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TitleTCL1A mediates DNA methylation defects in recurrent hydatidiform mole with NLRP7 pathogenic variants.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Year 2026
Publish dateMar 5, 2026
AuthorsZheng Gao / Qingting Liu / Lei Li / Ting Hu / Xukun Lu / Yu Wu / Dandan Qin / Xiaoxiao Wang / Chen Gu / Jinhong Li / Chengpeng Xu / Dan Zhou / Fan Zhou / YanLing Bai / Xiangjin Kang / Jianqiao Liu / Dong Deng / Lei Li /
PubMed AbstractPathogenic variants in NLRP7, implicated in 55% of recurrent hydatidiform mole characterized by hypomethylation at maternally methylated imprinted regions, are proposed to disrupt de novo DNA ...Pathogenic variants in NLRP7, implicated in 55% of recurrent hydatidiform mole characterized by hypomethylation at maternally methylated imprinted regions, are proposed to disrupt de novo DNA methylation in human oocytes. However, the precise mechanism remains unclear. Here, we identify TCL1A, a DNMT3A inhibitor, as an endogenous NLRP7-interacting partner. The cryo-EM structure of the NLRP7-TCL1A complex reveals its fundamental architecture. Comprehensive analysis demonstrates that the majority of recurrent hydatidiform mole-causing NLRP7 variants impair its interaction with TCL1A. Mechanistically, NLRP7 potentially safeguards oocyte methylome by sequestering TCL1A in the cytoplasm, thereby preventing its nuclear entry and subsequent suppression of DNMT3A-mediated de novo methylation. Combining in silico predictions and interaction analysis, we identify L766R as a pathogenic variant. These findings propose a cytoplasmic regulatory mechanism governing nuclear DNA methylation, explaining the hypomethylation pathogenesis in NLRP7 variant-associated recurrent hydatidiform mole.
External linksNat Commun / PubMed:41786744 / PubMed Central
MethodsEM (single particle)
Resolution3.58 - 4.12 Å
Structure data

63291

9lq2

EMDB-63291, PDB-9lq2:
Structure of human dimeric NLRP7-TCL1A complex
Method: EM (single particle) / Resolution: 3.58 Å

63292

9lq4

EMDB-63292, PDB-9lq4:
Structure of the human monomeric NLRP7-TCL1A complex
Method: EM (single particle) / Resolution: 4.12 Å

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / subcortical maternal complex

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