Modeling Inherited Disorders of Post-Lanosterol Cholesterol Biosynthesis: From Animal Models to Patient-Derived Stem Cells

Résumé fourni par la source

Altered post-lanosterol cholesterol biosynthesis causes a heterogeneous group of rare inherited metabolic disorders, including Smith-Lemli-Opitz syndrome, desmosterolosis, lathosterolosis, and congenital hemidysplasia with ichthyosiform nevus and limb defects syndrome. These conditions are characterized by impaired cholesterol synthesis together with the accumulation of disease-specific sterol intermediates. Current experimental and clinical evidence suggests that pathogenesis reflects both cholesterol insufficiency and sterol-mediated toxicity, including oxidative stress, perturbed developmental signaling, membrane dysfunction, and impaired neurodevelopment. Experimental models have played a central role in elucidating these mechanisms and in evaluating emerging therapeutic strategies. This review provides a comprehensive overview of currently available experimental models used to investigate inherited cholesterol biosynthesis disorders, including genetically engineered animal models, patient-derived fibroblasts, immortalized and CRISPR/Cas9-edited cell lines, and induced pluripotent stem cell-based systems. Particular emphasis is placed on Smith-Lemli-Opitz syndrome, the most extensively studied disorder within this group, while recent advances in modeling desmosterolosis, lathosterolosis, and congenital hemidysplasia with ichthyosiform nevus and limb defects syndrome are also critically discussed. We compare the strengths and limitations of each experimental platform, highlighting their contributions to understanding sterol metabolism, developmental abnormalities, and cell-type-specific disease mechanisms. Finally, we discuss current challenges and future perspectives, including the development of patient-specific induced pluripotent stem cell models, genome editing approaches, and next-generation multicellular systems. Collectively, this review provides an updated framework for selecting appropriate experimental models to investigate cholesterol biosynthesis disorders and accelerate the development of mechanism-based therapeutic strategies.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.