desmosterol and Abnormalities--Multiple

3β-Hydroxysterol Δ(24)-reductase (DHCR24) catalyzes the conversion of desmosterol to cholesterol. This ultimate step of cholesterol biosynthesis appears to be remarkable in its diverse functions and the number of diseases it is implicated in from vascular disease to Hepatitis C virus (HCV) infection to cancer to Alzheimer's disease. This review summarizes the present knowledge on the DHCR24 gene, sterol Δ(24)-reductase protein and the regulation of both. In addition, the functions of desmosterol, DHCR24 and their roles in human diseases are discussed. It is apparent that DHCR24 exerts more complex effects than what would be expected based on the enzymatic activity of sterol Δ(24)-reduction alone, such as its influence in modulating oxidative stress. Increasing information about DHCR24 membrane association, processing, enzymatic regulation and interaction partners will provide further fundamental insights into DHCR24 and its many and varied biological roles.

Topics: Abnormalities, Multiple; Cell Membrane; Cholesterol; Desmosterol; Epigenomics; Humans; Lipid Metabolism, Inborn Errors; Male; Nerve Tissue Proteins; Oxidative Stress; Oxidoreductases Acting on CH-CH Group Donors

Topics: Abnormalities, Multiple; Animals; Brain; Cell Membrane; Cholesterol; Dehydrocholesterols; Desmosterol; Female; Homeostasis; Lipid Metabolism, Inborn Errors; Male; Mice; Mutation; Nerve Tissue Proteins; Neurons; Oxidoreductases Acting on CH-CH Group Donors; Smith-Lemli-Opitz Syndrome; Sterols; Tandem Mass Spectrometry

Desmosterol (cholesta-5,24-dien-3beta-ol) is a minor sterol that forms as an intermediate in the cholesterol biosynthetic pathway when the 24-unsaturated sterol bond is reduced as the last step rather than earlier in the conversion of lanosterol to cholesterol. In 1998, FitzPatrick et al. reported a premature infant who died shortly after birth and had marked tissue elevations of desmosterol and a strikingly abnormal phenotype. We describe here the first living patient with desmosterolosis and show biochemical evidence in plasma and cultured lymphoblasts for an autosomal recessive deficiency of 24-dehydrocholesterol reductase (DHCR24). The infant has severe microcephaly, agenesis of the corpus callosum, downslanting palpebral fissures, micrognathia, submucous cleft palate, clubfoot, and a persistent patent ductus arteriosus. Plasma sterol quantification in the patient at age 2 years demonstrated a normal cholesterol level, but a 100-fold increased level of desmosterol (60 mcg/ml; nl 0.5 +/- 0.3 mcg/ml (SD)) suggesting deficient activity of 24-dehydrocholesterol (desmosterol) reductase (DHCR24). Both parents had mildly increased levels of desmosterol in plasma (mother: 1.4 mcg/ml; father: 1.8 mcg/ml), consistent with heterozygosity for DHCR24 deficiency. Analysis of sterol metabolism in cultured transformed lymphoblasts showed a 100-fold increased level of desmosterol and a moderately decreased level of cholesterol in the patient's cells and a 10-fold elevation of desmosterol in the mother's cells. At the age of 3.5 years, the patient stands but does not walk, uses a 5-word vocabulary, and lacks any major medical problems. This unique patient broadens the spectrum of inborn errors of cholesterol biosynthesis and suggests additional candidate clinical phenotypes associated with abnormal cholesterol metabolism.

Topics: Abnormalities, Multiple; Child, Preschool; Cholesterol; Desmosterol; Developmental Disabilities; Family Health; Humans; Lipid Metabolism, Inborn Errors; Lymphocytes; Male; Nerve Tissue Proteins; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Phenotype

Desmosterolosis is a rare, autosomal recessive, human disease characterized by multiple congenital anomalies in conjunction with grossly elevated levels of desmosterol and markedly reduced levels of cholesterol in all bodily tissues. Herein, we evaluated retinal sterol composition, histology, and electrophysiological function in an animal model that exhibited the biochemical features of desmosterolosis, produced by treating pregnant rats and their progeny with U18666A, an inhibitor of desmosterol reductase. Treated rats had cataracts, were substantially smaller, and had markedly high levels of desmosterol and profoundly low levels of cholesterol in their retinas and other tissues compared to age-matched controls. However, their retinas were histologically normal and electrophysiologically functional. These results suggest that desmosterol may be able to replace cholesterol in the retina, both structurally and functionally. These findings are discussed in the context of "sterol synergism".

Topics: Abnormalities, Multiple; Androstenes; Animals; Anticholesteremic Agents; Cholesterol; Desmosterol; Disease Models, Animal; Female; Humans; Lens, Crystalline; Lipid Metabolism, Inborn Errors; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Retina; Rod Cell Outer Segment; Sterols

We describe a child with lethal multiple malformations and generalised accumulation of desmosterol. The infant had macrocephaly, a hypoplastic nasal bridge, thick alveolar ridges, gingival nodules, cleft palate, total anomalous pulmonary venous drainage, ambiguous genitalia, short limbs, and generalised osteosclerosis. Gas chromatography-mass spectrometry demonstrated an abnormal accumulation of desmosterol in kidney, liver. and brain. Higher than normal levels of the same sterol were detected in plasma samples obtained from both parents. The biochemical phenotype in this infant is highly suggestive of a novel inborn error of cholesterol biosynthesis caused by an autosomal recessive deficiency of 3betahydroxysterol-delta24-reductase. A phenotypic overlap of this case with Raine syndrome was noted; however, desmosterol accumulation was not found on postmortem tissue samples from a previously reported case of this disorder.

Topics: Abnormalities, Multiple; Adult; Cholesterol; Desmosterol; Female; Gas Chromatography-Mass Spectrometry; Humans; Infant, Newborn; Lipid Metabolism, Inborn Errors; Male; Middle Aged; Phenotype; Syndrome; Tissue Distribution

Topics: Abnormalities, Multiple; Cholesterol; Desmosterol; Female; Gas Chromatography-Mass Spectrometry; Humans; Infant, Newborn; Lipid Metabolism, Inborn Errors; Syndrome; Tissue Distribution