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

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.

Pubmed ID: 12812989

Authors

  • Krakowiak PA
  • Wassif CA
  • Kratz L
  • Cozma D
  • Kovárová M
  • Harris G
  • Grinberg A
  • Yang Y
  • Hunter AG
  • Tsokos M
  • Kelley RI
  • Porter FD

Journal

Human molecular genetics

Publication Data

July 1, 2003

Associated Grants

None

Mesh Terms

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