Mutations in the Human Sterol Δ7-Reductase Gene at 11q12-13 Cause Smith-Lemli-Opitz Syndrome
Christopher A. Wassif,Cheryl L. Maslen,Stivelia Kachilele-Linjewile,Don S. Lin,Leesa M. Linck,William E. Connor,Robert D. Steiner,Forbes D. Porter +7 more
TLDR
It is demonstrated that the cDNA that is identified encodes the human sterol Delta7-reductase and that mutations in DHCR7 are responsible for at least some cases of SLOS.Abstract:
Summary 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 D 7 -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 D 7 -reductase. We cloned cDNA encoding a human sterol D 7 -reductase (DHCR7) on the basis of its homology with the sterol D 7 -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 D 7 -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 D 7 -reductase and thatread more
Citations
More filters
Journal ArticleDOI
Cleft lip and palate: understanding genetic and environmental influences.
TL;DR: Using a combination of epidemiology, careful phenotyping, genome-wide association studies and analysis of animal models, several distinct genetic and environmental risk factors have been identified and confirmed for non-syndromic CLP.
Journal ArticleDOI
Hirschsprung disease, associated syndromes and genetics: a review
Jeanne Amiel,Stanislas Lyonnet +1 more
TL;DR: Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment, which stands as a model for genetic disorders with complex patterns of inheritance.
Book ChapterDOI
Developmental roles and clinical significance of hedgehog signaling.
TL;DR: This review focuses on the developing systems themselves, providing a comprehensive survey of the role of Hedgehog signaling in each of these, and the increasing significance of Hedge Hog signaling in the clinical setting.
Journal ArticleDOI
The Smith-Lemli-Opitz syndrome
TL;DR: The recent recognition of the important role of cholesterol in vertebrate embryogenesis, especially with regard to the hedgehog embryonic signalling pathway and its effects on the expression of homeobox genes, has provided an explanation for the abnormal morphogenesis in the syndrome.
Journal ArticleDOI
The hedgehog signaling network
TL;DR: A balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other, and the upregulation of Patched expression, resulting in Patched protein at the cell membrane, sequesters hedgehog and limits its spread beyond the cells in which it is produced.
References
More filters
Journal Article
Protein Measurement with the Folin Phenol Reagent
TL;DR: Procedures are described for measuring protein in solution or after precipitation with acids or other agents, and for the determination of as little as 0.2 gamma of protein.
Journal ArticleDOI
Basic Local Alignment Search Tool
TL;DR: A new approach to rapid sequence comparison, basic local alignment search tool (BLAST), directly approximates alignments that optimize a measure of local similarity, the maximal segment pair (MSP) score.
Journal ArticleDOI
Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.
Stephen F. Altschul,Thomas L. Madden,Alejandro A. Schäffer,Jinghui Zhang,Zheng Zhang,Webb Miller,David J. Lipman +6 more
TL;DR: A new criterion for triggering the extension of word hits, combined with a new heuristic for generating gapped alignments, yields a gapped BLAST program that runs at approximately three times the speed of the original.
Journal ArticleDOI
A simple method for the isolation and purification of total lipides from animal tissues.
TL;DR: In this paper, the authors described a simplified version of the method and reported the results of a study of its application to different tissues, including the efficiency of the washing procedure in terms of the removal from tissue lipides of some non-lipide substances of special biochemical interest.
Journal ArticleDOI
Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function.
Chin Chiang,Ying Litingtung,Eric Lee,Keith E. Young,Jeffrey L Corden,Heiner Westphal,Philip A. Beachy +6 more
TL;DR: Targeted gene disruption in the mouse shows that the Sonic hedgehog(Shh) gene plays a critical role in patterning of vertebrate embryonic tissues, including the brain and spinal cord, the axial skeleton and the limbs.