A novel APOL1 membrane-addressing domain mutation (p.T272I) in Chinese twins with FSGS: implications for podocyte injury and ion channel disruption.

Apolipoprotein L1 (APOL1) risk variants are strongly associated with kidney diseases, including focal segmental glomerulosclerosis (FSGS), though known mutations (G1/G2) are primarily observed in African populations. This study reports a novel APOL1 mutation (p.T272I) identified in a pair of Chinese twins with FSGS, expanding the genetic spectrum of APOL1-related nephropathies. Whole exome sequencing detected the APOL1 mutation in the twins and excluded parental inheritance. Functional studies demonstrated that transfection of mutant APOL1 into human podocytes and HEK293T cells led to cytoplasmic lysis, disrupted F-actin organization, and reduced expression of nephrin and synaptopodin. The variant also induced mitochondrial dysfunction, increased the LC3-II/I ratio, activated p38 MAPK signaling, and altered chloride channel activity. Structural modeling via AlphaFold2 suggested conformational disturbance within the membrane-addressing domain. These findings reveal the first de novo APOL1 mutation in the Chinese population, implicating podocyte injury through cytoskeletal collapse, mitochondrial damage, altered autophagic markers, and ion channel dysfunction in FSGS pathogenesis. This study expands the spectrum of APOL1-related variants beyond G1/G2 and highlights underlying mechanisms for potential therapeutic targeting.