THAP11 is a zinc-finger transcription factor that serves dual roles in transcriptional regulation and chr16 accessibility modulation 1. Acting as both an activator and repressor of RNA polymerase II-dependent transcription, THAP11 functions within a complex with HCFC1 and ZNF143 to regulate diverse target genes and controls cobalamin metabolism through MMACHC gene expression regulation 2. The protein plays critical roles in cell growth and proliferation, with THAP11 alterations causing severe growth defects in cultured cells 2. Clinically, THAP11 mutations cause two distinct disease phenotypes. Biallelic loss-of-function mutations result in methylmalonic aciduria and homocystinuria type cblL, an inborn cobalamin disorder characterized by impaired MMACHC transcription 2. Conversely, pathogenic CAG trinucleotide repeat expansions (45-100 repeats) cause spinocerebellar ataxia 51 (SCA51), a late-onset neurodegenerative disorder 3. SCA51 involves gain-of-function mechanisms whereby mutant THAP11 with polyglutamine expansion forms cytoplasmic aggregates and triggers TREM2-mediated microglial activation, leading to cerebellar neurodegeneration 4. These findings establish THAP11 as essential for normal neural development and cellular metabolism, with distinct pathogenic mechanisms underlying different mutation classes.