TY - JOUR
T1 - Mutations in the human sterol Δ7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome
AU - Wassif, Christopher A.
AU - Maslen, Cheryl
AU - Kachilele-Linjewile, Stivelia
AU - Lin, Don
AU - Linck, Leesa M.
AU - Connor, William E.
AU - Steiner, Robert D.
AU - Porter, Forbes D.
N1 - Funding Information:
R.D.S. was supported in part by U.S. Public Health Service grant 5 M01 RR 00334 and by a Young Investigator Grant from the American Association of Pediatrics Section on Genetics and Birth Defects. We would like to express our thanks to Dr. Bruce Dowton and Rachel Slaugh for their help with this project. We would also like to express our appreciation to the families of the patients.
PY - 1998/7
Y1 - 1998/7
N2 - 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.
AB - 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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U2 - 10.1086/301936
DO - 10.1086/301936
M3 - Article
C2 - 9634533
AN - SCOPUS:0032231459
SN - 0002-9297
VL - 63
SP - 55
EP - 62
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -