title: 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.affiliation: Unit on Molecular Dysmorphology, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Patrycja A
authors.initials: PA
authors.lastname: Krakowiak
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wassif
authors.forename: Lisa
authors.initials: L
authors.lastname: Kratz
authors.forename: Diana
authors.initials: D
authors.lastname: Cozma
authors.forename: Martina
authors.initials: M
authors.lastname: Kovárová
authors.forename: Ginny
authors.initials: G
authors.lastname: Harris
authors.forename: Alexander
authors.initials: A
authors.lastname: Grinberg
authors.forename: Yinzi
authors.initials: Y
authors.lastname: Yang
authors.forename: Alasdair G W
authors.initials: AG
authors.lastname: Hunter
authors.forename: Maria
authors.initials: M
authors.lastname: Tsokos
authors.forename: Richard I
authors.initials: RI
authors.lastname: Kelley
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008956:Models, Chemical; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000172:deficiency* / Q000235:genetics*; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D012867:Skin / Q000473:pathology; D019082:Smith-Lemli-Opitz Syndrome / Q000235:genetics*; D013261:Sterols / Q000378:metabolism; D013997:Time Factors
chemical_list: D013261:Sterols; C033144:lathosterol delta-5-dehydrogenase; D002784:Cholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors