Overview

Pathogenicity: Nasu-Hakola Disease : Pathogenic, Frontotemporal Dementia : Pathogenic, Alzheimer's Disease : Possible Risk Modifier
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia, Nasu-Hakola Disease
Reference Assembly: GRCh37/hg19
Position: Chr6:41129295 C>T
dbSNP ID: rs104894002
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Nonsense
Codon Change: CAG to TAG
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 2

Findings

The rs104894002 variant introduces a premature stop codon in place of glutamine at amino acid 33. This variant, in a homozygous state, was first described in two Italian sisters afflicted with Nasu-Hakola disease (NHD, also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy) (Soragna et al., 2003), a rare, autosomal-recessive disease characterized by bone cysts and early onset frontotemporal dementia (Paloneva et al., 2002). Both sisters began exhibiting behavioral symptoms at age 30, and imaging showed diffuse cerebral atrophy and basal ganglia calcification (Soragna et al., 2003). Four unaffected family members – the parents, brother, and daughter of one of the affected sisters – were found to be heterozygous carriers of this variant. Although clinically normal, neuropsychological testing of the brother (at age 46) and daughter (at age 20) revealed deficits in visuospatial memory, and functional imaging showed hypoperfusion in the basal ganglia (Montalbetti et al., 2005).

Subsequently, a pair of Belgian siblings with NHD were found to be homozygous for the Q33Ter mutation (Klunemann et al., 2005). These patients began exhibiting personality and behavioral changes in their late 30s. MRI showed leukoencephalopathy with sparing of arcuate fibers, cerebral atrophy, and thinning of the corpus callosum; basal ganglia calcification was seen on CT; and SPECT revealed extensive cerebral hypoperfusion.

More recently, a fifth NHD patient homozygous for the Q33Ter variant was described (Ghezzi et al., 2017). Personality changes, disorientation, and memory disturbances began in her mid-30s. MRI showed diffuse cortical atrophy and white-matter loss, while FDG-PET revealed cortical hypometabolism. Possible amyloid deposition, detected by florbetapir-PET imaging at age 39, was reported. However, additional, quantitative analyses will be required to determine whether there is an actual association between the Q33Ter variant and amyloid pathology. The parents of this patient, heterozygous carriers of the Q33Ter variant, were cognitively normal at age 72.

An additional homozygous carrier of the Q33Ter variant presented FTD-like symptoms, but did not exhibit the bone cysts characteristic of NHD (Guerreiro et al., 2013). This Turkish man, the son of consanguineous parents, developed behavioral symptoms at 20 years of age, followed by seizures, and executive dysfunction and memory impairment by age 30. Magnetic resonance imaging revealed focal atrophy of the frontal and temporal lobes and white-matter abnormalities. A very low level of sTREM2 (relative to cognitively normal controls, and FTD and AD patients) was detected by ELISA in plasma from this patient (Kleinberger et al., 2014). This patient's mother and a brother, both unaffected, were heterozygous carriers of the Q33Ter variant; genetic information about his father was not available (Guerreiro et al., 2013).

Genetic case-control studies have yielded inconsistent results regarding whether the Q33Ter variant associates with FTD or Alzheimer’s disease when heterozygous. An Italian study found this variant in three of 352 FTD patients but in none of 484 controls (p = 0.042) (Borroni et al., 2014); the variant was found in one of 359 FTD cases and none of 1,094 controls in a Belgian cohort, a difference that did not reach statistical significance (Cuyvers et al., 2014). Two studies have reported an association of the Q33Ter variant with AD (Borroni et al., 2014; Song et al., 2017), while several other studies failed to confirm this association (Benitez et al., 2013; Cuyvers et al., 2014; Guerreiro et al., 2013; Jin et al., 2014; Pottier et al., 2013). The variant was not found in Japanese subjects (approximately 2,200 cases and 2,500 controls) (Miyashita et al., 2014).

Neuropathology

An AD patient heterozygous for the Q33Ter variant has been described as having typical AD pathology (Guerreiro et al., 2013).

Biological Effect

HeLa cells transfected with Q33Ter TREM2 failed to express any mutant protein, as expected due to the presence of the premature stop codon (Park et al., 2015). However, the apparent presence of sTREM2 in plasma from a homozygous carrier of this variant (see above) implies that there may be some translation of the truncated transcripts (Kleinberger et al., 2014).

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References

Paper Citations

1. Soragna D, Papi L, Ratti MT, Sestini R, Tupler R, Montalbetti L. An Italian family affected by Nasu-Hakola disease with a novel genetic mutation in the TREM2 gene. J Neurol Neurosurg Psychiatry. 2003 Jun;74(6):825-6. PubMed.
2. Paloneva J, Autti T, Hakola P, Haltia MJ. Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL). In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K, Amemiya A, Ledbetter N, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. 2002 Jan 24 [updated 2015 Mar 12].
3. Montalbetti L, Ratti MT, Greco B, Aprile C, Moglia A, Soragna D. Neuropsychological tests and functional nuclear neuroimaging provide evidence of subclinical impairment in Nasu-Hakola disease heterozygotes. Funct Neurol. 2005 Apr-Jun;20(2):71-5. PubMed.
4. Klünemann HH, Ridha BH, Magy L, Wherrett JR, Hemelsoet DM, Keen RW, De Bleecker JL, Rossor MN, Marienhagen J, Klein HE, Peltonen L, Paloneva J. The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology. 2005 May 10;64(9):1502-7. PubMed.
5. Ghezzi L, Carandini T, Arighi A, Fenoglio C, Arcaro M, De Riz M, Pietroboni AM, Fumagalli GG, Basilico P, Calvi A, Scarioni M, Colombi A, Serpente M, Marotta G, Benti R, Scarpini E, Galimberti D. Evidence of CNS β-amyloid deposition in Nasu-Hakola disease due to the TREM2 Q33X mutation. Neurology. 2017 Dec 12;89(24):2503-2505. Epub 2017 Nov 15 PubMed.
6. Guerreiro RJ, Lohmann E, Brás JM, Gibbs JR, Rohrer JD, Gurunlian N, Dursun B, Bilgic B, Hanagasi H, Gurvit H, Emre M, Singleton A, Hardy J. Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol. 2013 Jan;70(1):78-84. PubMed.
7. Kleinberger G, Yamanishi Y, Suárez-Calvet M, Czirr E, Lohmann E, Cuyvers E, Struyfs H, Pettkus N, Wenninger-Weinzierl A, Mazaheri F, Tahirovic S, Lleó A, Alcolea D, Fortea J, Willem M, Lammich S, Molinuevo JL, Sánchez-Valle R, Antonell A, Ramirez A, Heneka MT, Sleegers K, van der Zee J, Martin JJ, Engelborghs S, Demirtas-Tatlidede A, Zetterberg H, Van Broeckhoven C, Gurvit H, Wyss-Coray T, Hardy J, Colonna M, Haass C. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med. 2014 Jul 2;6(243):243ra86. PubMed.
8. Borroni B, Ferrari F, Galimberti D, Nacmias B, Barone C, Bagnoli S, Fenoglio C, Piaceri I, Archetti S, Bonvicini C, Gennarelli M, Turla M, Scarpini E, Sorbi S, Padovani A. Heterozygous TREM2 mutations in frontotemporal dementia. Neurobiol Aging. 2014 Apr;35(4):934.e7-10. Epub 2013 Oct 16 PubMed.
9. Cuyvers E, Bettens K, Philtjens S, Van Langenhove T, Gijselinck I, van der Zee J, Engelborghs S, Vandenbulcke M, Van Dongen J, Geerts N, Maes G, Mattheijssens M, Peeters K, Cras P, Vandenberghe R, De Deyn PP, Van Broeckhoven C, Cruts M, Sleegers K, BELNEU consortium. Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia. Neurobiol Aging. 2014 Mar;35(3):726.e11-9. Epub 2013 Oct 9 PubMed.
10. Song W, Hooli B, Mullin K, Jin SC, Cella M, Ulland TK, Wang Y, Tanzi RE, Colonna M. Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement. 2017 Apr;13(4):381-387. Epub 2016 Aug 9 PubMed.
11. Benitez BA, Cooper B, Pastor P, Jin SC, Lorenzo E, Cervantes S, Cruchaga C. TREM2 is associated with the risk of Alzheimer's disease in Spanish population. Neurobiol Aging. 2013 Jun;34(6):1711.e15-7. Epub 2013 Feb 5 PubMed.
12. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, Hardy J, Alzheimer Genetic Analysis Group. TREM2 variants in Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):117-27. Epub 2012 Nov 14 PubMed.
13. Jin SC, Benitez BA, Karch CM, Cooper B, Skorupa T, Carrell D, Norton JB, Hsu S, Harari O, Cai Y, Bertelsen S, Goate AM, Cruchaga C. Coding variants in TREM2 increase risk for Alzheimer's disease. Hum Mol Genet. 2014 Nov 1;23(21):5838-46. Epub 2014 Jun 4 PubMed.
14. Pottier C, Wallon D, Rousseau S, Rovelet-Lecrux A, Richard AC, Rollin-Sillaire A, Frebourg T, Campion D, Hannequin D. TREM2 R47H variant as a risk factor for early-onset Alzheimer's disease. J Alzheimers Dis. 2013;35(1):45-9. PubMed.
15. Miyashita A, Wen Y, Kitamura N, Matsubara E, Kawarabayashi T, Shoji M, Tomita N, Furukawa K, Arai H, Asada T, Harigaya Y, Ikeda M, Amari M, Hanyu H, Higuchi S, Nishizawa M, Suga M, Kawase Y, Akatsu H, Imagawa M, Hamaguchi T, Yamada M, Morihara T, Takeda M, Takao T, Nakata K, Sasaki K, Watanabe K, Nakashima K, Urakami K, Ooya T, Takahashi M, Yuzuriha T, Serikawa K, Yoshimoto S, Nakagawa R, Saito Y, Hatsuta H, Murayama S, Kakita A, Takahashi H, Yamaguchi H, Akazawa K, Kanazawa I, Ihara Y, Ikeuchi T, Kuwano R. Lack of genetic association between TREM2 and late-onset Alzheimer's disease in a Japanese population. J Alzheimers Dis. 2014;41(4):1031-8. PubMed.
16. Park JS, Ji IJ, An HJ, Kang MJ, Kang SW, Kim DH, Yoon SY. Disease-Associated Mutations of TREM2 Alter the Processing of N-Linked Oligosaccharides in the Golgi Apparatus. Traffic. 2015 May;16(5):510-8. Epub 2015 Feb 24 PubMed.

Further Reading