Objective: Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain in humans. The etiology is heterogeneous and remains unexplained in approximately 75% of patients. Because perturbations of cholesterol homeostasis are an important model system to study HPE pathogenesis in animals, we examined cholesterol biosynthesis in lymphoblastoid cell lines of 228 HPE patients.
Methods: Using [2-14C]acetate as substrate, we developed an in vitro loading test that clearly identifies abnormal elevations of C27 sterols in lymphoblast-derived cells.
Results: Twenty-two HPE cell lines (9.6%) had abnormal sterol pattern in the in vitro loading test. In one previously reported patient, Smith-Lemli-Opitz syndrome (SLOS) was diagnosed, whereas others also had clearly reduced cholesterol biosynthesis of uncertain cause. The mean (SD) cholesterol level was 58 (15.4)% and 82 (4.7)% of total sterols in these cell lines and controls, respectively. The pattern of accumulating sterols was different from known defects of cholesterol biosynthesis. In 6 of the patients with abnormal lymphoblast cholesterol metabolism, additional mutations in genes known to be associated with HPE or chromosomal abnormalities were observed.
Conclusions: Impaired cholesterol biosynthesis may be a contributing factor in the cause of HPE and should be considered in the evaluation of causes of HPE, even if mutations in HPE-associated genes have already been found.
- Smith-Lemli-Opitz syndrome
- cholesterol biosynthesis
- cholesterol precursors
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