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Human Molecular Genetics, 2003, Vol. 12, No. 13 1631-1641
DOI: 10.1093/hmg/ddg172
© 2003 Oxford University Press

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

Patrycja A. Krakowiak1, Christopher A. Wassif1, Lisa Kratz2, Diana Cozma1, Martina Kovárová3,4, Ginny Harris1, Alexander Grinberg5, Yinzi Yang6, Alasdair G.W. Hunter7, Maria Tsokos8, Richard I. Kelley2 and Forbes D. Porter1,*

1Unit on Molecular Dysmorphology, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA, 2The Johns Hopkins University, Kennedy Krieger Institute, Baltimore, MD 21205, USA, 3Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic, 4Molecular Inflammation Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA, 5Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA, 6National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA, 7Genetics Patient Service Unit, Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada and 8National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

Received March 31, 2003; Accepted May 7, 2003

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.

* To whom correspondence should be addressed at: HDB, NICHD, NIH, Bld. 10, Rm 9S241, 10 Center Dr., Bethesda, MD 20892, USA. Tel: +1 3014354432; Fax: +1 3014805791; Email: fdporter{at}helix.nih.gov


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