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

• Published in: Human molecular genetics 2003-07, Vol.12 (13), p.1631-1641
• Main Authors: Krakowiak, Patrycja A., Wassif, Christopher A., Kratz, Lisa, Cozma, Diana, Kovářová, Martina, Harris, Ginny, Grinberg, Alexander, Yang, Yinzi, Hunter, Alasdair G.W., Tsokos, Maria, Kelley, Richard I., Porter, Forbes D.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Cholesterol - metabolism; Fibroblasts - metabolism; Fibroblasts - ultrastructure; Fundamental and applied biological sciences. Psychology; Genotype; Homozygote; Humans; Infant, Newborn; Lipid Metabolism, Inborn Errors - genetics; Mice; Mice, Transgenic; Models, Chemical; Models, Genetic; Molecular and cellular biology; Molecular Sequence Data; Mutation; Oxidoreductases Acting on CH-CH Group Donors - deficiency; Oxidoreductases Acting on CH-CH Group Donors - genetics; Phenotype; Sequence Homology, Amino Acid; Skin - pathology; Smith-Lemli-Opitz Syndrome - genetics; Sterols - metabolism; Time Factors
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddg172

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.