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Human Molecular Genetics, 2003, Vol. 12, Review Issue 1 R75-R88
DOI: 10.1093/hmg/ddg072
© 2003 Oxford University Press

Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes

Gail E. Herman*

Center for Molecular and Human Genetics, Columbus Children's Research Institute and Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA

Received January 16, 2003; Accepted January 22, 2003


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 THE CHOLESTEROL BIOSYNTHESIS...
 DISORDERS OF POST-SQUALENE...
 SUMMARY
 REFERENCES
 
Since 1998, five disorders involving enzyme defects in post-squalene cholesterol biosynthesis have been identified—desmosterolosis, X-linked dominant chondrodysplasia punctata, CHILD syndrome, lathosterolosis, and hydrops-ectopic calcification-moth-eaten skeletal dysplasia. They join the most common cholesterol biosynthetic disorder, Smith–Lemli–Opitz syndrome, whose underlying defect was identified in 1993. All are associated with major developmental malformations that are unusual for metabolic disorders. The existence of mouse models for five of these disorders is beginning to enable more detailed developmental and in vitro studies examining the mechanisms involved in disease pathogenesis. 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.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
THE CHOLESTEROL BIOSYNTHESIS...
 DISORDERS OF POST-SQUALENE...
 SUMMARY
 REFERENCES
 
The structure of cholesterol was elucidated by Wieland and Dane in 1932, and Konrad Bloch was awarded the Nobel Prize in Medicine in 1954 for his work on cholesterol biosynthesis.{dagger} However, the first genetic defect of the cholesterol biosynthetic pathway, mevalonic aciduria, due to deficiency of the enzyme mevalonate kinase, was identified in 1986 (1–3). It remains the only recognized human disorder in the first half or ‘pre-squalene’ portion of the pathway, although a targeted mutation in the murine squalene synthase gene is associated with embryonic lethality and defects of neural tube closure (4).

In the past 10 years, proven or suspected human disorders involving each step of post-squalene cholesterol biosynthesis have been described. The frequency of the most common of these disorders, Smith–Lemli–Opitz syndrome (SLOS), and the range of malformations associated with them make cholesterol biosynthesis disorders the prototypic metabolic malformation syndromes. Although their pathogenesis is not well understood, they underline the important role(s) of cholesterol and its metabolic precursors in mammalian development.

This review will provide an overview of the cholesterol biosynthetic pathway and clinical features of the known human disorders of post-squalene cholesterol biosynthesis, including those recently described. Naturally occurring or engineered mouse models for some of these human disorders that may provide clues to pathogenesis will also be discussed.


   THE CHOLESTEROL BIOSYNTHESIS METABOLIC PATHWAY
TOP
 ABSTRACT
 INTRODUCTION
 THE CHOLESTEROL BIOSYNTHESIS...
DISORDERS OF POST-SQUALENE...
 SUMMARY
 REFERENCES
 
The 27 carbon cholesterol molecule is synthesized in a series of approximately 30 enzymatic reactions{ddagger} with all of the carbon atoms originally derived from acetate (2,5–7). The first sterol intermediate, lanosterol, is formed by the condensation of the 30 carbon isoprenoid squalene (Fig. 1), and subsequent enzymatic reactions define the ‘post-squalene’ half of the pathway (Table 1 and Fig. 2). The conversion of lanosterol to cholesterol involves the reduction of the C-24 double bond, removal of three methyl groups at the C-14 and C-4 positions, and ‘migration’ of the C-8(9) double bond (Fig. 2) (for a recent review, see 6). Some of the enzymatic reactions must occur in sequence; for example, {Delta}8–{Delta}7 isomerization cannot precede C-14{alpha} demethylation. The saturation of the C-24 double bond of lanosterol can occur at multiple points in the pathway, creating two immediate precursors for cholesterol, desmosterol [cholesta-5(6), 24-dien-3ß-ol] and 7-dehydrocholesterol (7DHC), whose relative abundance may vary among different tissues. Desmosterol, in particular, appears to be abundant in the developing mammalian brain (2).



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  		Figure 1. Overview of the cholesterol biosynthetic pathway. HMGR=HMG-CoA reductase, the rate limiting step for the entire enzymatic pathway. Nonsterol compounds, including isoprenoids, that are derived from cholesterol or intermediates in the biosynthetic pathway are shown in red.

 

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  		Table 1. Enzymes of human post-squalene cholesterol biosynthesis
 


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  		Figure 2. Post-squalene cholesterol biosynthesis. Human disorders and naturally occurring mouse mutants discussed in the text are shown in blue. Individual enzymes, denoted by numbers in parentheses are (1) lanosterol 14{alpha}-demethylase, (2) 3ß-hydroxysteroid-{Delta}14-reductase, (3) 3ß-hydroxysteroid C-4 sterol demethylase complex, (4) 3ß-hydroxysteroid-{Delta}8–{Delta}7-sterol isomerase (EBP), (5) 3ß-hydroxysteroid-{Delta}5-desaturase (lathosterol dehydrogenase), (6) 3ß-hydroxysteroid-{Delta}7-reductase (DHCR7), (7) 3ß-hydroxysteroid-{Delta}24-reductase. The C-4 sterol demethylase complex consists of a methyl oxidase, a 3ß-hydroxysteroid dehydrogenase (NSDHL), and a 3ß-keto-steroid reductase. Reduction of the C-24 double bond can occur at any point along the pathway, but is shown only as an alternative last step for simplification.

 
This complex biosynthetic pathway is intimately tied to a variety of important cellular functions and signaling pathways (Fig. 1). Cholesterol is a key component of cell membranes and the immediate precursor for the synthesis of all known steroid hormones and bile acids. Lipid rafts, that play important roles in cell membrane function, are enriched in cholesterol (reviewed in 8). Isoprenoid intermediates in the pre-squalene half of the pathway serve as precursors for the synthesis of isopentenyl tRNAs involved in protein synthesis; dolichol for N-linked glycosylation of proteins; ubiquinone and heme A that function in electron transport in the mitochondria; and farnesyl and geranylgeranyl moieties that result in the prenylation of key cellular proteins such as ras and anchor them to cell membranes.

Several post-squalene sterol intermediates serve additional cellular functions as well. The C-14 demethylated derivatives of lanosterol, 4,4-dimethyl-5{alpha}-cholesta-8,14,24-trien-3ß-ol and 4,4-dimethyl-5{alpha}-cholesta-8,24-dien-3ß-ol, have meiosis-stimulating activity and accumulate in the ovary and testis, respectively (9,10). 7-Dehydrocholesterol is the immediate precursor for vitamin D synthesis. In addition, cholesterol and other sterol intermediates can be converted to oxysterols that can act as regulatory signaling molecules and bind orphan nuclear receptors such as LXR{alpha} (11–13). Finally, active hedgehog signaling proteins, involved in numerous developmental processes, are modified by the addition of cholesterol that appears to be required for the proper action of the hedgehog morphogen gradients (14–16).

At least 22 genes are required for the enzymatic conversion of acetyl CoA to ergosterol, the major sterol of yeast (17,18). Compared with cholesterol, the C-28 sterol ergosterol contains additional double bonds at the C-7 and C-22 positions and a methyl group on the side chain C-24 carbon atom. The ergosterol biosynthetic pathway is conserved with higher eukaryotes through {Delta}8–{Delta}7 isomerization, a phenomenon that has been exploited in functional complementation assays (19–22), for gene isolation based on sequence homology (23,24), for heterologous enzyme expression of proteins not found in yeast (25,26) and even for enzyme purification (27). Selected human enzymes of post-squalene cholesterol biosynthesis have also been identified based on homology to sterol biosynthetic enzymes from Arabidopsis thaliana (24–26,28).

The first seven enzymes of cholesterol biosynthesis are soluble proteins with the exception of 3-hydroxy-3-methylglutaryl CoA reductase (HMGR), which is an integral endoplasmic reticulum (ER) membrane protein (5–7). HMG-CoA for cholesterol biosynthesis is generated within the cytosol. It is also synthesized within the mitochondria where its hydrolysis by HMG-CoA lyase generates ketones for energy during fasting (29). Reactions generating mevalonate can also occur within the peroxisome, and the subsequent reactions that result in the production of farnesyl-pyrophosphate are exclusively peroxisomal. The remainder of the biosynthetic reactions occur in the ER with enzymes and substrates that are membrane-bound. Thus, cholesterol biosynthetic enzymes are compartmentalized in the cytosol, ER and/or peroxisome, adding another level of complexity to the regulation of this metabolic pathway. It is believed that HMGR is encoded by a single locus that is alternatively targeted to the ER or peroxisome by an as yet unknown mechanism in mammals, although HMGR gene duplications occur in lower eukaryotic species (30). Regulation of the pathway includes sterol-mediated feedback of transcription of several of the genes, including the rate-limiting enzyme HMGR and HMG-CoA synthase, as well as a variety of post-transcriptional mechanisms (5,31,32). Recently, increased attention has been focused on the regulated degradation of HMGR in the ER (reviewed in 31).


   DISORDERS OF POST-SQUALENE CHOLESTEROL BIOSYNTHESIS
TOP
 ABSTRACT
 INTRODUCTION
 THE CHOLESTEROL BIOSYNTHESIS...
 DISORDERS OF POST-SQUALENE...
SUMMARY
 REFERENCES
 
Seven disorders of post-squalene cholesterol biosynthesis will be discussed below in the order in which they were initially identified. Several recent reviews have been published describing some of the disorders, and the reader is referred to them for more detailed information on some topics (2,3,33,34).

Smith–Lemli–Opitz syndrome (SLOS)
SLOS was the first described disorder of post-squalene cholesterol biosynthesis and is by far the most common, with an incidence of approximately 1/40 000 to 1/50 000 in the USA (reviewed in 35–38). It was initially described in 1964 as an autosomal recessive major malformation syndrome. In 1993, Irons et al. (39,40) detected decreased plasma cholesterol levels and elevated 7DHC in several patients with SLOS, suggesting an enzymatic deficiency of 7-dehydrocholesterol reductase (7DHCR). The biochemical abnormalities in SLOS have been well documented and are now routinely employed for diagnosis (35–38,41).

The presence of a reproducible biochemical abnormality in SLOS led to better diagnosis and definition of the clinical phenotype, which has been detailed in several recent reviews (35–38,41; and see Cunniff, C. Smith–Lemli–Opitz syndrome. In: GeneReviews Online Reviews at www.geneclinics.org). Briefly, patients with classic SLOS have characteristic facies that include microcephaly, ptosis, a small nose with anteverted nares and micrognathia; growth and mental retardation; poor feeding in infancy often requiring placement of a gastrostomy tube; hypogenitalism in males, ranging from cryptorchidism to complete sex reversal; and skeletal abnormalities, the most common of which are 2,3 toe syndactyly and postaxial polydactyly. Less frequent major malformations include cataracts (10–20%), cleft palate (40–50%), congenital heart defects (40%), pyloric stenosis or colonic aganglionosis (10% each), cholestatic liver disease (5%), renal anomalies (25–30%), congenital sensorineural hearing loss (10%) and structural CNS malformations (20–35%), including some form of holoprosencephaly in 5%. With the ability to perform biochemical diagnosis, it was recognized that the most severely affected patients die in the perinatal period with multiple congenital anomalies (so-called Type II SLOS) (42), while approximately 5% of the mildest patients may have normal intelligence. Many patients exhibit distinctive abnormal behaviors, including self-injury, and in one small study 10 out of 17 subjects (59%) met established diagnostic criteria for autism (43).

The human DHCR7 gene was independently cloned by two groups in 1998 (25,28), and more than 80 mutations have been identified in several hundred patients (summarized in 2,3). Four common mutations account for approximately 50% of the known alleles, the most common of which, IVS8-1G>C, affects a splice donor site in intron 8. This mutation is associated with insertion of 134 bp in the mRNA, resulting in a frameshift and premature truncation of the protein. A clinical severity scale has been developed for SLOS (35,44), and some genotype–phenotype correlations have been reported, although there are clearly exceptions (41,45,46). The ratio of cholesterol to total sterols may be a sensitive biochemical marker of clinical severity (3). There also appears to be a high perinatal mortality for infants with initial cholesterol levels <10 mg/dl (type II SLOS).

Management of SLOS now often includes cholesterol supplementation in the form of oils or egg yolks to ameliorate the deficiency in these infants and children (47–51). Such treatment can result in improved growth and behavior; however, there appears to be minimal effects on intellectual function, at least in part because of the synthesis of all brain cholesterol in situ (52), as well as the inability to reverse prenatal developmental insults. In addition, supplementation with bile acids and inhibition of the pathway above the metabolic block using simvastatin have been described (47–51,53–55).

Functional inhibition of DHCR7 in rats by the teratogenic agents AY9944 and BM 15766 produces major malformations that include holoprosencephaly, pituitary agenesis, limb anomalies and genitourinary malformations (56–60). The DHCR7 inhibitor YM9429 has more limited teratogenic effects, producing axial skeletal defects and cleft palate in rats (61). Treatment of pregnant apob-/- mice with BM 15766 results in a similar spectrum of anomalies (62), although the higher average plasma cholesterol levels in mice compared with rats required the use of the mutant strain with lower basal cholesterol values to observe any teratogenic effects. These studies were complicated by effects of low maternal cholesterol on the developing fetus in addition to teratogenic effects on the fetus itself.

Two engineered mouse models have recently been developed for SLOS in which maternal cholesterol and placental transfer are normal (63,64). For both, the biochemical abnormalities mimicked those of human SLOS patients, and Dhcr7 enzyme activity was undetectable in homozygous null animals. The first model was designed by replacing exons 3, 4 and part of exon 5 of the murine Dhcr7 gene with a neo gene cassette (63). The mutation produces perinatal lethality, with homozygous Dhcr7-/- pups dying within hours of birth as a consequence of respiratory failure and/or failure to suckle and feed. Examination of affected pups revealed significant intrauterine growth retardation, hypotonia with decreased movement, and craniofacial anomalies including cleft palate (9%) and a retained nasal plug (30%) that occasionally resulted in the lack of a nasal opening (9%). No skeletal or additional internal malformations were detected. Neurophysiological studies, including whole cell patch-clamp experiments performed on cortical neurons from brain slices, demonstrated a normal response to the application of the neurotransmitter GABA, but a markedly impaired response to glutamate. Glutamate stimulates NMDA receptors in the brain which have been implicated in normal suckling behavior in mice (65). The authors postulate that altered cholesterol metabolism in Dhcr7-/- pups could affect glutamate responsiveness by direct action on cellular membranes or indirectly through effects on the synthesis or function of brain neurosteroids.

In the second model, investigators generated a mouse containing a deletion of the last coding exon of the Dhcr7 gene, analogous to the defect with the human splicing mutation IVS8-1G>C (64). These homozygotes also died shortly after birth and did not suckle. They demonstrated immature lungs, distended bladders (90%), and 12% had a cleft palate. Extensive biochemical analyses, including examination of the regulation of the entire biosynthetic pathway, demonstrated decreased total sterol concentrations in numerous tissues, although 7DHC and 8-dehydrocholesterol (8DHC) were markedly elevated. Despite the reduced total sterols and cholesterol, HMG-CoA reductase (HMGR) mRNA levels, as well as those for other sterol regulatory proteins, remained unchanged. HMGR protein and enzyme activity were, however, paradoxically reduced, resulting from increased protein turnover. Down-regulation of HMGR by 7DHC has also been demonstrated in cultured fibroblasts from SLOS patients (66). In an in vivo study in which four SLOS patients were treated long-term with a high cholesterol diet and analyzed by measurement of 24 h mevalonate excretion, HMGR activity was subject to normal feedback inhibition and overall sterol synthesis and 7DHC levels also appeared to be decreased (67).

Desmosterolosis
Only two patients with desmosterolosis have been reported. The first was a dysmorphic female with macrocephaly, cleft palate, total anomalous pulmonary venous drainage, clitoromegaly, short limbs and generalized osteosclerosis, who died 1 h after birth (68). Her facial features were reminiscent of SLOS, and markedly increased levels of desmosterol were detected in tissue samples from the infant. A second patient was reported who, at 3 years of age, exhibited a much milder phenotype that included microcephaly, dysmorphic facies, submucous cleft of the palate, persistent patent ductus arteriosus and complete agenesis of the corpus callosum (69). Elevated desmosterol was detected in plasma from the patient, as well as in lymphoblasts cultured in lipid-depleted sera. Parents of both cases had mildly elevated levels of plasma desmosterol, consistent with autosomal recessive inheritance. Subsequently, Waterham et al. identified mutations in all four alleles from both patients and demonstrated their inability to convert desmosterol to cholesterol in a heterologous expression assay in yeast (26). The second patient had significant residual activity, consistent with his milder clinical course. The phenotypic spectrum for this disorder remains to be defined as additional patients are identified, and no mouse model exists currently for this disorder.

X-linked dominant chondrodysplasia punctata
X-linked dominant chondrodysplasia punctata (CDPX2, also called Conradi–Hunermann or Happle syndrome) is a rare X-linked disorder with skeletal, skin and ocular manifestations and presumed male lethality (for a recent, comprehensive review, see 70). Affected females typically have a scaly, erythematous eruption at birth that follows lines of X-inactivation, the so-called lines of Blaschko (71,72). This rash often fades within early infancy, although many females are left with variable ichthyosis, scarring alopecia, follicular atrophoderma and residual pigmentary abnormalities. Skeletal findings include asymmetric, often rhizomelic, shortening of the extremities, as well as scoliosis and occasional postaxial polydactyly. Radiographs in infancy demonstrate epiphyseal stippling, which is often widespread in this form of chondrodysplasia punctata and may include the vertebral column and tracheal cartilage. Other abnormalities may include congenital cataracts and/or microphthalmia and renal or cardiac malformations. Intelligence is usually normal, although the presence of a CNS malformation with concomitant mental retardation has occasionally been reported (70).

The gene defect in CDPX2 was identified in 1999 based on the finding of abnormal elevations of sterol precursors in tissue samples from several females with CDPX2, suggesting a block at the level of sterol-{Delta}8–{Delta}7-isomerase (21,73), and by homology with an X-linked mouse mutant called tattered (Td) (74 and see below). The gene, called EBP, for emopamil binding protein, was originally identified as a receptor for a variety of drugs, including tamoxifen (19,75). Forty-one different mutations spread throughout the human sterol-{Delta}8–{Delta}7-isomerase gene have now been reported in a total of 60 unrelated females with CDPX2 (21,74,76–81). Our recent study of 22 females with CDPX2 and EBP mutations demonstrates the utility of plasma sterol analysis for this disorder, including the detection of an asymptomatic mother of a sporadic case (79). Clear genotype–phenotype correlations have not been demonstrated for CDPX2, probably because effects of random X-inactivation play a dominant role in the determination of clinical severity.

Somatic mosaicism and heterozygous EBP mutations have now been reported in two males with features of typical CDPX2 and normal karyotypes (82,83). Gonadal mosaicism and/or somatic mosaicism have been documented in at least two families with affected females with important implications for genetic counseling (76). Finally, a hemizygous male with a non-mosaic EBP missense mutation (L18P) has been described (84). His mildly affected mother also carried the mutation, excluding somatic mosaicism in the proband. His phenotype is strikingly different from that seen in heterozygous females and includes significant hypotonia, seizures and mental retardation with grossly delayed motor milestones and no speech at 2.5 years of age. Other anomalies included a unilateral congenital cataract, crossed renal ectopia and ptosis, with facies reminiscent of SLOS. No epiphyseal stippling was noted on radiographs performed in infancy. Cholesterol levels were normal, but cholest-8(9)-en-3ß-ol and 8DHC were mildly increased in plasma and cultured skin fibroblasts. Long-term survival of this affected male probably reflects residual function of the mutant enzyme.

The missense mutations G107R and L132P/S133C in the murine Ebp sterol isomerase gene underlie the defects in the X-linked, semi-dominant, male-lethal tattered Td1H and TdHo mice (74,85). Affected, heterozygous Td females are dwarfed, may have cataracts and exhibit a hyperkeratotic eruption on postnatal day 4–5 that resolves and results in striping of the adult coat. As with human CDPX2 patients, cholest-8(9)-en-3ß-ol and 8DHC accumulate in plasma from Td/+ females (74). Affected hemizygous male embryos die between E12.5 and birth, depending on the exact genetic background, and exhibit non-immune hydrops with a short-limbed skeletal dysplasia, cleft palate and absent intestines. In TdHo male embryos, diminished expression of embryonic globin genes was detected at E12.5, as well as increased apoptosis of fetal yolk-sac-derived erythrocytes (86). The authors speculate that defective erythropoesis may contribute to the male embryonic lethality. Further characterization of these models has not been reported.

CHILD syndrome
CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma or nevus and limb defects) is also an X-linked male-lethal disorder with phenotypic similarities to CDPX2, but with a striking unilateral distribution of anomalies (for recent reviews, see 2,70). Unilateral ichthyosiform skin lesions are usually present at birth, persist throughout life, and often involve large regions on one side of the body, with a sharp line of demarcation in the midline. Small patches of involved skin may occur on the opposite side, although the face is typically spared. Alopecia may occur on the affected side and nail involvement is common. There are ipsilateral limb reduction defects with epiphyseal stippling noted on X-rays in infancy. Internal malformations including CNS, renal and cardiac have been reported, typically occurring on the affected side. Involvement of the right side occurs approximately twice as often as the left.

Although CDPX2 and CHILD syndrome have many similarities suggesting, perhaps, a common etiology, there are some notable differences. Cataracts are not found in CHILD syndrome. The skin lesions persist much more frequently in CHILD syndrome and the skeletal anomalies are more severe. There are also subtle histologic and ultrastructural differences noted on pathologic specimens from patients with the two conditions. However, the distinguishing features are not absolute as represented by a rare female with CHILD syndrome and bilateral, symmetric involvement (87) or by CDPX2 females with persistent diffuse erythroderma (88) or predominantly unilateral ichthyosis resembling that seen in CHILD syndrome (89).

Two females with clinical features of CHILD syndrome have been reported with EBP mutations (2,90) although there has been some disagreement about the diagnosis of these cases (91,92). Six additional CHILD syndrome patients have mutations in the NSDHL (NADH steroid dehydrogenase-like) gene, including a heterozygous male with somatic mosaicism (93) and the above-mentioned female with symmetrical skin involvement (94). NSDHL encodes a sterol dehydrogenase or decarboxylase that is part of the C-4 sterol demethylase protein complex and precedes the sterol-{Delta}8–{Delta}7-isomerase step in the cholesterol biosynthetic pathway (95) (Fig. 2). CHILD patients with NSDHL mutations tend to have more severe and persistent skin involvement than those with EBP mutations (96). Although all of the reported patients with defects in cholesterol biosynthetic enzymes have had right-sided disease, an NSDHL mutation has recently been detected in a CHILD female with left-sided involvement (97).

The first mutations in the Nsdhl gene were identified in several alleles of the bare patches (Bpa) mouse, an X-linked male lethal mutant with features very similar to those described in Td heterozygotes (95). Bpa females are dwarfed with abnormal deposits of calcium noted on skeletal sections of tail vertebrae, similar to radiographic epiphyseal stippling. Over 50% of Bpa females for the original allele (Bpa1H) have cataracts, often asymmetric, and some demonstrate microphthalmia. They develop a hyperkeratotic skin eruption on postnatal day 5–7 that resolves and produces a striping of the adult coat, similar to that in Td (98). Milder Bpa alleles, called striated (Str), were originally thought to be a distinct locus and are indistinguishable from normal littermates until day 12–14 when the striped coat is first apparent. Mutations in Nsdhl have been identified in 7 Bpa and Str alleles (95, G. Herman, unpublished results) including a nonsense mutation, K103X, in the original Bpa1H allele that has the most severe phenotype. Affected male embryos for several Bpa/Str alleles die between E9.5 and 12.5 and appear to have smaller, disorganized fetal placentas (G. Herman, unpublished results).

Bpa/Str females and affected male embryos with NSDHL mutations accumulate increased 4-methyl and 4,4-dimethyl sterol intermediates, although the amounts are much smaller than the sterol intermediates encountered in patients with SLOS and in Td mice with EBP mutations (95). The 4-methylsterol abnormalities are most easily detected in cultured cells grown in lipid-depleted media. CHILD females with EBP mutations have typical elevations of cholest-8(9)-en-3ß-ol and 8DHC in plasma, as in CDPX2 (2,90).

The unilateral distribution of lesions in CHILD syndrome, often with a midline demarcation, does not follow the pattern of X-inactivation and is difficult to explain. While there is often asymmetry in the striping of the coat in Bpa/Str females, limb reduction defects and unilateral diffuse skin lesions, as seen in human CHILD syndrome, have never been observed (G. Herman, unpublished results). Rather the patterned distribution of lesions in the mutant mice follows the lines of Blaschko and is consistent with random X-inactivation and functional mosaicism for an X-linked gene expressed in skin and hair follicles. In addition, human CHILD patients with NSDHL mutations do not have cataracts, while some mice with the severe Bpa1H allele do. Further, the detection of an identical NSDHL mutation in an infant with CHILD syndrome and her mildly affected mother excludes somatic mosaicism as an underlying mechanism for the unilateral distribution, at least in this case (93). Happle has proposed that midline early embryonic ‘organizer’ cells expressing the mutant NSDHL gene could affect the process of X-inactivation itself in CHILD syndrome and alter patterning of a large developmental field on one side of the body (71,93). This theory does not explain the differences detected between mice and humans with NSDHL mutations. It is possible that differences in the timing of X-inactivation, in cholesterol metabolism, or in transport of maternal cholesterol to the developing fetus, explain the species-specific features. It is unlikely that differences in the type or site of mutation explain them since missense mutations involving the same conserved amino acid have been detected in a CHILD female and an ENU-induced Bpa allele (G. Herman, unpublished results). It also remains unexplained why human EBP mutations tend to produce more symmetric disease compared to NSDHL mutations.

Lathosterolosis
In 2002, two unrelated males with lathosterolosis were described. Both patients exhibited an ‘SLOS-like’ phenotype. The first patient had microcephaly; dysmorphic facies with bilateral epicanthal folds, anteverted nares and micrognathia; polysyndactyly of the left foot; progressive cholestatic liver disease; conductive deafness; and severe psychomotor retardation (99). Brain imaging was normal and no ichthyosis, chondrodysplasia punctata or genital abnormalities were detected. A previous, karyotypically normal (46,XX) pregnancy was terminated at 22 weeks for multiple anomalies that included microcephaly, lumbosacral myelomeningocele, four limb hexadactyly and clubfeet. The second patient has been briefly described (100) and presented with craniofacial abnormalities including micrognathia, penoscrotal hypospadias and undescended testes, and postaxial polydactyly of the feet with 2,3-toe syndactyly.

Both patients had abnormal sterol profiles with accumulation of lathosterol in plasma (patient 1) or cultured fibroblasts (patient 2). Sterol C-5-desaturase (SC5D) enzyme activity in cultured fibroblasts from patient 2 was approximately 10% of normal. Using sequence from a human SC5D cDNA isolated by homology to the yeast enzyme, patient 1 was found to be a compound heterozygote for the missense mutations R29Q and G211D (99), while patient 2 was homozygous for the missense mutation Y46S (100). Detection of residual conversion of labeled mevalonate to cholesterol in cultured cells from both patients confirmed that these mutations act as hypomorphs, at least in vitro.

Porter et al. (100) have generated a mouse model for lathosterolosis by targeted disruption of the murine Sc5d gene in ES cells. In part, these efforts were initiated to examine whether some of the phenotypic features of SLOS are caused by a lack of cholesterol or by an accumulation of 7DHC. Both compounds would be expected to be low in a Sc5d-/- mouse. Homozygotes are stillborn, edematous and growth-retarded. Eighty-eight percent of homozygotes examined had a cleft palate, and they had plugged or absent nostrils. They exhibited a variety of skeletal defects including shortened limbs, kinked tail, postaxial polydactyly of the forelimbs, soft tissue syndactyly and a specific duplication of the distal phalanx of the fourth digit. They also had hypomineralization of the bones and an enlarged liver. Tissues and serum from affected pups demonstrated markedly elevated levels of lathosterol and decreased cholesterol.

Although the number of affected human patients is small, there are many similarities between their phenotype and that of the Sc5d-/- mouse. Their prolonged survival compared with the knock-out mouse could be related to the presence of hypomorphic alleles with residual enzyme activity in the human infants.

Hydrops-ectopic calcification-moth-eaten (HEM) or Greenberg skeletal dysplasia
HEM skeletal dysplasia was first described by Greenberg et al. in 1988 (101) in a stillborn infant and subsequent affected fetus from a consanguineous mating. The disorder appears to be uniformly lethal prenatally and has now been reported in a total of eight fetuses from seven unrelated families of diverse ethnic origin (101–105). Consanguinity was present in four of the families. Characteristic features include non-immune hydrops fetalis and a severe short-limbed dwarfism with markedly disorganized cartilaginous and bony architecture. Radiographic findings include a moth-eaten appearance to the long bones, as well as the presence of ectopic calcifications and platyspondyly. Two reported cases have demonstrated postaxial polydactyly involving the hands (102,105). While anomalies outside the skeleton appear uncommon, omphalocele, intestinal malrotation and hypolobated lungs were identified in a single case (103). Based on the presence of severely disorganized chondrogenesis and abnormal calcification that resembles that found in CDPX2, Kelley and Wilcox examined sterols extracted from cartilage from four fetuses with HEM and identified elevated levels of cholesta-8,14-dien-3ß-ol and cholesta-8,14,24-trien-3ß-ol, suggesting a block at the level of the 3ß-hydroxysteroid-{Delta}14-reductase (106) (Fig. 2).

Two candidate human sterol-{Delta}14-reductase enzymes have been identified based on homology with the yeast ERG24 gene. The first, TM7SF2, encodes a ubiquitously expressed ER transmembrane protein that is linked to the DHCR7 locus on chromosome 11q (24). The second is the lamin B receptor, a nuclear membrane protein whose C-terminal ~400 amino acids contain eight putative transmembrane domains with homology to sterol-{Delta}14-reductases from a variety of eukaryotes (20,24). While a bovine TM7SF2 cDNA transfected into COS-7 cells expressed sterol-{Delta}14-reductase activity (107), chimeric proteins containing portions of the human TM7SF2 cDNA fused to the Neurospora crassa erg-3 sterol-{Delta}14-reductase failed to complement N. crassa erg-3 or S. cerevisiae ERG24 mutants (108). However, a human LBR expression construct was able to rescue the ergosterol biosynthesis defect of ERG24 (20), suggesting that LBR possesses bona fide sterol-{Delta}14-reductase activity.

We (2) and others (105) have sequenced all of the exons of TM7SF2 from genomic DNA from several fetuses with HEM skeletal dysplasia, and no mutations were detected. However, Waterham et al. (105) identified a homozygous seven nucleotide substitution that introduces a stop codon in the C-terminus of the LBR gene in a single HEM fetus. Transfection of the normal LBR cDNA into patient fibroblasts resulted in a dramatic reduction in the accumulation of sterol intermediates, and the authors conclude that the LBR protein appears to function as the primary cellular sterol-{Delta}14-reductase.

Hoffmann et al. (109) reported heterozygous mutations in LBR in 20 families with Pelger–Huet anomaly (PHA), a benign autosomal dominant abnormality of leukocyte development that results in hypolobulation of neutrophils, as well as abnormal chromatin structure and nuclear shape. The mutations included a common founder splicing mutation within the sterol reductase domain of the protein, IVS12–5-10del, that results in skipping of exon 13, as well as frameshift and nonsense mutations spread throughout the gene. All would be predicted to result in decreased expression of the normal protein. A PHA homozygote from one family with the common splicing mutation exhibited mental retardation, macrocephaly and shortened third and fifth metacarpals. Lymphoblasts from this patient produced trace amounts of normal message and normal protein on western blots. Interestingly, the mother of the HEM patient reported by Waterham et al. (105) demonstrates PHA in 60% of her neutrophils; the father was unavailable for study. Heterozygous PHA has also been reported in mice, rabbits, dogs and cats (summarized in 110).

Finally, Shultz et al. (110) recently reported that three alleles of the ichthyosis mouse (ic) also result from mutations in Lbr. Heterozygous ic mice have white blood cell abnormalities very similar to those found in PHA, while homozygotes for the one allele whose phenotype was analyzed in detail, icJ, also exhibit sparse hair or complete alopecia, growth retardation, variable syndactyly and ichthyosis, particularly on the tail. Based on the frequencies of affected icJ/icJ pups, there is approximately 50% pre- or perinatal lethality for the mutation. Occasional surviving homozygotes also developed hydrocephalus characterized by dilatation of the lateral ventricles. Chromatin clumping noted in neutrophils was also detected in other cell types, including intestinal epithelial and cerebellar granule cells. DNA sequencing identified truncating mutations of Lbr in three available ic alleles: the extinct ic and ic4J alleles result from a nonsense mutation in the N-terminal lamin B binding domain and an insertion of four bases within the sterol-{Delta}14-reductase domain at the C-terminus of the protein, respectively. The icJ allele results from a 2 bp insertion that creates a frameshift and premature termination within the middle of the sterol-{Delta}14-reductase domain.

Thus, the ic/ic mouse, homozygous PHA and at least one case of human HEM skeletal dysplasia result from recessive mutations in the same gene, the lamin B receptor. While the nuclear clumping and chromatin abnormalities of LBR disorders are likely to be related to the lamin binding function of the protein, based on phenotypic similarities with other sterol biosynthesis disorders, many of the phenotypes may be related to lack of sterol-{Delta}14-reductase activity in affected cells. Differences in severity between homozygous PHA and HEM cases could result from residual enzyme activity in the former. While the phenotype of HEM appears more severe than that of surviving icJ homozygotes, studies of the ~50% of pups that do not survive may reveal additional anomalies. In addition, influences of genetic background on the ic phenotype have not been investigated, and there could be species-specific differences as discussed above for the X-linked biosynthetic disorders. Further studies of the mouse model and more HEM and PHA patients should help define the full spectrum of the phenotypes associated with LBR mutations.

Antley–Bixler syndrome
Antley–Bixler syndrome (ABS) is a heterogeneous malformation syndrome, with cardinal features of craniofacial dysmorphisms, including craniosynostosis and choanal atresia, and limb anomalies, such as radiohumeral synostosis and femoral bowing. Autosomal recessive inheritance has been suggested based on the presence of consanguinity and/or affected sibs in some families. There is a high mortality rate in the more than 50 cases reported to date (111,112). Heterozygous mutations in fibroblast growth factor receptor 2 (FGFR2) have been identified in several sporadic cases of ABS (112–114), although others have questioned the accuracy of the diagnosis in at least some of these cases (115). Reardon et al. (112) identified biochemical abnormalities of steroidogensis in several ABS patients, including one patient with an FGFR2 mutation, and suggested that some cases may thus be examples of digenic inheritance. Based on the presence of ambiguous or underdeveloped genitalia in some cases of ABS and the presence of a similar phenotype in four infants exposed in utero to fluconazole (116), an antifungal medication that inhibits lanosterol-14{alpha}-demethylase, it has been suggested that some cases of ABS may be caused by mutations in the lanosterol-14{alpha}-demethylase CYP51 or a related gene involved in cholesterol biosynthesis (3,112,116). Finally, Kelley et al. (117) performed sterol analysis on lymphoblast cell lines from two ABS cases with ambiguous genitalia, one with and the other without an FGFR2 mutation. When grown in lipid-depleted media, only cells from the patient without the FGFR2 mutation had markedly elevated levels of lanosterol and dehydrolanosterol, consistent with a defect in lanosterol-14{alpha} demethylation. However, no mutations were detected upon sequencing the 10 exons and intron–exon junctions of the human CYP51 gene from this patient, and the molecular defect leading to the abnormal sterol profile remains unknown. An as yet unidentified regulatory protein of the C-14 demethylation reaction, as has been found for the sterol C-4 demethylase in yeast (118), has been proposed as one possible explanation (117).


   SUMMARY
TOP
 ABSTRACT
 INTRODUCTION
 THE CHOLESTEROL BIOSYNTHESIS...
 DISORDERS OF POST-SQUALENE...
 SUMMARY
REFERENCES
 
Six confirmed defects of post-squalene cholesterol biosynthesis have now been described (Table 1 and Fig. 2). It is likely that some cases of ABS will result from defects in C-14 demethylation, and patients with mutations in the autosomal sterol-C4-methyl oxidase and sterol-C4-ketoreductase genes or accessory regulatory proteins may also be identified. Biochemical screening appears to be the most efficient and sensitive method to detect a potential cholesterol biosynthesis defect, although for some of the disorders, elevations of accumulating sterol intermediates in plasma are minimal or occasionally not detected.

There are some common phenotypic features among the disorders (Table 2), and all are associated with major malformations and dysmorphic facies, suggesting that perturbations of the pathway have potent teratogenic effects. In general, clinical severity, as measured by survival in the hemi- or homozygous state, decreases in later steps of the pathway. Skeletal abnormalities are also associated with each disorder, although the severity and frequency of such findings vary, from mild with occasional CDP in SLOS to severe and incompatible with survival in HEM dysplasia. Delayed development is associated with all three disorders in which homozygotes routinely survive beyond the newborn period. Normal intelligence in the two X-linked disorders almost certainly relates to the survival of heterozygous females, and, indeed, the recently reported male with a non-mosaic hemizygous EBP mutation exhibited mental retardation and seizures (84). In addition, the single reported male with a homozygous, hypomorphic mutation and prolonged survival in the LBR sterol-{Delta}14-reductase exhibited mental retardation (109).


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  		Table 2. Clinical features of human cholesterol biosynthesis disorders
 
What is not clear presently is the pathogenesis of these disorders. Speculations about pathogenesis have been provided in several recent reviews (2,3,33,34,70). One can postulate that pathogenicity results from a lack of cholesterol or related sterols, accumulation of toxic sterol intermediates above each enzyme block, abnormal feedback regulation of earlier steps in the pathway, including synthesis of key isoprenoid compounds, and/or abnormal signaling by hedgehog proteins that normally contain bound cholesterol. The survival to birth of SLOS patients with null alleles and plasma cholesterol levels <10 mg/dl would argue that a simple lack of cholesterol cannot explain the embryonic lethality of some of these disorders. Further, in preliminary experiments, we have demonstrated that cholesterol levels in tissues from affected Bpa/Str male embryos near the time of death are normal, probably as a result of placental transfer from the mother (G. Herman and R. Kelley, unpublished results). It is likely that at least some of the teratogenic effects in these disorders result from a lack of cholesterol for incorporation into membranes, particularly in the brain. In particular, methylated sterol intermediates are unable to fulfill the role of cholesterol within membranes and result in dramatic changes in fluidity within the lipid bilayers (119).

It is attractive to postulate important roles for hedgehog proteins—sonic hedgehog, Indian hedgehog and desert hedgehog—in disease pathogenesis. One or more of the hedgehog proteins are involved in many of the developmental processes that are perturbed in these disorders, including establishing a proper midline and left–right axis, proper differentiation of the lung and gut, chondrocyte differentiation and hair follicle development (14–16). While 7DHC can substitute for cholesterol in the auto-processing of and binding to hedgehog proteins, at least in vitro (120), it is unlikely that earlier intermediates, such as methylsterols, can perform these functions.

The existence of naturally occurring or targeted mouse mutations for most of the disorders should facilitate mechanistic studies, particularly during embryonic development. However, as evidenced by the striking phenotypic differences between human CHILD patients with NSDHL mutations and Bpa mice, the mouse may not recapitulate all of the features found in human fetuses and patients. Such differences may, in part, be due to differences between rodent and human cholesterol metabolism and transport by the placenta and fetus (for a recent review, see 121) and will need to be considered as functional studies are undertaken and mechanisms are proposed.


   ACKNOWLEDGEMENTS
 
I wish to thank Dr Hans Waterham and Dr Richard Kelley for sharing data prior to publication, Dr Hugo Caldas for critical review of the manuscript, and Ms Kathy Copas for help with its preparation. This work was supported by NIH R01 HD38572 and by funds from Columbus Children's Research Institute.


   FOOTNOTES
 
* To whom correspondence should be addressed at: Columbus Children's Research Institute, 700 Children's Dr. Rm W403, Columbus, OH 43205, USA. Tel: 614-722-2848; Fax: 614-722-2817; Email: hermang{at}pediatrics.ohio-state.edu Back

{dagger} A special issue of Biochimica Biophysica Acta entitled ‘Cholesterol in the year 2000’, volume 1529, 2000, is dedicated to Konrad Bloch and contains excellent reviews detailing some of the research on cholesterol metabolism since Bloch's initial discoveries. Back

{ddagger} Although there are approximately 30 enzymatic reactions in the cholesterol biosynthetic pathway, there are fewer distinct enzymes because more than one reaction may be catalyzed by a single enzyme (i.e. sterol C-4 methyl oxidase) and the C-4 demethylase complex of three enzymes is involved in sequential removal of both C-4 methyl groups. Back


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