thematic review Thematic Review Series: Genetics of Human Lipid Diseases Malformation syndromes caused by disorders of cholesterol synthesis Forbes D. Porter 1, * and Gail E. Herman † Program in Developmental Genetics and Endocrinology,* Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892; and Center for Molecular and Human Genetics, † The Research Institute at Nationwide Children’s Hospital and Department of Pediatrics, The Ohio State University, Columbus, OH 43205 Abstract Cholesterol homeostasis is critical for normal ( Figs. 1 and 2 ). In addition to cholesterol, mevalonate me- growth and development. In addition to being a major mem- tabolism also is involved in the synthesis of isoprenoids Downloaded from brane lipid, cholesterol has multiple biological functions. such as farnesylpyrophosphate, geranylgeranylpyrophos- These roles include being a precursor molecule for the syn- phate, heme, ubiquinones, and vitamin D. Cholesterol thesis of steroid hormones, neuroactive steroids, oxysterols, synthesis can be divided into two major components, and bile acids. Cholesterol is also essential for the proper maturation and signaling of hedgehog proteins, and thus presqualene cholesterol synthesis and postsqualene choles- cholesterol is critical for embryonic development. After terol synthesis. Presqualene cholesterol synthesis ( Fig. 1 ) www.jlr.org birth, most tissues can obtain cholesterol from either en- contributes to both sterol and isoprenoid synthesis, whereas dogenous synthesis or exogenous dietary sources, but prior postsqualene cholesterol synthesis ( Fig. 2 ) represents a to birth, the human fetal tissues are dependent on endoge- commitment to sterol and vitamin D synthesis. This review nous synthesis. Due to the blood-brain barrier, brain tissue will focus on malformation syndromes due to inborn er- at NIH Library, on January 20, 2011 cannot utilize dietary or peripherally produced cholesterol. rors of postsqualene cholesterol synthesis. Mevalonate ki- Generally, inborn errors of cholesterol synthesis lead to nase defi ciency, an inborn error of presqualene cholesterol both a defi ciency of cholesterol and increased levels of po- tentially bioactive or toxic precursor sterols. Over the past synthesis that can result in mevalonic aciduria or hyper- couple of decades, a number of human malformation syn- immunoglobulinemia D syndrome, has previously been dromes have been shown to be due to inborn errors of cho- reviewed by Hass and Hoffmann ( 1 ). The fi rst committed lesterol synthesis. Herein, we will review clinical and basic step of sterol synthesis involves the synthesis of lanosterol science aspects of Smith-Lemli-Opitz syndrome, desmo- from squalene-2,3-epoxide, a reaction catalyzed by lano- sterolosis, lathosterolosis, HEM dysplasia, X-linked domi- sterol synthase ( 2 ). Synthesis of cholesterol, a C27 sterol, nant chondrodysplasia punctata, Congenital Hemidysplasia from lanosterol, a C30 sterol, involves multiple enzymatic with Ichthyosiform erythroderma and Limb Defects reactions, including reduction of ⌬ 7, ⌬ 14, and ⌬ 24 double Syndrome, sterol-C-4 methyloxidase-like defi ciency, and bonds; removal of methyl groups at positions C4 ␣ , C4 ␤ , Antley-Bixler syndrome. —Porter, F. D., and G. E. Herman. Malformation syndromes caused by disorders of cholesterol synthesis. J. Lipid Res . 2011. 52: 6–34. Abbreviations: ABS, Antley-Bixler Syndrome; Bpa, bare patche; CDPX2, X-linked dominant chondrodysplasia punctata, Conradi-Huner- Supplementary key words cholesterol biosynthesis • Smith-Lemli- mann Syndrome; CHILD Syndrome, Congenital Hemidysplasia with Opitz syndrome • genetics Ichthyosiform erythroderma and Limb Defects Syndrome; 8(9)chl, cholesta-8(9)-en 3 ␤ -ol; CNS, central nervous system; CYP, cytochrome P450; CYP17A1, sterol 17 ␣ -hydroxylase; CYP21A2, sterol 21-hydroxylase; Altered cholesterol homeostasis contributes to multiple DHC, dehydrocholesterol; 7DHC, 7-dehydrocholesterol; 8DHC, 8-dehy- drocholesterol; DHCR7, 3 ␤ -hydroxysterol ⌬ 7-reductase; DHCR14, 3␤ - human diseases. These range from common disorders such hydroxysterol ⌬ 14-reductase; DHCR24, 3 ␤ -hydroxysterol ⌬ 24-reductase; as atherosclerotic cardiovascular disease and stroke to DSD, disordered sexual development; EBP, emopamil binding protein; rare genetic syndromes. Cholesterol can be endogenously ERG, ergosterol; FGFR2, fi broblast growth receptor 2; HEM dysplasia, ␤ synthesized from acetate in a series of enzymatic steps Hydrops-Ectopic Calcifi cation-Moth-Eaten Skeletal Dysplasia; 3 -HSD, 3 ␤ -hydroxysteroid dehydrogenase; HSD17B7, 3 ␤ -ketosterol reductase; LBR, Lamin B Receptor; LXR, liver X receptor; MAS, meiosis-activating sterol; PHA, Pelger-Huët anomaly; POR, Cytochrome P450 oxidore- This work was supported by the intramural research program of the Eunice Ken- ductase; PTCH, patched; SC4MOL, sterol-C-4 methyloxidase-like; SC5D, nedy Shriver National Institute of Child Health and Human Development ␤ ⌬ (F.D.P.) and partially supported by R01 from NICHD (HD38572) to G.E.H. 3 -hydroxysteroid- 5-desaturase; SHH, sonic hedgehog; SLOS, Smith- Lemli-Opitz Syndrome; SMO, Smoothened; SREBP2, sterol regulatory Manuscript received 4 July 2010 and in revised form 4 October 2010. element binding protein; Str, striated; Td, tattered. Published, JLR Papers in Press, October 5, 2010 1 To whom correspondence should be addressed. DOI 10.1194/jlr.R009548 e-mail: [email protected] 6 Journal of Lipid Research Volume 52, 2011 This article is available online at http://www.jlr.org membrane and decidua were included. Using the Dhcr7 mutant mouse model, Tint et al. (7 ) concluded that early in gestation (prior to a gestational age of 12 d), the dam is the major source of cholesterol and that fetal sterol syn- thesis becomes the primary source of cholesterol in mid to late gestation. A number of studies, in various species, have evaluated cholesterol transfer from maternal circulation to the fetus ( 4–12 ) and Lin et al. ( 13 ) showed transfer of 14 C-labeled cholesterol from maternal circulation to hu- man fetal tissues. However, it is not clear to what degree maternal cholesterol contributes to a normally developing fetus and if it is necessary for human fetal development. Complicating the interpretation of these results with re- spect to the impact that maternal cholesterol could have on human fetal development is the fact that in contrast to rodents, the human yolk sac involutes early in develop- ment. The blood-brain barrier also contributes to the fetal dependence on endogenous cholesterol synthesis for nor- Fig. 1. Presqualene cholesterol synthetic pathway. Cholesterol is mal development. A number of studies have shown that synthesized from acetate in a series of enzymatic reactions. The both the developing and mature central nervous system biosynthetic pathway can be divided into two components. The Downloaded from (CNS) are dependent on endogenous cholesterol synthe- presqualene cholesterol synthetic pathway is depicted in this fi gure. In addition to cholesterol, isoprenoid precursors are used to syn- sis ( 5, 7, 14–16 ). The dependence of fetal development on thesize heme A, dolichol, and ubiquinone. Protein prenylation is a endogenous synthesis of cholesterol explains why the in- post-translational modifi cation that involves the addition of either born errors of cholesterol synthesis, in contrast to most farnesyl or geranylgeranyl. Protein prenylation plays a role in local- inborn errors of metabolism, are associated with signifi - izing proteins to cellular membranes. Formation of squalene rep- www.jlr.org resents a commitment to sterol synthesis. Squalene undergoes cant disruptions of embryonic development. cyclization to form lanosterol, the fi rst sterol in the cholesterol syn- Over the past couple of decades, a number of human thetic pathway. PP: pyrophosphate. malformation syndromes have been associated with de- fects in sterol synthesis ( Fig. 2 ; Table 1 ). These include at NIH Library, on January 20, 2011 autosomal recessive disorders such as Smith-Lemli-Opitz and C14 to reduce the C30 precursor lanosterol to a C27 Syndrome (SLOS), lathosterolosis, desmosterolosis, and sterol; isomerization of the ⌬ 8(9) double bond to ⌬ 7(8); sterol-C-4 methyloxidase-like (SC4MOL) defi ciency, as well and a desaturation reaction to introduce the ⌬ 5 double as X-linked dominant disorders such as X-linked dominant bond found in cholesterol. chondrodysplasia punctata (CDPX2) and Congenital Hemi- The majority of inborn errors of metabolism are cata- dysplasia with Ichthyosiform erythroderma and Limb bolic defects involving small organic acids. In these disor- Defects (CHILD) syndrome. Furthermore, impaired cho- ders, ready transport across the placenta and maternal lesterol synthesis has been proposed to contribute to some metabolism of accumulating intermediates protect the de- cases of Antley-Bixler syndrome and Hydrops-Ectopic veloping fetus prior to birth. Although minor dysmorphic Calcifi cation-Moth-Eaten Skeletal Dysplasia (HEM dyspla- features can occasionally be found in some of these disor- sia). Prior reviews on SLOS and malformation syndromes ders, developmental malformations are not typically asso- due to inborn errors of cholesterol synthesis include those ciated with inborn errors of metabolism. The inborn errors by Anderson ( 17 ), Herman ( 18, 19 ), Kelley ( 20 ), Kelley and of cholesterol synthesis are anabolic defects