TY - JOUR
T1 - Lathosterolosis
T2 - An inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency
AU - Krakowiak, Patrycja A.
AU - Wassif, Christopher A.
AU - Kratz, Lisa
AU - Cozma, Diana
AU - Kovářová, Martina
AU - Harris, Ginny
AU - Grinberg, Alexander
AU - Yang, Yinzi
AU - Hunter, Alasdair G.W.
AU - Tsokos, Maria
AU - Kelley, Richard Ian
AU - Porter, Forbes D.
N1 - Funding Information:
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
PY - 2003/7/1
Y1 - 2003/7/1
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddg172
DO - 10.1093/hmg/ddg172
M3 - Review article
C2 - 12812989
AN - SCOPUS:10744228153
SN - 0964-6906
VL - 12
SP - 1631
EP - 1641
JO - Human molecular genetics
JF - Human molecular genetics
IS - 13
ER -