• Zhou Chen, Yinghui Zhang, and Xuezhi Zhao.
• Division of Nephrology, Shanghai Changzheng Hospital of Second Military Medical University, Kidney Institute of Chinese People's Liberation Army, Shanghai, China.
• Arch Med Sci. 2019 Jan 1; 15 (1): 165-173.

IntroductionFamilial focal and segmental glomerulosclerosis (FFSGS) was found in a large cohort of patients in our previous study. Under the sponsorship of the National Natural Science Foundation of China, we conducted linkage analysis and full exon sequencing on the genomes of 54 patients diagnosed with FFSGS. The results revealed a FAM40A gene signature in those patients. To determine whether FAM40A was associated with podocyte lesions and whether changes in the podocyte cytoskeleton could affect podocyte function, mouse podocytes (MPs) were used in this study.Material And MethodsFAM40A silencing, over-expression and mutant-type over-expression models of renal MPs were established, whereby roles of wild-type FAM40A and mutant FAM40A (c.1562T>C, p521M>T) in regulating the function of the MP cytoskeleton were explored by using cellular immunofluorescence, RT-qPCR and Western blot.ResultsFAM40A was expressed and localized in MPs and significantly enriched in the nucleus and perinuclear zone. Changes of FAM40A expression altered the morphology of the MPs and their cytoskeletal organization, which was characterized by disordered distribution of F-actin, loss of the foot process architecture and the functional protein of the slit diaphragm nephrin (p < 0.05 or p < 0.01). FAM40A mutation (p521M>T) led to the formation of round and blunt morphology of the MPs and loss of the foot-process structure. In addition, expression of the cytoskeletal protein F-actin was increased and concentrated in FAM40A mutated cells, whereas the expression of nephrin decreased in those cells (p < 0.01).ConclusionsFAM40A played an important role in maintaining the normal morphology and function of MPs by stabilizing the cytoskeleton of MPs. Moreover, mutant FAM40A (p521M>T) was able to alter the morphology and cytoskeleton of the MPs, and to decrease the expression of nephrin, which may be the main factor contributing to FSGS.

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