revealed diffuse cortical atrophy. The proband’s mother was diagnosed with probable AD at age 76, and her maternal grandmother was also reported to have suffered from dementia.
Whole-exome sequencing revealed a glycine-to-tryptophan substitution at amino acid 145 of TREM2. (No rare, disease-associated variants were found in other genes associated with AD, including APP, MAPT, GRN, PSEN1 and PSEN2, or in PRNP.) The proband, her affected mother, and two sisters were found to be heterozygous carriers of the TREM2 G145W variant. One sister, age 40, reported subjective cognitive impairment, while the other sister was unaffected at 61 years of age. An aunt, cognitively normal at 71 years, did not carry the variant. This segregation pattern suggests incomplete penetrance and/or a variable age of onset.
The G145W variant was not found in 1,269 controls or in 1,403 sporadic AD patients of Spanish or German decent. In the gnomAD database, this variant was found in a single individual with an unspecified neurological disorder.
The glycine-to-tryptophan substitution was predicted to be “probably damaging” by Polyphen-2 and to “affect protein function” by SIFT.
Heterologous expression systems were used to study the consequences of the G145W mutation. The mutation did not appear to affect membrane localization or glycosylation of the TREM2 protein, but did lead to a change in protein conformation. Amino acid 145 is located in an intrinsically disordered region (IDR) between the immunoglobulin-like and transmembrane domains, and the glycine-to-tryptophan substitution appears to result in shortening of the IDR. When co-expressed with its adaptor protein DAP12 in COS7 cells, the mutation resulted in weaker responses to stimulation, compared with wild-type TREM2—in this case, a change in cell size when the TREM2/DAP12 signaling complex was activated by antibody crosslinking of TREM2.
Last Updated: 01 Oct 2019
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- Karsak M, Glebov K, Scheffold M, Bajaj T, Kawalia A, Karaca I, Rading S, Kornhuber J, Peters O, Diez-Fairen M, Frölich L, Hüll M, Wiltfang J, Scherer M, Riedel-Heller S, Schneider A, Heneka MT, Fliessbach K, Sharaf A, Thiele H, Lennarz M, Jessen F, Maier W, Kubisch C, Ignatova Z, Nürnberg P, Pastor P, Walter J, Ramirez A. A rare heterozygous TREM2 coding variant identified in familial clustering of dementia affects an intrinsically disordered protein region and function of TREM2. Hum Mutat. 2020 Jan;41(1):169-181. Epub 2019 Sep 15 PubMed.
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