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000140970 037__ $$aDZNE-2020-07292
000140970 041__ $$aEnglish
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000140970 1001_ $$aKarsak, Meliha$$b0
000140970 245__ $$aA rare heterozygous TREM2 coding variant identified in familial clustering of dementia affects an intrinsically disordered protein region and function of TREM2.
000140970 260__ $$aNew York, NY [u.a.]$$bWiley-Liss$$c2020
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000140970 520__ $$aRare coding variants in the triggering receptor expressed on myeloid cells-2 (TREM2) gene have been associated with Alzheimer disease (AD) and homozygous TREM2 loss-of-function variants have been reported in families with monogenic frontotemporal-like dementia with/without bone abnormalities. In a whole-exome sequencing study of a family with probable AD-type dementia without pathogenic variants in known autosomal dominant dementia disease genes and negative for the apolipoprotein E (APOE) ε4 allele, we identified an extremely rare TREM2 coding variant, that is, a glycine-to-tryptophan substitution at amino acid position 145 (NM_018965.3:c.433G>T/p.[Gly145Trp]). This alteration is found in only 1 of 251,150 control alleles in gnomAD. It was present in both severely affected as well as in another putatively affected and one 61 years old as yet unaffected family member suggesting incomplete penetrance and/or a variable age of onset. Gly145 maps to an intrinsically disordered region (IDR) of TREM2 between the immunoglobulin-like and transmembrane domain. Subsequent cellular studies showed that the variant led to IDR shortening and structural changes of the mutant protein resulting in an impairment of cellular responses upon receptor activation. Our results, suggest that a p.(Gly145Trp)-induced structural disturbance and functional impairment of TREM2 may contribute to the pathogenesis of an AD-like form of dementia.
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000140970 650_2 $$2MeSH$$aAged
000140970 650_2 $$2MeSH$$aAlleles
000140970 650_2 $$2MeSH$$aAnimals
000140970 650_2 $$2MeSH$$aCell Line
000140970 650_2 $$2MeSH$$aDementia: diagnosis
000140970 650_2 $$2MeSH$$aDementia: genetics
000140970 650_2 $$2MeSH$$aFemale
000140970 650_2 $$2MeSH$$aGenetic Association Studies
000140970 650_2 $$2MeSH$$aGenetic Predisposition to Disease
000140970 650_2 $$2MeSH$$aGenetic Variation
000140970 650_2 $$2MeSH$$aHeterozygote
000140970 650_2 $$2MeSH$$aHumans
000140970 650_2 $$2MeSH$$aIntrinsically Disordered Proteins: genetics
000140970 650_2 $$2MeSH$$aMembrane Glycoproteins: genetics
000140970 650_2 $$2MeSH$$aMembrane Glycoproteins: metabolism
000140970 650_2 $$2MeSH$$aMiddle Aged
000140970 650_2 $$2MeSH$$aOpen Reading Frames: genetics
000140970 650_2 $$2MeSH$$aPedigree
000140970 650_2 $$2MeSH$$aPhenotype
000140970 650_2 $$2MeSH$$aProtein Transport
000140970 650_2 $$2MeSH$$aReceptors, Immunologic: genetics
000140970 650_2 $$2MeSH$$aReceptors, Immunologic: metabolism
000140970 650_2 $$2MeSH$$aSignal Transduction
000140970 650_2 $$2MeSH$$aExome Sequencing
000140970 7001_ $$aGlebov, Konstantin$$b1
000140970 7001_ $$aScheffold, Marina$$b2
000140970 7001_ $$aBajaj, Thomas$$b3
000140970 7001_ $$aKawalia, Amit$$b4
000140970 7001_ $$aKaraca, Ilker$$b5
000140970 7001_ $$aRading, Sebastian$$b6
000140970 7001_ $$aKornhuber, Johannes$$b7
000140970 7001_ $$0P:(DE-HGF)0$$aPeters, Oliver$$b8
000140970 7001_ $$aDiez-Fairen, Monica$$b9
000140970 7001_ $$aFrölich, Lutz$$b10
000140970 7001_ $$aHüll, Michael$$b11
000140970 7001_ $$0P:(DE-2719)2811317$$aWiltfang, Jens$$b12$$udzne
000140970 7001_ $$aScherer, Martin$$b13
000140970 7001_ $$aRiedel-Heller, Steffi$$b14
000140970 7001_ $$0P:(DE-2719)2812035$$aSchneider, Anja$$b15$$udzne
000140970 7001_ $$0P:(DE-2719)2000008$$aHeneka, Michael T$$b16$$udzne
000140970 7001_ $$0P:(DE-HGF)0$$aFliessbach, Klaus$$b17
000140970 7001_ $$aSharaf, Ahmed$$b18
000140970 7001_ $$aThiele, Holger$$b19
000140970 7001_ $$aLennarz, Martina$$b20
000140970 7001_ $$0P:(DE-2719)2000032$$aJessen, Frank$$b21$$udzne
000140970 7001_ $$0P:(DE-2719)2000015$$aMaier, Wolfgang$$b22$$udzne
000140970 7001_ $$aKubisch, Christian$$b23
000140970 7001_ $$aIgnatova, Zoya$$b24
000140970 7001_ $$aNürnberg, Peter$$b25
000140970 7001_ $$aPastor, Pau$$b26
000140970 7001_ $$0P:(DE-HGF)0$$aWalter, Jochen$$b27$$eCorresponding author
000140970 7001_ $$0P:(DE-HGF)0$$aRamirez, Alfredo$$b28
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