Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency.

Abstract

Lathosterol 5-desaturase catalyzes the conversion of lathosterol to 7-dehydrocholesterol in the next to last step of cholesterol synthesis. Inborn errors of cholesterol synthesis underlie a group of human malformation syndromes including Smith-Lemli-Opitz syndrome, desmosterolosis, CHILD syndrome, CDPX2 and lathosterolosis. We disrupted the lathosterol 5-desaturase gene (Sc5d ) in order to further our understanding of the pathophysiological processes underlying these disorders and to gain insight into the corresponding human disorder. Sc5d (-/-) pups were stillborn, had elevated lathosterol and decreased cholesterol levels, had craniofacial defects including cleft palate and micrognathia, and limb patterning defects. Many of the malformations found in Sc5d (-/-) mice are consistent with impaired hedgehog signaling, and appear to be a result of decreased cholesterol rather than increased lathosterol. A patient initially described as atypical SLOS with mucolipidosis was shown to have lathosterolosis by biochemical and molecular analysis. We identified a homozygous mutation of SC5D (137A>C, Y46S) in this patient. An unique aspect of the lathosterolosis phenotype is the combination of a malformation syndrome with an intracellular storage defect.

• Authors: Patrycja A Krakowiak, Christopher A Wassif, Lisa Kratz, Diana Cozma, Martina Kovárová, Ginny Harris, Alexander Grinberg, Yinzi Yang, Alasdair G W Hunter, Maria Tsokos, Richard I Kelley, Forbes D Porter
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 12 Issue 13 Pg. 1631-41 (Jul 01 2003) ISSN: 0964-6906 [Print] England
• PMID: 12812989 (Publication Type: Case Reports, Journal Article)

Chemical References

• Sterols
• lathosterol delta-5-dehydrogenase
• Cholesterol
• Oxidoreductases Acting on CH-CH Group Donors

Topics

• Amino Acid Sequence
• Animals
• Cholesterol (metabolism)
• Fibroblasts (metabolism, ultrastructure)
• Genotype
• Homozygote
• Humans
• Infant, Newborn
• Lipid Metabolism, Inborn Errors (genetics)
• Mice
• Mice, Transgenic
• Models, Chemical
• Models, Genetic
• Molecular Sequence Data
• Mutation
• Oxidoreductases Acting on CH-CH Group Donors (deficiency, genetics)
• Phenotype
• Sequence Homology, Amino Acid
• Skin (pathology)
• Smith-Lemli-Opitz Syndrome (genetics)
• Sterols (metabolism)
• Time Factors