Molecular characteristics

All TPFS patients to date have had a missense substitution at amino acid 65 of the PCGF2 protein. These have included NM_007144.2 c.194C>T, p.(Pro65Leu) in 11 unrelated individuals and c.193C>T, p.(Pro65Ser) in a pair of monozygotic twin sister.

Further research is required to define the pathophysiologic mechanism of TPFS. PCGF2 is part of a multiprotein complex called the polycomb repressive complex 1 (PRC1). PRC1 controls gene expression in embryonic and adult stem cells by histone modification. The Pro65 of PCGF2 is situated next to an extended loop region. The loop region has been implicated in binding to nucleosomes. It has been proposed that the Pro65 mutations may reduce the ability of PCGF2 to bind nucleosome. This may have dominant-negative effects on PRC1 function, altering the developmental program of multiple cell types and therefore lead to the complex human phenotype (Turnpenny et al. 2018).