smith lemli opitz syndrome


Summary: An autosomal recessive disorder of CHOLESTEROL metabolism. It is caused by a deficiency of 7-dehydrocholesterol reductase, the enzyme that converts 7-dehydrocholesterol to cholesterol, leading to an abnormally low plasma cholesterol. This syndrome is characterized by multiple CONGENITAL ABNORMALITIES, growth deficiency, and INTELLECTUAL DISABILITY.

Top Publications

  1. Fitzky B, Witsch Baumgartner M, Erdel M, Lee J, Paik Y, Glossmann H, et al. Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc Natl Acad Sci U S A. 1998;95:8181-6 pubmed
    ..The missense mutations L99P, V326L, R352W, R404C, and G410S reduced heterologous protein expression by >90%. Our results strongly suggest that defects in the DHCR7 gene cause the SLOS. ..
  2. Winter J, Lehmann T, Suckow V, Kijas Z, Kulozik A, Kalscheuer V, et al. Duplication of the MID1 first exon in a patient with Opitz G/BBB syndrome. Hum Genet. 2003;112:249-54 pubmed
    ..This duplication introduces a premature termination codon. In addition, we could significantly lower the threshold for mutation detection on the DNA level by combining SSCP analysis with DHPLC technology. ..
  3. Tulenko T, Boeze Battaglia K, Mason R, Tint G, Steiner R, Connor W, et al. A membrane defect in the pathogenesis of the Smith-Lemli-Opitz syndrome. J Lipid Res. 2006;47:134-43 pubmed
    ..These data indicate that the disturbance in membrane sterol content in SLOS, likely at the level of membrane caveolae, directly contributes to the widespread tissue abnormalities in this disease. ..
  4. Landry J, Mager D. Widely spaced alternative promoters, conserved between human and rodent, control expression of the Opitz syndrome gene MID1. Genomics. 2002;80:499-508 pubmed
    ..Together, these results suggest that alternative promoters are important in the complex transcriptional regulation of MID1 expression in several species. ..
  5. Matsumoto Y, Morishima K, Honda A, Watabe S, Yamamoto M, Hara M, et al. R352Q mutation of the DHCR7 gene is common among Japanese Smith-Lemli-Opitz syndrome patients. J Hum Genet. 2005;50:353-6 pubmed
    ..These results suggest that R352Q is a predominant founder mutation in Japanese SLOS patients. ..
  6. Valencia A, Rajadurai A, Carle A, Kochevar I. 7-Dehydrocholesterol enhances ultraviolet A-induced oxidative stress in keratinocytes: roles of NADPH oxidase, mitochondria, and lipid rafts. Free Radic Biol Med. 2006;41:1704-18 pubmed
    ..These results indicate that 7-DHC enhances rapid UVA-induced ROS and PGE(2) formation by enhancing free radical-mediated membrane lipid oxidation and suggests that this mechanism might underlie the UVA photosensitivity in SLOS. ..
  7. Waterham H, Wijburg F, Hennekam R, Vreken P, Poll The B, Dorland L, et al. Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene. Am J Hum Genet. 1998;63:329-38 pubmed
    ..Our data demonstrate that Smith-Lemli-Opitz syndrome is caused by mutations in the gene coding for 7-dehydrocholesterol reductase. ..
  8. Schweiger S, Foerster J, Lehmann T, Suckow V, Muller Y, Walter G, et al. The Opitz syndrome gene product, MID1, associates with microtubules. Proc Natl Acad Sci U S A. 1999;96:2794-9 pubmed
    ..These data give an idea of the possible molecular pathomechanism underlying the OS phenotype. ..
  9. Wassif C, Krakowiak P, Wright B, Gewandter J, Sterner A, Javitt N, et al. Residual cholesterol synthesis and simvastatin induction of cholesterol synthesis in Smith-Lemli-Opitz syndrome fibroblasts. Mol Genet Metab. 2005;85:96-107 pubmed

More Information


  1. Herman G. Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes. Hum Mol Genet. 2003;12 Spec No 1:R75-88 pubmed
    ..In this review, an overview of the cholesterol biosynthetic pathway will be presented. Clinical features of the human disorders and mouse models of post-squalene cholesterol biosynthesis will then be discussed. ..
  2. Opitz J, Gilbert Barness E, Ackerman J, Lowichik A. Cholesterol and development: the RSH ("Smith-Lemli-Opitz") syndrome and related conditions. Pediatr Pathol Mol Med. 2002;21:153-81 pubmed
    ..Thus, developmental pathology plays an integral, vital role in preventive medicine. ..
  3. Berring E, Borrenpohl K, Fliesler S, Serfis A. A comparison of the behavior of cholesterol and selected derivatives in mixed sterol-phospholipid Langmuir monolayers: a fluorescence microscopy study. Chem Phys Lipids. 2005;136:1-12 pubmed
    ..These results are discussed in relation to SLOS pathobiology. ..
  4. Perry J, Short K, Romer J, Swift S, Cox T, Ashworth A. FXY2/MID2, a gene related to the X-linked Opitz syndrome gene FXY/MID1, maps to Xq22 and encodes a FNIII domain-containing protein that associates with microtubules. Genomics. 1999;62:385-94 pubmed
    ..The FXY/MID1 protein has previously been shown to colocalize with microtubules, and here we show that the FXY2 protein similarly associates with microtubules in a manner that is dependent on the carboxy-terminal B30.2 domain. ..
  5. Buchner G, Montini E, Andolfi G, Quaderi N, Cainarca S, Messali S, et al. MID2, a homologue of the Opitz syndrome gene MID1: similarities in subcellular localization and differences in expression during development. Hum Mol Genet. 1999;8:1397-407 pubmed
    ..Together, these data suggest that midin and MID2 have a similar biochemical function but a different physiological role during development. ..
  6. Yu H, Lee M, Starck L, Elias E, Irons M, Salen G, et al. Spectrum of Delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome. Hum Mol Genet. 2000;9:1385-91 pubmed
    ..We estimate that between 33 and 42% of the variation in the SLOS severity score is accounted for by variation in plasma cholesterol. Thus, factors other than plasma cholesterol are additionally involved in determining severity. ..
  7. Rossi M, Vajro P, Iorio R, Battagliese A, Brunetti Pierri N, Corso G, et al. Characterization of liver involvement in defects of cholesterol biosynthesis: long-term follow-up and review. Am J Med Genet A. 2005;132A:144-51 pubmed
    ..Periodic liver function evaluations are recommended in these patients. ..
  8. Moebius F, Fitzky B, Lee J, Paik Y, Glossmann H. Molecular cloning and expression of the human delta7-sterol reductase. Proc Natl Acad Sci U S A. 1998;95:1899-902 pubmed
    ..013 microM), BM15766 (IC50 1.2 microM), and triparanol (IC50 14 microM). Our work paves the way to clarify whether a defect in the delta7-sterol reductase gene underlies the Smith-Lemli-Opitz syndrome. ..
  9. Jong Hee Chae -, Ki Joong Kim -, Yong Seung Hwang -, Ki C, Kim J. Identification of a novel DHCR7 mutation in a Korean patient with Smith-Lemli-Opitz syndrome. J Child Neurol. 2007;22:1297-300 pubmed
    ..The Lys376ArgfsX37 mutation is a novel mutation, and to the best of the authors' knowledge, this is the first report of a clinically and genetically confirmed case of Smith-Lemli-Opitz syndrome in Korea. ..
  10. Witsch Baumgartner M, Clayton P, Clusellas N, Haas D, Kelley R, Krajewska Walasek M, et al. Identification of 14 novel mutations in DHCR7 causing the Smith-Lemli-Opitz syndrome and delineation of the DHCR7 mutational spectra in Spain and Italy. Hum Mutat. 2005;25:412 pubmed
    ..Thr93Met on the J haplotype as the most frequent Mediterranean founder mutation. ..
  11. Witsch Baumgartner M, Fitzky B, Ogorelkova M, Kraft H, Moebius F, Glossmann H, et al. Mutational spectrum in the Delta7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome. Am J Hum Genet. 2000;66:402-12 pubmed
    ..Homozygosity for 0 mutations in DHCR7 appears compatible with life, suggesting that cholesterol may be synthesized in the absence of this enzyme or that exogenous sources of cholesterol can be used. ..
  12. Porter F. Human malformation syndromes due to inborn errors of cholesterol synthesis. Curr Opin Pediatr. 2003;15:607-13 pubmed
  13. Cainarca S, Messali S, Ballabio A, Meroni G. Functional characterization of the Opitz syndrome gene product (midin): evidence for homodimerization and association with microtubules throughout the cell cycle. Hum Mol Genet. 1999;8:1387-96 pubmed
    ..We suggest that midin is involved in the formation of multiprotein structures acting as anchor points to microtubules and that impaired association with these cytoskeletal structures causes OS developmental defects. ..
  14. Keller R, Arnold T, Fliesler S. Formation of 7-dehydrocholesterol-containing membrane rafts in vitro and in vivo, with relevance to the Smith-Lemli-Opitz syndrome. J Lipid Res. 2004;45:347-55 pubmed
    ..These results are discussed in the context of the SLOS phenotype, particularly with regard to the associated central nervous system defects. ..
  15. Yu H, Wessels A, Chen J, Phelps A, Oatis J, Tint G, et al. Late gestational lung hypoplasia in a mouse model of the Smith-Lemli-Opitz syndrome. BMC Dev Biol. 2004;4:1 pubmed
    ..The molecular mechanism of impaired lung development associated with sterol deficiency by Dhcr7 loss is still unknown, but these results do not support the involvement of dysregulated Shh-Patched-Gli pathway in causing this defect. ..
  16. Fitzky B, Moebius F, Asaoka H, Waage Baudet H, Xu L, Xu G, et al. 7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome. J Clin Invest. 2001;108:905-15 pubmed
    ..This effect might exacerbate abnormal development in SLOS by increasing the fetal cholesterol deficiency. ..
  17. Krakowiak P, Wassif C, Kratz L, Cozma D, Kovarova M, Harris G, et al. Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency. Hum Mol Genet. 2003;12:1631-41 pubmed
    ..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. ..
  18. Cooper M, Wassif C, Krakowiak P, Taipale J, Gong R, Kelley R, et al. A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat Genet. 2003;33:508-13 pubmed
    ..We further find that sterol depletion affects the activity of Smoothened (Smo), an essential component of the Hh signal transduction apparatus. ..
  19. Yu H, Patel S. Recent insights into the Smith-Lemli-Opitz syndrome. Clin Genet. 2005;68:383-91 pubmed
    ..This mini review summarizes the recent insights into SLOS genetics, pathophysiology and potential therapeutic approaches for the treatment of SLOS. ..
  20. Andersson H, Frentz J, Martinez J, Tuck Muller C, Bellizaire J. Adrenal insufficiency in Smith-Lemli-Opitz syndrome. Am J Med Genet. 1999;82:382-4 pubmed
    ..We hypothesize that deficiency of cholesterol, an adrenal hormone precursor, may lead to insufficient synthesis of adrenal steroid hormones. ..
  21. Kovarova M, Wassif C, Odom S, Liao K, Porter F, Rivera J. Cholesterol deficiency in a mouse model of Smith-Lemli-Opitz syndrome reveals increased mast cell responsiveness. J Exp Med. 2006;203:1161-71 pubmed
    ..These findings provide the first evidence of lipid raft dysfunction in SLOS and may explain the observed association of allergy with SLOS. ..
  22. Wassif C, Maslen C, Kachilele Linjewile S, Lin D, Linck L, Connor W, et al. Mutations in the human sterol delta7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. Am J Hum Genet. 1998;63:55-62 pubmed
    ..Our results demonstrate both that the cDNA that we have identified encodes the human sterol Delta7-reductase and that mutations in DHCR7 are responsible for at least some cases of SLOS. ..
  23. Short K, Hopwood B, Yi Z, Cox T. MID1 and MID2 homo- and heterodimerise to tether the rapamycin-sensitive PP2A regulatory subunit, alpha 4, to microtubules: implications for the clinical variability of X-linked Opitz GBBB syndrome and other developmental disorders. BMC Cell Biol. 2002;3:1 pubmed
    ..Overlap in the clinical features of FG and Opitz GBBB syndromes warrants investigation of Alpha 4 as a candidate for causing FG syndrome. ..
  24. Wassif C, Zhu P, Kratz L, Krakowiak P, Battaile K, Weight F, et al. Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith--Lemli--Opitz syndrome. Hum Mol Genet. 2001;10:555-64 pubmed
  25. Ginat S, Battaile K, Battaile B, Maslen C, Gibson K, Steiner R. Lowered DHCR7 activity measured by ergosterol conversion in multiple cell types in Smith-Lemli-Opitz syndrome. Mol Genet Metab. 2004;83:175-83 pubmed
    ..Finally, the data suggest a threshold enzyme activity of 8% conversion, below which disease occurs. ..
  26. Berti C, Fontanella B, Ferrentino R, Meroni G. Mig12, a novel Opitz syndrome gene product partner, is expressed in the embryonic ventral midline and co-operates with Mid1 to bundle and stabilize microtubules. BMC Cell Biol. 2004;5:9 pubmed
    ..Impairment in Mig12/Mid1-mediated microtubule dynamic regulation, during the development of embryonic midline, may cause the pathological signs observed in Opitz syndrome patients. ..
  27. Plosch T, Van Straten E, Kuipers F. Cholesterol transport by the placenta: placental liver X receptor activity as a modulator of fetal cholesterol metabolism?. Placenta. 2007;28:604-10 pubmed
    ..Here we discuss the potential role of the placenta in the regulation of fetal cholesterol homeostasis and strategies to influence maternal-fetal cholesterol transfer. ..
  28. Irons M, Nores J, Stewart T, Craigo S, Bianchi D, D Alton M, et al. Antenatal therapy of Smith-Lemli-Opitz syndrome. Fetal Diagn Ther. 1999;14:133-7 pubmed
    ..SLOS may be added to the growing list of human genetic disorders for which prenatal diagnosis is available and therapeutic intervention may be possible. ..
  29. Valenza M, Cattaneo E. Cholesterol dysfunction in neurodegenerative diseases: is Huntington's disease in the list?. Prog Neurobiol. 2006;80:165-76 pubmed
    ..In particular, we consider the available clinical, biological and molecular evidence indicating a potential dysregulation of cholesterol homeostasis in Huntington's disease. ..
  30. Waye J, Eng B, Potter M, Nowaczyk M, McFadden D, Langlois S. De novo mutation of the DHCR7 gene in a fetus with severe Smith-Lemli-Opitz (or RSH) syndrome. Am J Med Genet A. 2007;143A:1799-801 pubmed
  31. Marcos J, Guo L, Wilson W, Porter F, Shackleton C. The implications of 7-dehydrosterol-7-reductase deficiency (Smith-Lemli-Opitz syndrome) to neurosteroid production. Steroids. 2004;69:51-60 pubmed
    ..Even though the new neuroactive steroids identified were unlikely to have been formed in the brain, it is likely that mechanisms for their synthesis are operable in this organ. ..
  32. Shackleton C, Roitman E, Guo L, Wilson W, Porter F. Identification of 7(8) and 8(9) unsaturated adrenal steroid metabolites produced by patients with 7-dehydrosterol-delta7-reductase deficiency (Smith-Lemli-Opitz syndrome). J Steroid Biochem Mol Biol. 2002;82:225-32 pubmed
    ..We have yet to prove the activity of adrenal 21-hydroxylase, 11beta-hydroxylase or 5alpha-reductase towards 7- or 8-dehydroprecursors. ..
  33. Craigie R, Ba ath M, Fryer A, Baillie C. Surgical implications of the Smith-Lemli-Opitz syndrome. Pediatr Surg Int. 2005;21:482-4 pubmed
    ..We present two fatal cases of SLOS with near-total Hirschsprung's disease; the surgical, anaesthetic, and medical aspects of the cases are discussed, and a literature review is presented. ..
  34. Jezela Stanek A, Małunowicz E, Ciara E, Popowska E, Goryluk Kozakiewicz B, Spodar K, et al. Maternal urinary steroid profiles in prenatal diagnosis of Smith-Lemli-Opitz syndrome: first patient series comparing biochemical and molecular studies. Clin Genet. 2006;69:77-85 pubmed
    ..We conclude that steroid measurements in maternal urine are a reliable means of prenatal diagnosis for SLOS. ..
  35. Valencia A, Kochevar I. Ultraviolet A induces apoptosis via reactive oxygen species in a model for Smith-Lemli-Opitz syndrome. Free Radic Biol Med. 2006;40:641-50 pubmed
    ..These results support a ROS-mediated apoptotic mechanism for the enhanced UVA-induced inflammation in SLO-S patients. ..
  36. Rossi M, D Armiento M, Parisi I, Ferrari P, Hall C, Cervasio M, et al. Clinical phenotype of lathosterolosis. Am J Med Genet A. 2007;143A:2371-81 pubmed
    ..This condition partially overlaps with other defects of sterol metabolism, suggesting intriguing pathogenic links among these conditions. ..
  37. Boland M, Tatonetti N. Investigation of 7-dehydrocholesterol reductase pathway to elucidate off-target prenatal effects of pharmaceuticals: a systematic review. Pharmacogenomics J. 2016;16:411-29 pubmed publisher
    ..First-trimester exposure to DHCR7 inhibitors resulted in outcomes similar to those of known teratogens (50 vs 48% born-healthy). DHCR7 activity should be considered during drug development and prenatal toxicity assessment. ..
  38. Sharif N, Korade Z, Porter N, Harrison F. Oxidative stress, serotonergic changes and decreased ultrasonic vocalizations in a mouse model of Smith-Lemli-Opitz syndrome. Genes Brain Behav. 2017;16:619-626 pubmed publisher
    ..We propose that changes to the oxidative environment during development can have a significant impact on the development of serotonergic function and that this contributes to behavioral differences observed in the mutant mice. ..
  39. Pappu A, Connor W, Merkens L, Jordan J, Penfield J, Illingworth D, et al. Increased nonsterol isoprenoids, dolichol and ubiquinone, in the Smith-Lemli-Opitz syndrome: effects of dietary cholesterol. J Lipid Res. 2006;47:2789-98 pubmed
    ..Therefore, in SLOS, a secondary peripheral regulation of isoprenoid synthesis may be stimulated. ..
  40. Skirton H, Evans R, Evans E. More than just science: one family's story of a chromosome translocation diagnosis. Paediatr Nurs. 2004;16:18-21 pubmed
  41. Fliesler S, Peachey N, Richards M, Nagel B, Vaughan D. Retinal degeneration in a rodent model of Smith-Lemli-Opitz syndrome: electrophysiologic, biochemical, and morphologic features. Arch Ophthalmol. 2004;122:1190-200 pubmed
    ..This animal model may also be of use in evaluating therapeutic treatments for SLOS and in understanding the slow phototransduction kinetics observed in patients with SLOS. ..
  42. Remke S. Home care and pediatric palliative care: forging new partnerships for kids. Caring. 2007;26:28-30, 32 pubmed
  43. Xiong Q, Ruan B, Whitby F, Tuohy R, Belanger T, Kelley R, et al. A colorimetric assay for 7-dehydrocholesterol with potential application to screening for Smith-Lemli-Opitz syndrome. Chem Phys Lipids. 2002;115:1-15 pubmed
    ..Decomposition of 7DHC was effectively retarded by storage at low temperature and by precoating of the cards with antioxidants. The combined results provide a foundation for development of a simple, automated test for SLOS screening. ..
  44. Boesze Battaglia K, Damek Poprawa M, Mitchell D, Greeley L, Brush R, Anderson R, et al. Alteration of retinal rod outer segment membrane fluidity in a rat model of Smith-Lemli-Opitz syndrome. J Lipid Res. 2008;49:1488-99 pubmed publisher
    ..These findings are consistent with reduced ROS membrane fluidity in the SLOS rat model, relative to controls, primarily due to the dramatic reduction in membrane DHA levels, rather than altered sterol composition. ..
  45. Liss J, Lukaszuk K, Bruszczyńska A, Szczerkowska Z, Rebala K. Pregnancy and life after preimplantation genetic diagnosis of Smith-Lemli-Opitz syndrome. Fertil Steril. 2008;90:2011.e13-6 pubmed publisher
    ..This is the first report of preimplantation genetic diagnosis for Smith-Lemli-Opitz syndrome, allowing transfer of mutation-free embryos and successful pregnancies. ..
  46. Lalovic A, Merkens L, Russell L, Arsenault Lapierre G, Nowaczyk M, Porter F, et al. Cholesterol metabolism and suicidality in Smith-Lemli-Opitz syndrome carriers. Am J Psychiatry. 2004;161:2123-6 pubmed
    ..These results, based on a unique study design, provide additional evidence supporting the relationship between cholesterol metabolism and suicidal behavior. ..
  47. Rakheja D, Boriack R. Precholesterol sterols accumulate in lipid rafts of patients with Smith-Lemli-Opitz syndrome and X-linked dominant chondrodysplasia punctata. Pediatr Dev Pathol. 2008;11:128-32 pubmed
    ..We suggest that such alterations in the lipid raft sterol environment may affect the biology of cells and the development of fetuses with cholesterol biosynthetic disorders...
  48. Guizzetti M, Costa L. Sonic hedgehog in Smith-Lemli-Opitz syndrome and tumor development. J Pediatr Hematol Oncol. 2008;30:641-2 pubmed publisher
  49. De Brasi D, Esposito T, Rossi M, Parenti G, Sperandeo M, Zuppaldi A, et al. Smith-Lemli-Opitz syndrome: evidence of T93M as a common mutation of delta7-sterol reductase in Italy and report of three novel mutations. Eur J Hum Genet. 1999;7:937-40 pubmed
    ..Furthermore, we identified three novel mutations, two missense mutations (N407Y and E448K), and a 33 bp deletion spanning part of exon 5 and the donor splice site of intron 5. ..
  50. Anstey A. School in photodermatology: Smith-Lemli-Opitz syndrome. Photodermatol Photoimmunol Photomed. 2006;22:200-4 pubmed
    ..However, preliminary evidence points to the deranged cholesterol metabolism that characterizes the syndrome as causal in this UVA-mediated photosensitivity disorder. ..
  51. Shan H, Wilson W. Ternary gradient elution markedly improves silver-ion high performance liquid chromatography of unsaturated sterols. Steroids. 2002;67:917-23 pubmed
    ..The overall results represent a major advance in chromatographic methods for resolving mixtures of unsaturated sterols differing in the number and position of olefinic bonds. ..
  52. Marcos J, Craig W, Palomaki G, Kloza E, Haddow J, Roberson M, et al. Maternal urine and serum steroid measurements to identify steroid sulfatase deficiency (STSD) in second trimester pregnancies. Prenat Diagn. 2009;29:771-80 pubmed publisher
    ..6% FPR. Maternal urine steroid measurements are effective for detecting STSD, including those with point mutations and those with full deletions. ..
  53. Tierney E, Nwokoro N, Porter F, Freund L, Ghuman J, Kelley R. Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome. Am J Med Genet. 2001;98:191-200 pubmed
    ..1993, 1994]. Thus, SLOS is a metabolic disorder that can be associated with autism and other behavioral characteristics that define a distinctive and diagnostically important behavioral disorder. ..