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@ARTICLE{Karsak:140970,
      author       = {Karsak, Meliha and Glebov, Konstantin and Scheffold, Marina
                      and Bajaj, Thomas and Kawalia, Amit and Karaca, Ilker and
                      Rading, Sebastian and Kornhuber, Johannes and Peters, Oliver
                      and Diez-Fairen, Monica and Frölich, Lutz and Hüll,
                      Michael and Wiltfang, Jens and Scherer, Martin and
                      Riedel-Heller, Steffi and Schneider, Anja and Heneka,
                      Michael T and Fliessbach, Klaus and Sharaf, Ahmed and
                      Thiele, Holger and Lennarz, Martina and Jessen, Frank and
                      Maier, Wolfgang and Kubisch, Christian and Ignatova, Zoya
                      and Nürnberg, Peter and Pastor, Pau and Walter, Jochen and
                      Ramirez, Alfredo},
      title        = {{A} rare heterozygous {TREM}2 coding variant identified in
                      familial clustering of dementia affects an intrinsically
                      disordered protein region and function of {TREM}2.},
      journal      = {Human mutation},
      volume       = {41},
      number       = {1},
      issn         = {1059-7794},
      address      = {New York, NY [u.a.]},
      publisher    = {Wiley-Liss},
      reportid     = {DZNE-2020-07292},
      pages        = {169-181},
      year         = {2020},
      abstract     = {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.},
      keywords     = {Aged / Alleles / Animals / Cell Line / Dementia: diagnosis
                      / Dementia: genetics / Female / Genetic Association Studies
                      / Genetic Predisposition to Disease / Genetic Variation /
                      Heterozygote / Humans / Intrinsically Disordered Proteins:
                      genetics / Membrane Glycoproteins: genetics / Membrane
                      Glycoproteins: metabolism / Middle Aged / Open Reading
                      Frames: genetics / Pedigree / Phenotype / Protein Transport
                      / Receptors, Immunologic: genetics / Receptors, Immunologic:
                      metabolism / Signal Transduction / Exome Sequencing},
      cin          = {AG Wiltfang / Clinical Dementia Research Bonn / AG Heneka ;
                      AG Heneka / AG Jessen / U Clinical Researchers - Bonn},
      ddc          = {610},
      cid          = {I:(DE-2719)1410006 / I:(DE-2719)1011305 /
                      I:(DE-2719)1011303 / I:(DE-2719)1011102 /
                      I:(DE-2719)7000001},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342) / 344
                      - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-342 / G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31464095},
      doi          = {10.1002/humu.23904},
      url          = {https://pub.dzne.de/record/140970},
}