The genetic causes of basal ganglia calcification, dementia, and bone cysts

Klünemann, Hans-Hermann; Ridha, Basil H.; Magy, Laurent; Wherrett, John R.; Hemelsoet, Dimitri; Keen, R W; Bleecker, Jan De; Rossor, Martin N.; Marienhagen, Jörg; Klein, Helmfried E.; Peltonen, Leena; Paloneva, Juha

doi:10.1212/01.wnl.0000160304.00003.ca

Cited by 203 publications

(189 citation statements)

References 24 publications

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“…Seminal studies by Peltonen and colleagues identified loss of function mutations in Trem2 and DAP12, as the genetic cause of the recessive genetic disorder, Nasu-Hakola disease [3][4][5]. Nasu-Hakola disease is defined by early onset cognitive dementia and bone abnormalities [1,2].…”

Section: Discussionmentioning

confidence: 99%

“…Individuals with this disease die by their fourth or fifth decade. Seminal studies by Peltonen and colleagues identified loss of function mutations in two separate genes as the causes of this rare disorder: Triggering Receptor Expressed on Myeloid cells-2 (Trem2) and DNAX-activating protein of molecular mass 12 kDa (DAP12), also referred to as killer-cell activating receptor-associated protein (KARAP) and TYROBP [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

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Developmental Regulation of TREM2 and DAP12 Expression in the Murine CNS: Implications for Nasu-Hakola Disease

Thrash

Torbett

2008

Neurochem Res

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Trem2 is an orphan, DAP12 associated receptor constitutively expressed in vivo by subsets of microglia in the healthy adult murine CNS and in vitro by subsets of oligodendrocytes in neonatal mixed glial cultures. Loss of a functional Trem2 signaling pathway is the genetic cause of NasuHakola disease. Whether the early onset cognitive dementia and myelin-pallor associated with this disorder are due to deficits in functional Trem2 signaling in microglia and/or oligodendrocytes is still being debated. Here, we find that Trem2/DAP12 expression is detected in embryonic day 14 CNS mRNA. Using dual immunohistochemistry/in situ hybridization, we find that both Trem2 and DAP12 expression always co-localized with markers of microglia/macrophages. However, Trem2/ DAP12 positive microglia are found in very close apposition with CNP+ oligodendrocytes prior to myelination (post-natal day 1). In addition, CNS expression of TREM2 and DAP12 are not detected in PU.1KO which lack microglia and macrophages. Our data provide continuing support for NasuHakola disease being identified as a cognitive disorder caused by a primary dysfunction of CNS microglia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Developmental Regulation of TREM2 and DAP12 Expression in the Murine CNS: Implications for Nasu-Hakola Disease

Thrash

Torbett

2008

Neurochem Res

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“…Nasu-Hakola disease (NHD), also designated polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; OMIM 221770), is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by genetic mutations of either triggering receptor expressed on myeloid cells 2 (TREM2) or TYRO protein tyrosine kinase binding protein (TYROBP), alternatively named DNAXactivation protein 12 (DAP12), both of which are expressed on microglia in the brain (1). Clinically, the patients with NHD show recurrent bone fractures during the third decade of life, and a frontal lobe syndrome during the fourth decade of life, and progressive dementia and death until the fifth decade of life (2).…”

Section: Introductionmentioning

confidence: 99%

Alzheimer's disease pathology in Nasu-Hakola disease brains

Satoh

Kino

Yanaizu

et al. 2018

IRDR

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“…PSEN1 (presenilin 1), PSEN2 (presenilin 2) and APP (amyloid precursor protein) are implicated in early onset AD [Filley et al, 2007]. DAP12 named also TYROBP (TYRO protein tyrosine kinase binding protein; MIM# 604142) and TREM2 (triggering receptors expressed on myeloid cells-2; MIM# 605086) are responsible for PLOSL (Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy; MIM# 221770), an autosomal recessive disease characterized by early-onset progressive dementia and bone cysts [Paloneva et al, 2000;Kondo et al, 2002;Paloneva et al, 2002;Klünemann et al, 2005].…”

Section: Introductionmentioning

confidence: 99%

Mutations inTREM2lead to pure early-onset dementia without bone cysts

et al. 2008

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A genome-wide screen using 382 STR markers to localize and identify the gene implicated in early-onset dementia (EOD) without bone cysts in a Lebanese family with three affected subjects was conducted. A unique locus homozygous by descent at chromosome 6p21.2 locus was identified. Candidate genes were explored by fluorescent sequencing and the effect of the identified mutation was confirmed by qualitative and quantitative RT-PCR. The genetic analysis revealed a novel deletion, c.40+3delAGG, in the 5' consensus donor splice site in intron 1 of TREM2 gene which is known to be responsible for PLOSL (Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy) also designated as Nasu-Hakola disease. In silico analysis predicted a lower strength for the novel donor splice site. Qualitative RT-PCR revealed normal transcript while quantitative RT-PCR showed over twofold down-regulation of TREM2 transcripts. The expression profile of six genes SPP1, NEDD9, FSCN, BCL3, NFKBIA and CCL2 known as disrupted in TREM2-deficient samples was studied and showed same expression profile as TREM2-mutated samples except for CCL2 which was normally regulated. The significantly-reduced expression of TREM2 in our patients and the expression profiles of the six studied genes confirm a role for TREM2 in this distinct phenotype of EOD without bone cysts. To our knowledge, this is the first report of mutations in TREM2 causing a pure dementia.

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The genetic causes of basal ganglia calcification, dementia, and bone cysts

Abstract: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy should be considered in adult patients under age 50 years with dementia and basal ganglia calcification. Radiographs of ankles and wrists, and DNA test in uncertain cases, confirm the diagnosis.

Cited by 203 publications

References 24 publications

Developmental Regulation of TREM2 and DAP12 Expression in the Murine CNS: Implications for Nasu-Hakola Disease

Developmental Regulation of TREM2 and DAP12 Expression in the Murine CNS: Implications for Nasu-Hakola Disease

Alzheimer's disease pathology in Nasu-Hakola disease brains

Mutations inTREM2lead to pure early-onset dementia without bone cysts

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