INTRODUCTION: The DHCR24 gene encodes an enzyme that converts desmosterol to cholesterol in the last step of cholesterol synthesis. Desmosterolosis is an autosomal-recessive disorder that is caused by mutation in the DHCR24 gene, resulting multiple developmental anomalies.
OBJECTIVE: The objective of this study was to understand the pathophysiology of desmosterolosis.
METHODS:DHCR24-knockout mice were used in this study. All homozygous mice (−/−) died soon after birth. DHCR24−/− mice demonstrated features of lethal restrictive dermopathy, associated with impaired skin barrier function as a result of hyperproliferation of undifferentiated keratinocytes throughout the epidermis. One other possible cause for neonatal death in DHCR24−/− mice is respiratory failure, as evidenced by severe cyanosis immediately after birth. We therefore studied the lung development of these mice. Lungs from the newborn alive pups were subjected to weight measurement and histologic and Western blot analyses.
RESULTS:DHCR24−/− mice were identified by their phenotype and genotyping. Lung-to-body weight ratio was decreased in DHCR24−/−. The space between lung surface and the thoracic wall was significantly increased as a result of less expansion of the lung. The majority of the lung portion consisted of collapsed alveoli and decreased saccular space in DHCR24−/− mice. No differentiation defect in alveolar type I cell was detected by Western blot and immunohistochemistry with anti-T1 α antibody, a type I cell–specific marker. Immunohistochemistry with anti–caveolin 1 demonstrated no change in vascular development.
CONCLUSIONS: A distinct saccular hypoplasia in DHCR24−/− mice suggests that there is an important role of DHCR24 in lung development. Additional experiments with surfactant compositions are needed to explore the underlying respiratory pathology.
Submitted by Rusella Mirza
- Copyright © 2008 by the American Academy of Pediatrics