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

PA Krakowiak, CA Wassif, L Kratz… - Human molecular …, 2003 - academic.oup.com
PA Krakowiak, CA Wassif, L Kratz, D Cozma, M Kovářová, G Harris, A Grinberg, Y Yang…
Human molecular genetics, 2003academic.oup.com
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 …
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.
Oxford University Press