TY  - JOUR
AU  - Karsak, Meliha
AU  - Glebov, Konstantin
AU  - Scheffold, Marina
AU  - Bajaj, Thomas
AU  - Kawalia, Amit
AU  - Karaca, Ilker
AU  - Rading, Sebastian
AU  - Kornhuber, Johannes
AU  - Peters, Oliver
AU  - Diez-Fairen, Monica
AU  - Frölich, Lutz
AU  - Hüll, Michael
AU  - Wiltfang, Jens
AU  - Scherer, Martin
AU  - Riedel-Heller, Steffi
AU  - Schneider, Anja
AU  - Heneka, Michael T
AU  - Fliessbach, Klaus
AU  - Sharaf, Ahmed
AU  - Thiele, Holger
AU  - Lennarz, Martina
AU  - Jessen, Frank
AU  - Maier, Wolfgang
AU  - Kubisch, Christian
AU  - Ignatova, Zoya
AU  - Nürnberg, Peter
AU  - Pastor, Pau
AU  - Walter, Jochen
AU  - Ramirez, Alfredo
TI  - A rare heterozygous TREM2 coding variant identified in familial clustering of dementia affects an intrinsically disordered protein region and function of TREM2.
JO  - Human mutation
VL  - 41
IS  - 1
SN  - 1059-7794
CY  - New York, NY [u.a.]
PB  - Wiley-Liss
M1  - DZNE-2020-07292
SP  - 169-181
PY  - 2020
AB  - Rare coding variants in the triggering receptor expressed on myeloid cells-2 (TREM2) gene have been associated with Alzheimer disease (AD) and homozygous TREM2 loss-of-function variants have been reported in families with monogenic frontotemporal-like dementia with/without bone abnormalities. In a whole-exome sequencing study of a family with probable AD-type dementia without pathogenic variants in known autosomal dominant dementia disease genes and negative for the apolipoprotein E (APOE) ε4 allele, we identified an extremely rare TREM2 coding variant, that is, a glycine-to-tryptophan substitution at amino acid position 145 (NM_018965.3:c.433G>T/p.[Gly145Trp]). This alteration is found in only 1 of 251,150 control alleles in gnomAD. It was present in both severely affected as well as in another putatively affected and one 61 years old as yet unaffected family member suggesting incomplete penetrance and/or a variable age of onset. Gly145 maps to an intrinsically disordered region (IDR) of TREM2 between the immunoglobulin-like and transmembrane domain. Subsequent cellular studies showed that the variant led to IDR shortening and structural changes of the mutant protein resulting in an impairment of cellular responses upon receptor activation. Our results, suggest that a p.(Gly145Trp)-induced structural disturbance and functional impairment of TREM2 may contribute to the pathogenesis of an AD-like form of dementia.
KW  - Aged
KW  - Alleles
KW  - Animals
KW  - Cell Line
KW  - Dementia: diagnosis
KW  - Dementia: genetics
KW  - Female
KW  - Genetic Association Studies
KW  - Genetic Predisposition to Disease
KW  - Genetic Variation
KW  - Heterozygote
KW  - Humans
KW  - Intrinsically Disordered Proteins: genetics
KW  - Membrane Glycoproteins: genetics
KW  - Membrane Glycoproteins: metabolism
KW  - Middle Aged
KW  - Open Reading Frames: genetics
KW  - Pedigree
KW  - Phenotype
KW  - Protein Transport
KW  - Receptors, Immunologic: genetics
KW  - Receptors, Immunologic: metabolism
KW  - Signal Transduction
KW  - Exome Sequencing
LB  - PUB:(DE-HGF)16
C6  - pmid:31464095
DO  - DOI:10.1002/humu.23904
UR  - https://pub.dzne.de/record/140970
ER  -