Mutations in the human sterol Δ7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome

Christopher A. Wassif, Cheryl Maslen, Stivelia Kachilele-Linjewile, Don Lin, Leesa M. Linck, William E. Connor, Robert D. Steiner, Forbes D. Porter

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    314 Citations (Scopus)

    Abstract

    The Smith-Lemli-Opitz syndrome (SLOS; also known as 'RSH syndrome' [MIM 270400]) is an autosomal recessive multiple malformation syndrome due to a defect in cholesterol biosynthesis. Children with SLOS have elevated serum 7- dehydrocholesterol (7-DHC) levels and typically have low serum cholesterol levels. On the basis of this biochemical abnormality, it has been proposed that mutations in the human sterol Δ7-reductase (7-DHC reductase; E.C. 1.3.1.21) gene cause SLOS. However, one could also propose a defect in a gene that encodes a protein necessary for either the expression or normal function of sterol Δ7-reductase. We cloned cDNA encoding a human sterol Δ7- reductase (DHCR7) on the basis of its homology with the sterol Δ7-reductase from Arabidopsis thaliana, and we confirmed the enzymatic function of the human gene product by expression in SLOS fibroblasts. SLOS fibroblasts transfected with human sterol Δ7-reductase cDNA showed a significant reduction in 7-DHC levels, compared with those in SLOS fibroblasts transfected with the vector alone. Using radiation-hybrid mapping, we show that the DHCR7 gene is encoded at chromosome 11q12-13. To establish that defects in this gene cause SLOS, we sequenced cDNA clones from SLOS patients. In three unrelated patients we have identified four different mutant alleles. Our results demonstrate both that the cDNA that we have identified encodes the human sterol Δ7-reductase and that mutations in DHCR7 are responsible for at least some cases of SLOS.

    Original languageEnglish (US)
    Pages (from-to)55-62
    Number of pages8
    JournalAmerican Journal of Human Genetics
    Volume63
    Issue number1
    DOIs
    StatePublished - Jul 1998

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    Smith-Lemli-Opitz Syndrome
    Sterols
    Oxidoreductases
    Mutation
    Complementary DNA
    Genes
    Fibroblasts
    Cholesterol
    Radiation Hybrid Mapping
    Chromosomes, Human, Pair 13
    Serum
    Arabidopsis
    Clone Cells
    Alleles
    Gene Expression

    ASJC Scopus subject areas

    • Genetics

    Cite this

    Wassif, C. A., Maslen, C., Kachilele-Linjewile, S., Lin, D., Linck, L. M., Connor, W. E., ... Porter, F. D. (1998). Mutations in the human sterol Δ7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. American Journal of Human Genetics, 63(1), 55-62. https://doi.org/10.1086/301936

    Mutations in the human sterol Δ7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. / Wassif, Christopher A.; Maslen, Cheryl; Kachilele-Linjewile, Stivelia; Lin, Don; Linck, Leesa M.; Connor, William E.; Steiner, Robert D.; Porter, Forbes D.

    In: American Journal of Human Genetics, Vol. 63, No. 1, 07.1998, p. 55-62.

    Research output: Contribution to journalArticle

    Wassif, CA, Maslen, C, Kachilele-Linjewile, S, Lin, D, Linck, LM, Connor, WE, Steiner, RD & Porter, FD 1998, 'Mutations in the human sterol Δ7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome', American Journal of Human Genetics, vol. 63, no. 1, pp. 55-62. https://doi.org/10.1086/301936
    Wassif, Christopher A. ; Maslen, Cheryl ; Kachilele-Linjewile, Stivelia ; Lin, Don ; Linck, Leesa M. ; Connor, William E. ; Steiner, Robert D. ; Porter, Forbes D. / Mutations in the human sterol Δ7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. In: American Journal of Human Genetics. 1998 ; Vol. 63, No. 1. pp. 55-62.
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    abstract = "The Smith-Lemli-Opitz syndrome (SLOS; also known as 'RSH syndrome' [MIM 270400]) is an autosomal recessive multiple malformation syndrome due to a defect in cholesterol biosynthesis. Children with SLOS have elevated serum 7- dehydrocholesterol (7-DHC) levels and typically have low serum cholesterol levels. On the basis of this biochemical abnormality, it has been proposed that mutations in the human sterol Δ7-reductase (7-DHC reductase; E.C. 1.3.1.21) gene cause SLOS. However, one could also propose a defect in a gene that encodes a protein necessary for either the expression or normal function of sterol Δ7-reductase. We cloned cDNA encoding a human sterol Δ7- reductase (DHCR7) on the basis of its homology with the sterol Δ7-reductase from Arabidopsis thaliana, and we confirmed the enzymatic function of the human gene product by expression in SLOS fibroblasts. SLOS fibroblasts transfected with human sterol Δ7-reductase cDNA showed a significant reduction in 7-DHC levels, compared with those in SLOS fibroblasts transfected with the vector alone. Using radiation-hybrid mapping, we show that the DHCR7 gene is encoded at chromosome 11q12-13. To establish that defects in this gene cause SLOS, we sequenced cDNA clones from SLOS patients. In three unrelated patients we have identified four different mutant alleles. Our results demonstrate both that the cDNA that we have identified encodes the human sterol Δ7-reductase and that mutations in DHCR7 are responsible for at least some cases of SLOS.",
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    AU - Lin, Don

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    AU - Connor, William E.

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