TMEM106B Haplotype as Genetic Modifier in FTD — Mechanism and Therapeutic Exploitation

SUMMARY

# TMEM106B Haplotype as Genetic Modifier in FTD — Mechanism and Therapeutic Exploitation ## Background and Rationale Validation experiment to elucidate how the TMEM106B protective haplotype modifies FTD disease course, with implications for therapeutic target identification. **Protocol**: (1) CRISPR-engineered iPSC lines: isogenic GRN+/- (FTD risk) with either TMEM106B risk or protective haplotype (4 lines total). Differentiate to cortical neurons, microglia, and astrocytes. (2) Multi-omic prof

METHODOLOGY NOTES

**Phase 1: Patient Cohort Assembly and Genetic Characterization (Months 1-6)** • Recruit n=500 FTD patients with confirmed pathogenic mutations (C9orf72, MAPT, GRN) and n=500 age-matched controls • Extract genomic DNA from peripheral blood samples using Qiagen QIAamp DNA Blood Maxi Kit • Perform whole genome sequencing (30x coverage) on Illumina NovaSeq 6000 platform • Genotype TMEM106B rs1990622 and rs3173615 variants using TaqMan assays in triplicate • Construct TMEM106B haplotypes (protective vs. risk) based on linkage disequilibrium patterns • Collect detailed clinical phenotyping including age of onset, disease duration, CDR-FTLD scores **Phase 2: Functional Mechanism Investigation (Months 7-18)** • Generate iPSC lines from n=24 FTD patients (12 protective haplotype, 12 risk haplotype) • Differentiate iPSCs to cortical neurons using dual SMAD inhibition protocol (21-day protocol) • Perform TMEM106B protein quantification via Western blot and immunofluorescence microscopy • Measur