Novel cataract-causing variant c.177dupC in c-MAF regulates the expression of crystallin genes for cell apoptosis via a mitochondria-dependent pathway

Congenital cataract (CC) is regarded as the most common hereditary ophthalmic disease in children. Mutations in CC-associated genes play important roles in CC formation, which provides the basis for molecular diagnosis and therapy. Among these CC-associated genes, v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (c-MAF) is considered an important transcription factor for eye and lens development. In this study, we recruited a three-generation Chinese Han family with CC. Gene sequencing revealed a novel duplication mutation in c-MAF (NM_005360.5: c.177dup) that caused frameshifting at residue 60 (p. M60fs) of c-MAF. Additionally, in the patient blood samples, the expression levels of related crystallin and noncrystallin genes confirmed that this novel duplication variant impaired the transactivation of c-MAF. Further functional analyses suggested that the c-MAF mutant induces the transcriptional inhibition of CRYAA and CRYGA and subsequently influences ME and G6PD expression levels, ultimately resulting in ROS generation and further leading to cell apoptosis via mitochondria-dependent pathways. In conclusion, we report a novel c-MAF heterozygous mutation that plays a vital role in CC formation in a Chinese family, broadening the genetic spectrum of CC.