Why does the protective TMEM106B T185S variant fail to show protection in mouse models despite human genetic evidence?

OPEN

Human genetic studies consistently show the T185S variant is protective in FTLD-GRN carriers, yet this study found no protective effect in Grn knockout mice. This species-specific discordance suggests critical differences in disease mechanisms or variant function that could impact translational research. Gap type: contradiction Source paper: Lack of a protective effect of the Tmem106b "protective SNP" in the Grn knockout mouse model for frontotemporal lobar degeneration. (2023, Acta neuropathologica communications, PMID:36707901)

Priority: 0.82 Domain: neurodegeneration Hypotheses: 0
📊 Landscape Analysis

Landscape Summary: Why does the protective TMEM106B T185S variant fail to show protection in mouse models despite human genetic evidence? is a 0.82 priority gap in neurodegeneration. It has 0 linked hypotheses with average composite score 0.000. Status: open.

Key Unanswered Questions

Key Researchers

Colonna, Sevlever, et al. (TREM2 biology)

Clinical Trials

Why does the protective TMEM106B T185S variant fail to show protection in mouse models despite human genetic evidence? — INVOKE-2 (completed)

📈 Living Dashboards
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Hypotheses
0.000
Top Score
0.000
Avg Score
0
Debates
0.00
Avg Quality
0%
Resolution
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Mechanistic Families
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Hypothesis Score Distribution

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🌊 Knowledge Graph Connections

activates (2)

GAUCHER DISEASETMEM106BTMEM106BC9orf72

associated with (9)

ALZHEIMER DISEASETMEM106BTMEM106BneurodegenerationTMEM106BFtdTMEM106BAgingTMEM106BAmyotrophic Lateral Sclerosis
▸ Show 4 more

biomarker for (5)

TMEM106BSchizophreniaTMEM106BDementiaTMEM106BAmyotrophic Lateral SclerosisTMEM106BAlsTMEM106BAging

causes (10)

TMEM106BAmyotrophic Lateral SclerosisTMEM106BAlsTMEM106BFtdTMEM106BDementiaTMEM106BAlzheimer
▸ Show 5 more

data in (3)

TMEM106Bbenchmark_ot_ad_answer_key:TMEM106Bbenchmark_ot_ad_answer_key:TMEM106BTMEM106Bds-83b31ef18d49TMEM106B

exacerbates (1)

TMEM106BPPT1

increases risk (1)

TMEM106BGRN

interacts with (2)

C9orf72TMEM106BTMEM106BDementia

modulates (1)

TMEM106Blysosomal function

participates in (2)

TMEM106Boxidative stress responseTMEM106Blipid metabolism

provides data for (1)

TMEM106Bds-83b31ef18d49

regulates (8)

TMEM106BCell Subtype ProportionTMEM106BTDP-43 pathologyTMEM106Bendosome-lysosome functionTMEM106BAlsTMEM106BAmyotrophic Lateral Sclerosis
▸ Show 3 more

therapeutic target (4)

TMEM106BMsTMEM106BDementiaTMEM106BAlzheimerTMEM106BAls

treats (1)

TMEM106BGAUCHER DISEASE
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