TREM2 Gene Compound Heterozygosity in Neurodegenerative Disorders

Article type: Research Article

Authors: Berdyński, Mariusz^a | Ludwiczak, Jan^{b; c} | Barczak, Anna^d | Barcikowska-Kotowicz, Maria^e | Kuźma-Kozakiewicz, Magdalena^{f; g} | Dunin-Horkawicz, Stanisław^b | Żekanowski, Cezary^a | Borzemska, Beata^{a; *}

Affiliations: [a] Department of Neurogenetics and Functional Genomics, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland | [b] Laboratory of Structural Bioinformatics, Centre of New Technologies, University of Warsaw, Warsaw, Poland | [c] Laboratory of Bioinformatics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland | [d] Rare and Civilisation Diseases Research Platform, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland | [e] Department of Neurology, Central Clinical Hospital of the Ministry of Interior, Warsaw, Poland | [f] Neurodegenerative Diseases Research Group, Medical University of Warsaw, Warsaw, Poland | [g] Department of Neurology, Medical University of Warsaw, Warsaw, Poland

Correspondence: [*] Correspondence to: Beata Borzemska, PhD, DSc, Department of Neurogenetics and Functional Genomics, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland. Tel.: +48 22 608 65 38; E-mail: beatab@imdik.pan.pl.

Abstract: Background:Homozygous variants of the TREM2 and TYROBP genes have been shown to be causative for multiple bone cysts and neurodegeneration leading to progressive dementia (NHD, Nasu-Hakola disease). Objective:To determine if biallelic variants of these genes and/or oligogenic inheritance could be responsible for a wider spectrum of neurodegenerative conditions. Methods:We analyzed 52 genes associated with neurodegenerative disorders using targeted next generation sequencing in a selected group of 29 patients (n = 14 Alzheimer’s disease, n = 8 frontotemporal dementia, n = 7 amyotrophic lateral sclerosis) carrying diverse already determined rare variants in exon 2 of TREM2. Molecular modeling was used to get an insight into the potential effects of the mutation. Results:We identified a novel mutation c.401_406delinsTCTAT; p.(Asp134Valfs*55) in exon 3 of TREM2 in an Alzheimer’s disease patient also carrying the p.Arg62His TREM2 variant. Molecular modeling revealed that the identified mutation prevents anchoring of the TREM2 protein in the membrane, leaving the core of the Ig-like domain intact. Conclusion:Our results expand the spectrum of neurodegenerative diseases, where the carriers of biallelic mutations in TREM2 have been described for Alzheimer’s disease, and highlight the impact of variant burden in other genes on phenotypic heterogeneity.

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, behavioral variant of frontotemporal dementia, compound heterozygosity, TREM2, TYROBP, variant burden

DOI: 10.3233/JAD-220210

Journal: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1211-1219, 2022