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Abstract

Nance–Horan syndrome (NHS) is a rare X-linked genetic disorder characterized by congenital cataracts, dental anomalies, and neurodevelopmental impairments, caused by mutations in the NHS gene. In this study, two novel NHS mutations, c.3847C>T and c.2519_2520del, were identified in two unrelated Chinese Han families, and their pathogenic molecular mechanisms were elucidated. Functional analyses revealed that the c.3847C>T mutation exerts a dual pathogenic effect: It disrupts extracellular matrix homeostasis by downregulating COL4A1 and upregulating MMP9 , and it triggers oxidative stress, evidenced by elevated ROS levels, altered BAX/BCL-2 ratio, and reduced GPX4 expression, ultimately leading to apoptosis and impaired cell migration. In contrast, the c.2519_2520del mutation primarily impairs mitochondrial function, as indicated by decreased membrane potential, reduced ATP production, and downregulation of ALDH3A1 and SOD2 . This mitochondrial dysfunction is further exacerbated by suppressed PGC-1α expression, contributing to metabolic disturbances, and by p21 -mediated cell cycle arrest. These findings, for the first time, demonstrate that distinct types of NHS mutations cause disease via divergent mechanisms, extracellular matrix disruption versus mitochondrial dysfunction, providing molecular insights into the clinical phenotypic heterogeneity of NHS and laying a theoretical foundation for the development of mutation-specific precision therapies.