**1. Introduction**

Cholesterol is essential for normal cellular function. All nucleated cells can synthesise cholesterol from acetyl-CoA in the isoprenoid biosynthesis pathway via enzymatic reactions that are localised to the endoplasmic reticulum. Isoprenoids function in a variety of important cellular processes, including cell growth and differentiation, protein glycosylation, as precursors of oxysterols, steroid hormones and bile, in mitochondrial electron transport and signal transduction pathways, especially that of the hedgehog pathway [1–3]. Cholesterol biosynthesis is divided into two major pathways: pre-squalene cholesterol synthesis and post-squalene cholesterol synthesis. Pre-squalene cholesterol synthesis contributes to both sterol and isoprenoid synthesis, whereas post-squalene cholesterol synthesis is a committed pathway to sterol and vitamin D synthesis [3].

Isoprenoid biosynthesis (**Figure 1**) begins with the C2 compound acetyl-CoA, which, via six subsequent enzyme reactions, is converted into isopentenylpyrophosphate, the basic C5 isoprene unit used for synthesis of all subsequent

#### **Figure 1.**

*Schematic representation of the human cholesterol biosynthesis pathway. HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; P, phosphate; PP, pyrophosphate; MA, mevalonic aciduria, HIDS, hyper IgD syndrome; SQSD, squalene synthase deficiency; LSS, lanosterol synthase deficiency; HEM, hydrops-ectopic calcificationmoth-eaten; CHILD, congenital hemidysplasia with ichthyosiform erythroderma and limb defects; CDPX2, X-linked chondrodysplasia punctate 2; SLOS, Smith-Lemli-Opitz syndrome.*

isoprenoids [3]. The first committed step to the production of sterol isoprenoids is C30 squalene (composed of 6 isoprene units) which, after cyclisation, is converted into C30 lanosterol (4,4,14-α-trimethyl-cholesta-8(9),24-dien-3β-ol) [4]. Following this transformation, cholesterol can be synthesised via one of two independent routes; the Bloch pathway [5] or the Kandutsch-Russell pathway [6]. Both pathways utilise the same enzymes, but in different orders in a tissue-dependent manner, leading to the formation of different intermediates [7]. C27 cholesterol is subsequently produced from lanosterol via a series of at least eight different enzyme reactions, including one demethylation at C14, two demethylations at C4, one isomerisation of the D8 [9] double bond to D7, three reductions of the D24, D14 and D7 double bonds and one desaturation between C-5 and C-6 [3].

Currently, 10 Mendelian disorders of cholesterol biosynthesis have been characterised, all with complex multisystem clinical phenotypes, supporting the importance of cholesterol in embryogenesis and development (see **Figure 1** and **Table 1**). Currently, the only reported defects in the pre-squalene pathway are the mevalonate kinase deficiency allelic conditions of mevalonic aciduria (MA, OMIM 610377) and hyper IgD syndrome (HIDS, OMIM 260960), squalene synthase deficiency (SQSD, OMIM 618156) and lanosterol synthase deficiency (LSS, OMIM 600909). Six Mendelian diseases in the post-squalene pathway have been reported: hydrops-ectopic calcification-moth-eaten skeletal dysplasia (HEM, OMIM 215140), congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome (CHILD, OMIM 308050), chondrodysplasia punctate 2 (CDPX2, OMIM 302960), lathosterolosis (OMIM 607330), Smith-Lemli-Opitz syndrome (SLOS, OMIM 270440) and desmosterolosis (OMIM 602398). Improved understanding of molecular mechanisms associated with intracellular trafficking of cholesterol and regulation of key rate limiting steps in cholesterol synthesis (e.g. via the ubiquitin proteasome system) has generated opportunities for identification of other novel Mendelian defects associated with cholesterol homeostasis [8, 9].

**133**

**Syndrome**

MA HIDS SQSD

LSS HEM skeletal dysplasia

CHILD CDPX2 Lathosterolosis

SLOS Desmosterolosis

**Table 1.**

*Known human defects of cholesterol biosynthesis.*

602398

1p32.3

*DHCR24*

607330 270400

11q13.4

*DHCR7*

11q23.3-q24.1

*SC5DL*

3β-hydroxysteroid-

7-dehydrocholesterol reductase

24-dehydrocholesterol reductase

Δ5-desaturase

302960

Xp11.22–23

*EBP*

3β-hydroxysteroid-

isomerase

Δ8


308050

Xq28

*NSDHL*

Sterol C4-demethylase aka

3β-hydroxysteroid dehydrogenase

600909

215140

1q42.12

*LBR*

3β-hydroxysteroid-sterol

21q22.3

*LSS*

Lanosterol synthase

Δ14-reductase

260960 618156

8p23.1

*FDFT1*

12q24.11

*MVK*

Mevalonate kinase

Squalene synthase

610377

12q24.11

*MVK*

Mevalonate kinase

**OMIM**

**Chromosome location**

**Gene**

**Enzyme**

**Key features** Autoinflammatory flares, dysmorphia, DD, psychomotor retardation and hepatosplenomegaly

Recurrent cyclical fevers and abdominal pain

Dysmorphia, DD, male genital malformations, brain malformations, seizures and abnormal urine organic acids

Congenital cataracts and hypotrichosis

Non-immune hydrops fetalis, stippling and erroneous

calcification and dwarfism

Unilateral ichthyosis, male-lethal, ipsilateral limb reduction

Rhizomelia, calcific stippling cataracts

Microcephaly, cataracts, poly and syndactyly, DD, II

2–3 syndactyly, cleft palate, II, typical craniofacial stigmata

SLOS-like dysmorphia, CHD, microcephaly, DD, II

AR

AR

AR

XLD

XLD

AR AR

AR AR

*Human Cholesterol Biosynthesis Defects DOI: http://dx.doi.org/10.5772/intechopen.87150*

> AR

**Inheritance**


### *Human Cholesterol Biosynthesis Defects DOI: http://dx.doi.org/10.5772/intechopen.87150*

*Apolipoproteins, Triglycerides and Cholesterol*

into C30 lanosterol (4,4,14-

isoprenoids [3]. The first committed step to the production of sterol isoprenoids is C30 squalene (composed of 6 isoprene units) which, after cyclisation, is converted

*Schematic representation of the human cholesterol biosynthesis pathway. HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; P, phosphate; PP, pyrophosphate; MA, mevalonic aciduria, HIDS, hyper IgD syndrome; SQSD, squalene synthase deficiency; LSS, lanosterol synthase deficiency; HEM, hydrops-ectopic calcificationmoth-eaten; CHILD, congenital hemidysplasia with ichthyosiform erythroderma and limb defects; CDPX2,* 

this transformation, cholesterol can be synthesised via one of two independent routes; the Bloch pathway [5] or the Kandutsch-Russell pathway [6]. Both pathways utilise the same enzymes, but in different orders in a tissue-dependent manner, leading to the formation of different intermediates [7]. C27 cholesterol is subse

quently produced from lanosterol via a series of at least eight different enzyme reactions, including one demethylation at C14, two demethylations at C4, one isomerisation of the D8 [9] double bond to D7, three reductions of the D24, D14 and

Currently, 10 Mendelian disorders of cholesterol biosynthesis have been characterised, all with complex multisystem clinical phenotypes, supporting the importance of cholesterol in embryogenesis and development (see **Figure**

**1**). Currently, the only reported defects in the pre-squalene pathway are the mevalonate kinase deficiency allelic conditions of mevalonic aciduria (MA, OMIM 610377) and hyper IgD syndrome (HIDS, OMIM 260960), squalene synthase deficiency (SQSD, OMIM 618156) and lanosterol synthase deficiency (LSS, OMIM 600909). Six Mendelian diseases in the post-squalene pathway have been reported: hydrops-ectopic calcification-moth-eaten skeletal dysplasia (HEM, OMIM 215140), congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome (CHILD, OMIM 308050), chondrodysplasia punctate 2 (CDPX2, OMIM 302960), lathosterolosis (OMIM 607330), Smith-Lemli-Opitz syndrome (SLOS, OMIM 270440) and desmosterolosis (OMIM 602398). Improved understanding of molecular mechanisms associated with intracellular trafficking of cholesterol and regulation of key rate limiting steps in cholesterol synthesis (e.g. via the ubiquitin proteasome system) has generated opportunities for identification of other novel

D7 double bonds and one desaturation between C-5 and C-6 [3].

*X-linked chondrodysplasia punctate 2; SLOS, Smith-Lemli-Opitz syndrome.*

Mendelian defects associated with cholesterol homeostasis [8, 9].

α-trimethyl-cholesta-8(9),24-dien-3

β-ol) [4]. Following


**1** and

**132**

**Table**

**Figure 1.**

**Table 1.**

*Known human defects of cholesterol biosynthesis.*

Modulating flux through the cholesterol biosynthesis pathway has been of interest for many years as a pharmacological treatment option for hypercholesterolemia. The statin family of drugs inhibit HMG-CoA reductase, the rate limiting step in the pre-squalene pathway, and similar efforts have focused on inhibitors of squalene synthase as this enzyme is the first committed step in cholesterol biosynthesis. Animal and human models of squalene synthase inhibitors generated a complex array of farnesol-derived metabolites [10–12], the recognition of which was instrumental in describing SQSD, a newly described pre-squalene cholesterol biosynthesis defect [4]. That pathogenesis of the cholesterol biosynthesis defects is complex, reflective of the multisystem nature of the clinical phenotypes.
