Disorders of Cholesterol Biosynthesis, Genetics of


Smith–Lemli–Opitz syndrome (SLOS) is the most common and best understood of the inborn errors of cholesterol metabolism. Comprising a heterogeneous group of disorders, inborn errors in cholesterol biosynthesis result in characteristic but variable phenotypes. SLOS is an inherited disorder caused by mutations in DHCR7 which encodes the final enzyme in the cholesterol synthetic pathway. There are eight other cholesterol biosynthesis disorders described in the pre‐Squalene and post‐Squalene pathways. Phenotypic features of SLOS and the other eight disorders are thought to be related to cholesterol deficiency and/or accumulation of cholesterol precursors and their metabolites. A better understanding of SLOS and these other inborn errors of cholesterol biosynthesis may shed light on the importance of cholesterol biosynthesis in embryo‐ and morphogenesis as well as provide clues to treatment.

Key Concepts

  • Developing brain tissue is dependent on endogenous cholesterol biosynthesis.
  • Cholesterol is a fundamental component of cell membranes and myelin, a precursor of bile acids, Vitamin D and steroid hormones synthesis and is crucial in cellular signalling.
  • Cholesterol influences embryonic and postnatal development.
  • Cholesterol can play a role in autism and socio‐behavioural problems.
  • Inborn errors of cholesterol metabolism are a heterogeneous group of at least nine disorders, with more likely to be identified.

Keywords: Smith–Lemli–Opitz syndrome; inborn error of metabolism; Squalene; sterol; cholesterol; cholesterol biosynthesis

Figure 1. Cholesterol biosynthesis pathway with affected gene and sterol metabolism disorders delineated. Affected enzyme defects are shown in italics, affected gene shown in CAPS and italics inserted along the link to the call outs, and the corresponding sterol metabolism disorders are inserted in the call outs. Disorders, genes and enzyme defects are schematically highlighted in the pre‐Squalene and post‐Squalene pathway. Lanosterol synthesis at the end of the pre‐Squalene pathway is the first important committed step of cholesterol synthesis in the post‐Squalene pathway. Affected genes: MVK, mevalonate kinase; POR, cytochrome P450 oxidoreductase; MSMO1 (SC4MOL), methylsterol monooxygenase1 (Sterol‐C4‐methyl oxidase); NSDHL, NAD(P) dependent steroid dehydrogenase‐like; EBP, emopamil‐binding protein; SC5DL, sterol C5‐desaturase like; DHCR24, 24‐dehydrocholesterol reductase; DHCR7, 7‐dehydrocholesterol reductase. Sterol Metabolism Disorders: MVA – mevalonic aciduria; HIDS – hyper‐IgD and periodic fever syndrome; POROK3 – Porokeratosis 3, multiple types; ABS1 – Antley–Bixler syndrome with genital anomalies and disordered steroidogenesis; MCCPD – Microcephaly, congenital cataract, and psoriasiform dermatitis; CHILD, Congenital Hemidysplasia with Icthyosiform nevus and limb defects; CDPX2, X‐linked Dominant Chondrodysplasia Punctata 2; SLOS – Smith–Lemli–Opitz syndrome.
Figure 2. Typical phenotypic facial features of children with SLOS include microcephaly, small low‐set ears, a broad high forehead, blepharoptosis, epicanthal folds, a broad nasal bridge, a short nose with anteverted nares, cleft palate and micrognathia.


Andersson HC, Kratz L and Kelley R (2002) Desmosterolosis presenting with multiple congenital anomalies and profound developmental delay. American Journal of Medical Genetics 113: 315–319.

Aughton DJ, Kelley RI, Metzenberg A, Pureza V and Pauli RM (2003) X‐linked dominant chondrodysplasia punctata (CDPX2) caused by a single gene mosaicism in a male. American Journal of Medical Genetics 116A: 255–260.

Battaile KP and Steiner RD (2000) Smith–Lemli–Opitz syndrome: the first malformation syndrome associated with defective cholesterol synthesis. Molecular Genetics and Metabolism 71 (1–2): 154–162.

Battaile KP, Battaile BC, Merkens LS, Maslen CL and Steiner RD (2001) Carrier frequency of the common mutation IVS8‐1G>C in DHCR7 and estimate of the expected incidence of Smith–Lemli–Opitz syndrome. Molecular Genetics and Metabolism 72 (1): 67–71.

Braverman N, Lin P, Moebius FF, et al. (1999) Mutations in the gene encoding 3β‐hydroxysteroid Δ8,7‐isomerase cause X‐linked dominant Conradi–Huenermann syndrome. Nature Genetics 22: 291–294.

Brunetti‐Pierri N, Gaetano C, Rossi M, et al. (2002) Lathosterolosis, a novel multiple‐malformation/mental retardation syndrome due to a deficiency of 3β‐hydroxysterol Δ5‐desaturase. American Journal of Human Genetics 71: 952–958.

Caruso PA, Poussaint TY, Tzika AA, et al. (2004) MRI and 1H MRS findings in Smith–Lemli–Opitz syndrome. Neuroradiology 46 (1): 3–14. Epub 2003 November 5.

Chaudhury S, Hormaza L, Mohammad S, et al. (2012) Liver transplantation followed by allogeneic hematopoietic stem cell transplantation for atypical mevalonic aciduria. American Journal of Transplantation 12 (6): 1627–1631. DOI: 10.1111/j.1600-6143.2011.03989.x.

Cooper MK, Wasif CA, Krakowiak PA, et al. (2003) A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nature Genetics 33: 508–513.

Correa‐Cerro LS, Wassif CA, Kratz L, et al. (2006) Development and characterization of a hypomorphic Smith–Lemli–Opitz syndrome mouse model and efficacy of simvastatin therapy. Human Molecular Genetics 15: 839–851.

Derry JM, Gormally E, Means GD, et al. (1999) Mutations in a delta8‐delta7sterol isomerase in the tattered mouse and X‐linked dominant chondrodysplasia punctata. Nature Genetics 22: 286–290.

Elias ER, Hansen RM, Irons M, Quinn NB and Fulton AB (2003) Rod photoreceptor responses in children with Smith–Lemli–Opitz syndrome. Archives of Ophthalmology 121 (12): 1738–1743.

Engelking LJ, Evers BM, Richardson JA, et al. (2006) Severe facial clefting in Insig‐deficient mouse embryos caused by sterol accumulation and reversed by lovastatin. Journal of Clinical Investigation 116 (9): 2345–2365.

Fitzpatrick DR, Keeling JW, Evans MJ, et al. (1998) Clinical phenotype of desmosterolosis. American Journal of Medical Genetics 75: 145–152.

Fliesler SJ, Vaughan DK, Jenewein EC, et al. (2007) Partial rescue of retinal function and sterol steady‐state in a rat model of Smith–Lemli–Opitz syndrome. Pediatric Research 61 (3): 273–278.

Grange DK, Kratz LE, Braverman NE and Kelley RI (2000) CHILD syndrome caused by deficiency of 3β‐hydroxysteroid Δ8,7‐isomerase. American Journal of Medical Genetics 90: 328–335.

Happle R (1979) X‐linked dominant chondrodysplasia punctata. Review of literature and report of a case. Human Genetics 53 (1): 65–73.

He M, Smith LD, Chang R, Li X and Vockley J (2014) The role of sterol‐C4‐methyl oxidase in epidermal biology. Biochim. Biophys. Acta. 1841: 331–335. DOI: 10.1016/j.

Hoffman GF, Gibson KM, Brandt IK, et al. (1986) Mevalonic aciduria: an inborn error of cholesterol and nonsterol isoprene biosynthesis. New England Journal of Medicine 314: 1610–1614.

Irons M, Elias ER, Abuelo D, et al. (1997) Treatment of Smith–Lemli–Opitz syndrome: results of a multicenter trial. American Journal of Medical Genetics 68 (3): 311–314.

Jurevics HA, Kidwai FZ and Morell P (1997) Sources of cholesterol during development of the rat fetus and fetal organs. Journal of Lipid Research 38 (4): 723–733.

Kelley RI, Wilcox WG, Smith M, et al. (1999) Abnormal sterol metabolism in patients with Conradi–Huenermann–Happle syndrome and sporadic lethal chondrodysplasia punctata. American Journal of Medical Genetics 83: 213–219.

Kelley RI, Kratz LE, Glaser RL, et al. (2002) Abnormal sterol metabolism in a patient with Antley–Bixler syndrome and ambiguous genitalia. American Journal of Medical Genetics 110: 95–102.

Krakowiak PA, Wassif CA, Kratz L, et al. (2003) Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5‐desaturase deficiency. Human Molecular Genetics 12 (13): 1631–1641.

Liu XY, Dangel AW, Kelley RI, et al. (1999) The gene mutated in bare patches and striated mice encodes a novel 3β‐hydroxysteroid dehydrogenase. Nature Genetics 22: 182–187.

McLarren KW, Severson TM, du Souich C, et al. (2010) Hypomorphic temperature‐sensitive alleles of NSDHL cause CK syndrome. American Journal of Human Genetics 87 (6): 905–914. DOI: 10.1016/j.ajhg.2010.11.004.

Mulders‐Manders CM and Simon A (2015) Hyper‐IgD syndrome/mevalonate kinase deficiency: what is new? Seminars in Immunopathology 37 (4): 371–376. DOI: 10.1007/s00281-015-0492-6.

Natowicz MR and Evans JE (1994) Abnormal bile acids in the Smith–Lemli–Opitz syndrome. American Journal of Medical Genetics 50 (4): 364–367.

Offiah AC, Mansour S, Jeffrey I, et al. (2003) Greenberg dysplasia (HEM) and lethal x linked dominant Conradi–Huenermann chondrodysplasia punctuate (CDPX2): presentation of two cases with overlapping phenotype. Journal of Medical Genetics 40 (12): e129.

Porter J, Porter K and Young P (1996a) Cholesterol modification of hedgehog signaling proteins in animal development. Science 274: 255–259.

Porter JA, Ekker SC, Park WJ, et al. (1996b) Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy‐terminal auto processing domain. Cell 86 (1): 21–34.

Reardon W, Smith A, Honour JW, et al. (2000) Evidence for digenic inheritance in some cases of Antley–Bixler syndrome? Journal of Medical Genetics 37: 26–32.

Rossi M, Vajro P, Iorio R, et al. (2005) Characterization of liver involvement in defects of cholesterol biosynthesis: long‐term follow‐up and review. American Journal of Medical Genetics 132 (2): 144–151.

Schafer BL, Bishop RW, Kratunis VJ, et al. (1992) Molecular cloning of human mevalonate kinase and identification of a missense mutation in the genetic disease mevalonic aciduria. Journal of Biological Chemistry 267: 13229–13238.

Schneiders MS, Houten SM, Turkenburg M, Wanders RJ and Waterham HR (2006) Manipulation of isoprenoid biosynthesis as a possible therapeutic option in mevalonate kinase deficiency. Arthritis and Rheumatism 54 (7): 2306–2313.

Shefer S, Salen G, Batta AK, et al. (1995) Markedly inhibited 7‐dehydrocholesterol‐delta 7‐reductase activity in liver microsomes from Smith–Lemli–Opitz homozygotes. Journal of Clinical Investigation 96 (4): 1779–1785.

Sikora DM, Ruggiero M, Petit‐Kekel K, et al. (2004) Cholesterol supplementation does not improve developmental progress in Smith–Lemli–Opitz syndrome. Journal of Pediatrics 144 (6): 783–791.

Sikora DM, Pettit‐Kekel K, Penfield J, Merkens LS and Steiner RD (2006) The near universal presence of autism spectrum disorders in children with Smith–Lemli–Opitz syndrome. American Journal of Medical Genetics, Part A 140 (14): 1511–1518.

Smith DW, Lemli L and Opitz JM (1964) A newly recognized syndrome of multiple congenital anomalies. Journal of Pediatrics 64: 210–217.

Tierney E, Bukelis I, Thompson R, et al. (2006) Abnormalities of cholesterol metabolism in autism spectrum disorders. American Journal of Medical Genetics 141B: 666–668.

Tint GS, Irons M, Elias ER, et al. (1994) Defective cholesterol biosynthesis associated with the Smith–Lemli–Opitz syndrome. New England Journal of Medicine 330: 107–113.

Wassif CA, Zhu P, Kratz L, et al. (2001) Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith–Lemli–Opitz syndrome. Human Molecular Genetics 10: 555–564.

Wassif CA, Krakowiak PA, Wright BS, et al. (2005) Residual cholesterol synthesis and simvastatin induction of cholesterol synthesis in Smith–Lemli–Opitz syndrome fibroblasts. Molecular Genetics and Metabolism 85 (2): 96–107. Epub February 5.

Wassif CA, Kratz L, Sparks SE, et al. (2016) A placebo‐controlled trial of simvastatin therapy in Smith–Lemli–Opitz syndrome. Genetics in Medicine. DOI: 10.1038/gim.2016.102.

Waterham HR, Koster J, Romeijn GJ, et al. (2001) Mutations in the DHCR24 gene encoding 3β‐hydroxysterol Δ24‐reductase cause autosomal recessive desmosterolosis. American Journal of Medical Genetics 69: 685–694.

Xu G, Salen G, Shefer S, et al. (1995) Treatment of the cholesterol biosynthetic defect in Smith–Lemli–Opitz syndrome reproduced in rats by BM 15.766. Gastroenterology 109 (4): 1301–1307.

Xu G, Servatius RJ, Shefer S, et al. (1998) Relationship between abnormal cholesterol synthesis and retarded learning in rats. Metabolism, Clinical and Experimental 47 (7): 878–882.

Zhang S‐Q, Jiang T, Li M, et al. (2012) Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis. Nature Genetics 44 (10): 1156–1160.

Further Reading

Correa‐Cerro LS and Porter FD (2005) 3beta‐hydroxysterol Delta7‐reductase and the Smith–Lemli–Opitz syndrome. Molecular Genetics and Metabolism 84 (2): 112–126. Epub 2004 December 19. Review. PMID: 15670717 [PubMed – indexed for MEDLINE].

Jira PE, Waterham HR, Wanders RJ, et al. (2003) Smith–Lemli–Opitz syndrome and the DHCR7 gene. Annals of Human Genetics 67 (Pt 3): 269–280. Review. PMID: 12914579 [PubMed – indexed for MEDLINE].

Kanungo S, Soares N, He M and Steiner R (2013) Sterol metabolism disorders and neurodevelopment. Developmental Disabilities Research Reviews 17: 197–210.

Opitz JM, Gilbert‐Barness E, Ackerman J and Lowichik A (2002) Cholesterol and development: the RSH (“Smith–Lemli–Opitz”) syndrome and related conditions. Pediatric Pathology & Molecular Medicine 21 (2): 153–181. Review. PMID: 11942534 [PubMed – indexed for MEDLINE].

Woollett LA (2005) Maternal cholesterol in fetal development: transport of cholesterol from the maternal to the fetal circulation. American Journal of Clinical Nutrition 82 (6): 1155–1161. Review. PMID: 16332646 [PubMed – indexed for MEDLINE].

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Kanungo, Shibani, and Steiner, Robert D(Mar 2017) Disorders of Cholesterol Biosynthesis, Genetics of. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020223.pub2]