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A rare heterozygous TREM2 coding variant identified in familial clustering of dementia affects an intrinsically disordered protein region and function of TREM2

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A rare heterozygous TREM2 coding variant identified in familial clustering of dementia affects an intrinsically disordered protein region and function of TREM2. / Karsak, Meliha; Glebov, Konstantin; Scheffold, Marina; Bajaj, Thomas; Kawalia, Amit; Karaca, Ilker; Rading, Sebastian; Kornhuber, Johannes; Peters, Oliver; Diez-Fairen, Monica; Frölich, Lutz; Hüll, Michael; Wiltfang, Jens; Scherer, Martin; Riedel-Heller, Steffi; Schneider, Anja; Heneka, Michael T; Fliessbach, Klaus; Sharaf, Ahmed; Thiele, Holger; Lennarz, Martina; Jessen, Frank; Maier, Wolfgang; Kubisch, Christian; Ignatova, Zoya; Nürnberg, Peter; Pastor, Pau; Walter, Jochen; Ramirez, Alfredo.

In: HUM MUTAT, Vol. 41, No. 1, 01.2020, p. 169-181.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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 2020, 'A rare heterozygous TREM2 coding variant identified in familial clustering of dementia affects an intrinsically disordered protein region and function of TREM2', HUM MUTAT, vol. 41, no. 1, pp. 169-181. https://doi.org/10.1002/humu.23904

APA

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, M. T., Fliessbach, K., Sharaf, A., ... Ramirez, A. (2020). A rare heterozygous TREM2 coding variant identified in familial clustering of dementia affects an intrinsically disordered protein region and function of TREM2. HUM MUTAT, 41(1), 169-181. https://doi.org/10.1002/humu.23904

Vancouver

Karsak M, Glebov K, Scheffold M, Bajaj T, Kawalia A, Karaca I et al. 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. https://doi.org/10.1002/humu.23904

Bibtex

@article{f4d14ec9dbaf446193403b5dded22f8a,
title = "A rare heterozygous TREM2 coding variant identified in familial clustering of dementia affects an intrinsically disordered protein region and function of TREM2",
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.",
author = "Meliha Karsak and Konstantin Glebov and Marina Scheffold and Thomas Bajaj and Amit Kawalia and Ilker Karaca and Sebastian Rading and Johannes Kornhuber and Oliver Peters and Monica Diez-Fairen and Lutz Fr{\"o}lich and Michael H{\"u}ll and Jens Wiltfang and Martin Scherer and Steffi Riedel-Heller and Anja Schneider and Heneka, {Michael T} and Klaus Fliessbach and Ahmed Sharaf and Holger Thiele and Martina Lennarz and Frank Jessen and Wolfgang Maier and Christian Kubisch and Zoya Ignatova and Peter N{\"u}rnberg and Pau Pastor and Jochen Walter and Alfredo Ramirez",
note = "{\textcopyright} 2019 The Authors. Human Mutation published by Wiley Periodicals, Inc.",
year = "2020",
month = jan,
doi = "10.1002/humu.23904",
language = "English",
volume = "41",
pages = "169--181",
journal = "HUM MUTAT",
issn = "1059-7794",
publisher = "Wiley-Liss Inc.",
number = "1",

}

RIS

TY - JOUR

T1 - A rare heterozygous TREM2 coding variant identified in familial clustering of dementia affects an intrinsically disordered protein region and function of TREM2

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

N1 - © 2019 The Authors. Human Mutation published by Wiley Periodicals, Inc.

PY - 2020/1

Y1 - 2020/1

N2 - 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.

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.

U2 - 10.1002/humu.23904

DO - 10.1002/humu.23904

M3 - SCORING: Journal article

C2 - 31464095

VL - 41

SP - 169

EP - 181

JO - HUM MUTAT

JF - HUM MUTAT

SN - 1059-7794

IS - 1

ER -