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

Patrycja A. Krakowiak, Christopher A. Wassif, Lisa Kratz, Diana Cozma, Martina Kovářová, Ginny Harris, Alexander Grinberg, Yinzi Yang, Alasdair G W Hunter, Maria Tsokos, Richard I. Kelley, Forbes D. Porter

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1631-1641
Number of pages11
JournalHuman Molecular Genetics
Volume12
Issue number13
DOIs
StatePublished - Jul 1 2003

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Cholesterol
Micrognathism
Smith-Lemli-Opitz Syndrome
Mucolipidoses
Hedgehogs
Cleft Palate
Extremities
Phenotype
Mutation
lathosterol delta-5-dehydrogenase
Lathosterolosis
Genes
lathosterol

ASJC Scopus subject areas

  • Genetics

Cite this

Lathosterolosis : An inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency. / Krakowiak, Patrycja A.; Wassif, Christopher A.; Kratz, Lisa; Cozma, Diana; Kovářová, Martina; Harris, Ginny; Grinberg, Alexander; Yang, Yinzi; Hunter, Alasdair G W; Tsokos, Maria; Kelley, Richard I.; Porter, Forbes D.

In: Human Molecular Genetics, Vol. 12, No. 13, 01.07.2003, p. 1631-1641.

Research output: Contribution to journalArticle

Krakowiak, PA, Wassif, CA, Kratz, L, Cozma, D, Kovářová, M, Harris, G, Grinberg, A, Yang, Y, Hunter, AGW, Tsokos, M, Kelley, RI & Porter, FD 2003, 'Lathosterolosis: An inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency', Human Molecular Genetics, vol. 12, no. 13, pp. 1631-1641. https://doi.org/10.1093/hmg/ddg172
Krakowiak, Patrycja A. ; Wassif, Christopher A. ; Kratz, Lisa ; Cozma, Diana ; Kovářová, Martina ; Harris, Ginny ; Grinberg, Alexander ; Yang, Yinzi ; Hunter, Alasdair G W ; Tsokos, Maria ; Kelley, Richard I. ; Porter, Forbes D. / Lathosterolosis : An inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency. In: Human Molecular Genetics. 2003 ; Vol. 12, No. 13. pp. 1631-1641.
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