THAP11 was first reported in relation to autosomal recessive methylmalonic acidemia with homocystinuria in 2017 (Quintana AM, et al., 2017, PMID: 28449119). THAP11 encodes a transcription factor that plays a central role for embryogenesis and the pluripotency of embryonic stem cells. It forms a complex with HCF-1, a transcriptional coregulator essential for cell-cycle progression and cell proliferation, and together they regulate the expression of MMACHC among other targets. Only one variant (Phe80Leu) has been reported in one proband (PMID: 28449119), resulting in loss of binding to the MMACHC promoter, and thus resulting in metabolic abnormalities similar to MMACHC deficiency, such as reduced adenosylcobalamin and methylcobalamin as well as decreased [14C]propionate and [14C]methyltetrahydrofolate incorporation. Experimentally, this gene-disease relationship is supported by its interaction with HCFC1 and their function in transcriptional regulation (PMID: 31905202) which was altered in patient cells (PMID: 28449119) and HEK293 cells expressing the Phe80Leu variant (PMID: 31905202). Additionally, knockdown in zebrafish (PMID: 28449119) resulted in phenotypes similar to other cobalamin C deficiencies, and a Phe80Leu knockin mouse model recapitulated the metabolic abnormalities observed in the patient (PMID: 35013307). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
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