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

Patrycja A. Krakowiak, Christopher A. Wassif, Lisa Kratz, Diana Cozma, Martina Kovářová, Ginny Harris, Alexander Grinberg, Yinzi Yang, Alasdair G W Hunter, Maria Tsokos, Richard I. Kelley, Forbes D. Porter

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1631-1641
Number of pages11
JournalHuman Molecular Genetics
Volume12
Issue number13
DOIs
Publication statusPublished - Jul 1 2003

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ASJC Scopus subject areas

  • Genetics

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