Smith-Lemli-Opitz Syndrome and the DHCR 7 Gene

Smith-Lemli-Opitz syndrome, a severe developmental disorder associated with multiple congenital anomalies, is caused by a defect of cholesterol biosynthesis. Low cholesterol and high concentrations of its direct precursor, 7-dehydrocholesterol, in plasma and tissues are the diagnostic biochemical hallmarks of the syndrome. The plasma sterol concentrations correlate with severity and disease outcome. Mutations in the DHCR7 gene lead to deficient activity of 7-dehydrocholesterol reductase (DHCR7), the final enzyme of the cholesterol biosynthetic pathway. The human DHCR7 gene is localised on chromosome 11q13 and its structure has been characterized. Ninetyone different mutations in the DHCR7 gene have been published to date. This paper is a review of the clinical, biochemical and molecular genetic aspects.

[1]  R. Happle.  X-Linked dominant chondrodysplasia punctata , 1979, Human Genetics.

[2]  M. Nowaczyk,et al.  Smith-Lemli-Opitz syndrome: new mutation with a mild phenotype. , 2002, American journal of medical genetics.

[3]  G. Herman,et al.  Inborn errors of sterol biosynthesis. , 2003, Annual review of genomics and human genetics.

[4]  Hans R. Waterham,et al.  Mutations in the 3β-Hydroxysterol Δ24-Reductase Gene Cause Desmosterolosis, an Autosomal Recessive Disorder of Cholesterol Biosynthesis , 2001 .

[5]  N. Maeda,et al.  7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome. , 2001, The Journal of clinical investigation.

[6]  F. Porter,et al.  Genetic disorders of cholesterol biosynthesis in mice and humans. , 2001, Molecular genetics and metabolism.

[7]  R. Kelley,et al.  Inherited disorders of cholesterol biosynthesis. , 2001, Neuropediatrics.

[8]  R. Hennekam,et al.  Novel mutations in the 7-dehydrocholesterol reductase gene of 13 patients with Smith--Lemli--Opitz syndrome. , 2001, Annals of human genetics.

[9]  I. Glass,et al.  Novel mutation in the Delta7-dehydrocholesterol reductase gene in an Australian patient with Smith-Lemli-Opitz syndrome. , 2001, American journal of medical genetics.

[10]  U. Seedorf,et al.  Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations , 2001, European Journal of Human Genetics.

[11]  H. Waterham,et al.  Biochemical and genetic aspects of 7-dehydrocholesterol reductase and Smith-Lemli-Opitz syndrome. , 2000, Biochimica et biophysica acta.

[12]  R. Wanders,et al.  Biochemical and genetic aspects of mevalonate kinase and its deficiency. , 2000, Biochimica et biophysica acta.

[13]  C. Maslen,et al.  Mutation analysis and description of sixteen RSH/Smith-Lemli-Opitz syndrome patients: polymerase chain reaction-based assays to simplify genotyping. , 2000, American journal of medical genetics.

[14]  R. Steiner,et al.  Smith-Lemli-Opitz syndrome: the first malformation syndrome associated with defective cholesterol synthesis. , 2000, Molecular genetics and metabolism.

[15]  R. Wevers,et al.  Simvastatin: a new therapeutic approach for Smith-Lemli-Opitz syndrome , 2000 .

[16]  Hongwei Yu,et al.  Spectrum of Delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome. , 2000, Human molecular genetics.

[17]  R. Hennekam,et al.  The Smith-Lemli-Opitz syndrome , 2000, Journal of Medical Genetics.

[18]  R. Hennekam,et al.  and molecular cytogenetic of a large de novo interstitial , 2022 .

[19]  H. Glossmann,et al.  Genetic Defects in Postsqualene Cholesterol Biosynthesis , 2000, Trends in Endocrinology & Metabolism.

[20]  R. Carrozzo,et al.  Novel 7-DHCR mutation in a child with Smith-Lemli-Opitz syndrome. , 2000, American journal of medical genetics.

[21]  Hongwei Yu,et al.  Detection of a common mutation in the RSH or Smith-Lemli-Opitz syndrome by a PCR-RFLP assay: IVS8-G-->C is found in over sixty percent of US propositi. , 2000, American journal of medical genetics.

[22]  U. Seedorf,et al.  Mutational Spectrum in the Δ7-Sterol Reductase Gene and Genotype-Phenotype Correlation in 84 Patients with Smith-Lemli-Opitz Syndrome , 2000 .

[23]  D. Behúlová,et al.  Incidence of Smith-Lemli-Opitz syndrome in Slovakia. , 2000, American journal of medical genetics.

[24]  E. Hafen,et al.  Dispatched, a Novel Sterol-Sensing Domain Protein Dedicated to the Release of Cholesterol-Modified Hedgehog from Signaling Cells , 1999, Cell.

[25]  A. Ciccodicola,et al.  Smith-Lemli-Opitz syndrome: evidence of T93M as a common mutation of Δ7-sterol reductase in Italy and report of three novel mutations , 1999, European Journal of Human Genetics.

[26]  D. Neklason,et al.  Biochemical variants of Smith-Lemli-Opitz syndrome. , 1999, American journal of medical genetics.

[27]  J. Opitz,et al.  RSH (so-called Smith-Lemli-Opitz) syndrome. , 1999, Current opinion in pediatrics.

[28]  H. Waterham,et al.  Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome , 1999, Nature Genetics.

[29]  Joost P.H. Drenth,et al.  Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome , 1999, Nature Genetics.

[30]  G. Utermann,et al.  Molecular genetics of the Smith-Lemli-Opitz syndrome and postsqualene sterol metabolism. , 1999, Current opinion in lipidology.

[31]  C. Maslen,et al.  A simple PCR-based assay allows detection of a common mutation, IVS8-1G-->C, in DHCR7 in Smith-Lemli-Opitz syndrome. , 1999, Genetic testing.

[32]  H. Waterham,et al.  Unexpected molecular findings in 2 previously described brothers with Smith-Lemli-Opitz syndrome. , 1999, Genetic counseling.

[33]  R. Desnick,et al.  Regulation of rat hepatic 3beta-hydroxysterol delta7-reductase: substrate specificity, competitive and non-competitive inhibition, and phosphorylation/dephosphorylation. , 1998, Journal of lipid research.

[34]  P. Vreken,et al.  Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene. , 1998, American journal of human genetics.

[35]  R. Kelley,et al.  RSH/Smith-Lemli-Opitz syndrome: mutations and metabolic morphogenesis. , 1998, American journal of human genetics.

[36]  G. Utermann,et al.  Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[37]  J. Goldstein,et al.  Topology of SREBP Cleavage-activating Protein, a Polytopic Membrane Protein with a Sterol-sensing Domain* , 1998, The Journal of Biological Chemistry.

[38]  D. S. Lin,et al.  Mutations in the human sterol delta7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. , 1998, American journal of human genetics.

[39]  R M Winter,et al.  Smith-Lemli-Opitz syndrome: a variable clinical and biochemical phenotype. , 1998, Journal of medical genetics.

[40]  P. Beachy,et al.  Teratogen-mediated inhibition of target tissue response to Shh signaling. , 1998, Science.

[41]  M. Lyon,et al.  Sonic hedgehog is not required for polarising activity in the Doublefoot mutant mouse limb bud. , 1998, Development.

[42]  R. Winter,et al.  Clinical phenotype of desmosterolosis. , 1998, American journal of medical genetics.

[43]  Joon-No Lee,et al.  Molecular cloning and expression of the human delta7-sterol reductase. , 1998 .

[44]  K. Sulik,et al.  Limb, genital, CNS, and facial malformations result from gene/environment-induced cholesterol deficiency: further evidence for a link to sonic hedgehog. , 1997, American journal of medical genetics.

[45]  M. Tsai,et al.  Identification of a novel sonic hedgehog response element in the chicken ovalbumin upstream promoter-transcription factor II promoter. , 1997, Molecular endocrinology.

[46]  K. Yoshizato,et al.  Expression of Sonic hedgehog gene in regenerating newt limb blastemas recapitulates that in developing limb buds. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[47]  T. Reh,et al.  Sonic Hedgehog Promotes Rod Photoreceptor Differentiation in Mammalian Retinal Cells In Vitro , 1997, The Journal of Neuroscience.

[48]  W. Pavan,et al.  Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. , 1997, Science.

[49]  G. Eichele,et al.  Sonic hedgehog participates in craniofacial morphogenesis and is down-regulated by teratogenic doses of retinoic acid. , 1997, Developmental biology.

[50]  A. Honda,et al.  Rapid identification of Smith-Lemli-Opitz syndrome homozygotes and heterozygotes (carriers) by measurement of deficient 7-dehydrocholesterol-delta 7-reductase activity in fibroblasts. , 1997, Metabolism: clinical and experimental.

[51]  R. Wevers,et al.  New treatment strategy for Smith-Lemli-Opitz syndrome , 1997, The Lancet.

[52]  A. Moser,et al.  Clinical and biochemical spectrum of patients with RSH/Smith-Lemli-Opitz syndrome and abnormal cholesterol metabolism. , 1997, American journal of medical genetics.

[53]  G Salen,et al.  Clinical effects of cholesterol supplementation in six patients with the Smith-Lemli-Opitz syndrome (SLOS) , 1997, American journal of medical genetics.

[54]  A. Honda,et al.  Measurement of 3 beta-hydroxysteroid delta 7-reductase activity in cultured skin fibroblasts utilizing ergosterol as a substrate: a new method for the diagnosis of the Smith-Lemli-Opitz syndrome. , 1996, Journal of lipid research.

[55]  P. Beachy,et al.  Cholesterol Modification of Hedgehog Signaling Proteins in Animal Development , 1996, Science.

[56]  Eugene V Koonin,et al.  Hedgehog Patterning Activity: Role of a Lipophilic Modification Mediated by the Carboxy-Terminal Autoprocessing Domain , 1996, Cell.

[57]  A. Rahier,et al.  Sterol biosynthesis: strong inhibition of maize delta 5,7-sterol delta 7-reductase by novel 6-aza-B-homosteroids and other analogs of a presumptive carbocationic intermediate of the reduction reaction. , 1996, Biochemistry.

[58]  U. Seedorf,et al.  Smith-Lemli-Opitz Syndrome: Treatment with Cholesterol and Bile Acids , 1996, Neuropediatrics.

[59]  S. Kumar,et al.  Evolution of the hedgehog gene family. , 1996, Genetics.

[60]  N. Venizelos,et al.  Detection of defective 3 beta-hydroxysterol delta 7-reductase activity in cultured human fibroblasts: a method for the diagnosis of Smith-Lemli-Opitz syndrome. , 1996, Journal of inherited metabolic disease.

[61]  P. Beachy,et al.  A potential catalytic site revealed by the 1.7-Å crystal structure of the amino-terminal signalling domain of Sonic hedgehog , 1995, Nature.

[62]  V. P. Johnson,et al.  Correlation of severity and outcome with plasma sterol levels in variants of the Smith-Lemli-Opitz syndrome. , 1995, The Journal of pediatrics.

[63]  N. Copeland,et al.  Cloning, expression, and chromosomal location of SHH and IHH: two human homologues of the Drosophila segment polarity gene hedgehog. , 1995, Genomics.

[64]  Y. Paik,et al.  Cholesterol biosynthesis from lanosterol: regulation and purification of rat hepatic sterol 8-isomerase. , 1995, Journal of biochemistry.

[65]  J. Opitz,et al.  RSH/SLO ("Smith-Lemli-Opitz") syndrome: historical, genetic, and developmental considerations. , 1994, American journal of medical genetics.

[66]  J. Opitz,et al.  Cholesterol metabolism in the RSH/Smith-Lemli-Opitz syndrome: summary of an NICHD conference. , 1994, American journal of medical genetics.

[67]  G Salen,et al.  Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. , 1994, The New England journal of medicine.

[68]  R. Simon,et al.  The intracellular targeting and membrane topology of 3-hydroxy-3-methylglutaryl-CoA reductase. , 1992, The Journal of biological chemistry.

[69]  J. Goldstein,et al.  Regulation of the mevalonate pathway , 1990, Nature.

[70]  D. Rimoin,et al.  A new autosomal recessive lethal chondrodystrophy with congenital hydrops. , 1988, American journal of medical genetics.

[71]  K. Gibson,et al.  Mevalonic aciduria--an inborn error of cholesterol and nonsterol isoprene biosynthesis. , 1986, The New England journal of medicine.

[72]  R. Happle,et al.  The CHILD syndrome , 1980, European Journal of Pediatrics.

[73]  J. Opitz,et al.  A NEWLY RECOGNIZED SYNDROME OF MULTIPLE CONGENITAL ANOMALIES. , 1964, The Journal of pediatrics.

[74]  C. Perry.  Clinical Features , 2004, Bristol medico-chirurgical journal.