Computational molecular characterization of a novel SLC20A2 variant associated with primary familial brain calcification

• Published in: Scientific reports Vol. 15; no. 1; pp. 18682 - 8
• Main Authors: Lan, Shih-Chun, Huang, Yu-Sung, Tsai, Jia-Yin, Lan, Min-Yu, Sun, Yuh-Ju, Chang, Yung-Yee
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.05.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 631/114/2410; 631/114/2411; 631/208; 631/208/737; 692/699; 692/699/375; 692/699/375/365; Brain - diagnostic imaging; Brain - pathology; Brain Diseases - diagnostic imaging; Brain Diseases - genetics; Brain Diseases - pathology; Calcification; Calcinosis - diagnostic imaging; Calcinosis - genetics; Calcinosis - pathology; Conformation; Genetic screening; Humanities and Social Sciences; Humans; Molecular Dynamics Simulation; multidisciplinary; Mutation; Mutation, Missense; Neuroimaging; P631S variant; Pathogenicity; Phosphate transporter; Primary Familial brain calcification; Science; Science (multidisciplinary); SLC20 A2; Sodium-dependent phosphate transporter; Sodium-Phosphate Cotransporter Proteins, Type III - chemistry; Sodium-Phosphate Cotransporter Proteins, Type III - genetics; Sodium-Phosphate Cotransporter Proteins, Type III - metabolism; Primary Familial brain calcification; Molecular dynamics simulation; Sodium-dependent phosphate transporter; P631S variant; SLC20 A2
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-025-03953-1

SLC20A2 , encoding human type III sodium-dependent phosphate transporter 2 ( h PiT2), 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 h PiT2 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 h PiT2 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 h PiT2. The pathogenicity of the novel SLC20A2 variant p.Pro631Ser is supported by the computational simulations for molecular characteristics of the variant h PiT2. The findings also highlight the role of TM8 helix in maintaining normal h PiT2 functions.