摘要
SLC20A2, encoding human type III sodium-dependent phosphate transporter 2 (hPiT2), is the gene most frequently associated with primary familial brain calcification (PFBC). The mechanism by which a SLC20A2 mutation causes phosphate transporter dysfunction may depend on the functional region of hPiT2 being affected. We presented clinical and brain imaging data of a patient with idiopathic brain calcification. Genetic testing detected a novel, de novo and in silico-predicted deleterious variant, c.1891 C > T (p.Pro631Ser), in SLC20A2. Computational simulations revealed that, compared to the wild type, this variant hPiT2 was associated with a higher root mean square deviation in molecular dynamics, a smaller value with a wider range for the kink angle of transmembrane helix 8 (TM8), and a less flexible TM8 structural conformation. These molecular characteristics were also observed in the known pathogenic missense variants in the TM8 of hPiT2. The pathogenicity of the novel SLC20A2 variant p.Pro631Ser is supported by the computational simulations for molecular characteristics of the variant hPiT2. The findings also highlight the role of TM8 helix in maintaining normal hPiT2 functions.