High Bone Density Due to a Mutation in LDL-Receptor–Related Protein 5
Lynn M. Boyden, Ph.D., Junhao Mao, Ph.D., Joseph Belsky, M.D., Lyle Mitzner, M.D., Anita Farhi, R.N., Mary A. Mitnick, Ph.D., Dianqing Wu, Ph.D., Karl Insogna, M.D., and Richard P. Lifton, M.D., Ph.D.
Background Osteoporosis is a major public health problem oflargely unknown cause. Loss-of-function mutations in the genefor low-density lipoprotein receptor–related protein 5(LRP5), which acts in the Wnt signaling pathway, have been shownto cause osteoporosis–pseudoglioma.
Methods We performed genetic and biochemical analyses of a kindredwith an autosomal dominant syndrome characterized by high bonedensity, a wide and deep mandible, and torus palatinus.
Results Genetic analysis revealed linkage of the syndrome tochromosome 11q12–13 (odds of linkage, >1 million to1), an interval that contains LRP5. Affected members of thekindred had a mutation in this gene, with valine substitutedfor glycine at codon 171 (LRP5V171). This mutation segregatedwith the trait in the family and was absent in control subjects.The normal glycine lies in a so-called propeller motif thatis highly conserved from fruit flies to humans. Markers of boneresorption were normal in the affected subjects, whereas markersof bone formation such as osteocalcin were markedly elevated.Levels of fibronectin, a known target of signaling by Wnt, adevelopmental protein, were also elevated. In vitro studiesshowed that the normal inhibition of Wnt signaling by anotherprotein, Dickkopf-1 (Dkk-1), was defective in the presence ofLRP5V171 and that this resulted in increased signaling due tounopposed Wnt activity.
Conclusions The LRP5V171 mutation causes high bone density,with a thickened mandible and torus palatinus, by impairingthe action of a normal antagonist of the Wnt pathway and thusincreasing Wnt signaling. These findings demonstrate the roleof altered LRP5 function in high bone mass and point to Dkkas a potential target for the prevention or treatment of osteoporosis.
Osteoporosis is a major public health problem, and its prevalenceis increasing.1,2,3 In the United States, nearly 1 million fracturesoccur annually in people over the age of 65 years, the majorityof which are due to osteoporosis.1,4 Osteoporotic fracturesare associated with substantial morbidity, and the estimatedrate of death in the first year after a hip fracture is 25 to30 percent.5,6
Bone mass, a major determinant of the risk of osteoporotic fracture,increases during childhood and adolescence, reaching a peakat about the age of 20 years.7 Twin and family studies indicatethat genetic factors account for approximately 75 percent ofthe variation in peak bone mass,7 although the genes that contributeto this variation are largely unknown.
In this setting, the investigation of rare mendelian disordersmay identify pathways that affect the trait. One disorder characterizedby increased bone density with largely normal bone is an autosomaldominant disease with variable clinical features, includingentrapment neuropathies, increased levels of alkaline phosphatase,a square jaw, and torus palatinus.8,9,10,11,12,13,14,15 In 1997,Johnson et al. reported the linkage of a gene causing nonsyndromichigh bone mass in a single family to a 30-cM region of 11q12–13with a lod score of 5.74.16 Because few kindreds have been studied,the question of whether these varied clinical manifestationsarise from mutations in the same gene or in different geneshas not been answered.
Osteoporosis–pseudoglioma, an autosomal recessive diseasecharacterized by low bone mass, with childhood fractures andabnormal eye development, has also been mapped to 11q12–13.17The disorder has recently been shown to be due to an inheritedloss of function of the gene for low-density lipoprotein receptor–relatedprotein 5 (LRP5).18 This protein is involved in the Wnt signalingpathway, acting as a coreceptor for Wnt, a developmental protein,and as a target for the inhibitory effects of Dickkopf (Dkk),another developmental protein, on Wnt signaling.19,20,21 Thesefindings suggest a link between Wnt signaling through LRP5 andbone density, and they raise the question of whether gain-of-functionmutations in the LRP5 gene cause high bone mass. We performedgenetic and biochemical analyses in a kindred with an autosomaldominant syndrome characterized by high bone density, a wideand deep mandible, and torus palatinus.
Methods
Subjects
Twenty members of a kindred of white ancestry from Connecticutparticipated in the study. The protocol was approved by theHuman Investigation Committee at Yale University School of Medicine.All the subjects (or their guardians, in the case of minors)provided written informed consent. Assent was also obtainedfrom minors. The subjects provided a medical history and a bloodsample for DNA preparation. Bone density was measured in 16of the 20 kindred members. The four members in whom bone densitywas not measured included two children (10 and 13 years old),one person who died before the study, and one person who declinedto participate. We performed detailed serum and urinary biochemicalmeasurements in four kindred members with very high bone density;these values were compared with the values in nine healthy controlsubjects.
Bone-Density Measurements
We measured bone mineral density in the lumbar spine, femoralneck, and total body, using dual-energy x-ray absorptiometrywith a densitometer (QDR 4500W, Hologic, or DPXL, Lunar). Theresults are expressed as z scores (the number of standard deviationsfrom the mean value for persons in the general population matchedfor age, sex, and race).
Biochemical Evaluation
Serum levels of parathyroid hormone and tartrate-resistant acidphosphatase and plasma levels of vitamin D metabolites weremeasured as previously reported.22,23 Serum calcium was measuredwith the use of flame atomic absorptiometry. Serum creatinineand phosphate levels and levels of the brain isoform of creatinekinase were measured with the use of an AutoAnalyzer (model747-200, Hitachi) in the clinical-chemistry laboratory of Yale–NewHaven Hospital in New Haven, Connecticut. Serum osteocalcin,bone-specific alkaline phosphatase, urinary N-telopeptide oftype 1 collagen, the receptor for activation of nuclear factor-Bligand, osteoprotegerin, transforming growth factor 1 (TGF-1),and fibronectin were measured with the use of commercial kits.Mean (±SD) values in affected subjects and controls werecompared with the use of unpaired two-tailed t-tests.
Genetic Studies
Polymorphic markers on 11q were genotyped with the use of apolymerase-chain-reaction (PCR) assay and specific fluorescentprimers and genomic DNA from members of the kindred as the template.The products were fractionated by electrophoresis on an ABI3700 DNA analyzer (Applied Biosystems), and genotypes were determinedwith the use of Genotyper software. We analyzed linkage withthe use of the Linkage program, specifying high bone densityas an autosomal dominant trait with a disease-allele frequencyof 0.00001, complete penetrance, and a phenocopy prevalenceof 0.00001. Unstudied obligate carriers were classified as "phenotypeunknown." Altering the specified model had minor effects onthe lod score.
LRP5 mutations in members of the kindred were sought by PCRamplification of short segments spanning the coding region andintron–exon boundaries of LRP5; the products were analyzedby electrophoresis under nondenaturing conditions. Identifiedvariants were subjected to DNA sequencing. The controls were210 unrelated white persons not known to have abnormalitiesin bone density.
In Vitro Biochemical Studies
We used a well-characterized signaling system in the mouse fibroblastNIH3T3 cell line to examine the effect of mutant LRP5 on Wntsignaling.19 In each experiment, plasmids encoding LEF-1 (atranscription factor activated by Wnt signaling) constitutivelyexpressed from a cytomegalovirus promoter, luciferase undercontrol of an LEF-1–responsive promoter, and green fluorescentprotein were introduced by transfection into cells seeded in24-well plates. In addition, plasmids encoding wild-type (normal)LRP5 or LRP5V171, Wnt-1, and Dkk type 1 (Dkk-1) were transfectedin indicated combinations. The total amount of DNA transfectedin each experiment was kept constant (0.5 µg per well)by the addition of varying amounts of a plasmid encoding -galactosidase(LacZ). One day after transfection, the cells were lysed, andthe levels of luciferase activity and green fluorescent proteinwere measured; luciferase activity was normalized accordingto the green fluorescent protein level in order to account forvariation in the efficiency of transfection. Each experimentwas conducted in triplicate. Values are reported as means ±SD.
Results
Identification of the Kindred
The kindred was identified when two persons found on clinicalscreening to have extremely high bone density (Subjects 3 and6) were incidentally noted to be related to one another. Inaddition to high bone density, both had a strikingly wide anddeep mandible (Figure 1A and Figure 1B) and torus palatinus(Figure 1C). Radiographic studies showed normal skeletal morphologyexcept for dramatically thickened mandibular ramii (Figure 1D),marked cortical thickening in long bones (Figure 1E), and densevertebrae (Figure 1F). There was no radiographic evidence ofosteopetrosis, and the shape of the vertebral bodies was normal.There were no cranial-nerve palsies. Both persons were asymptomaticbut noted difficulty staying afloat while swimming. They reportedthat other family members had the same facial features, promptingan investigation of the kindred.
Figure 1. Clinical and Radiographic Features of Affected Members of the Kindred.
Photographs of an affected member at the ages of 12 years (Panel A) and 45 years (Panel B) show the development of the wide, deep mandible that was characteristic of all affected members of the kindred. A large, lobulated torus palatinus in an affected member (Panel C, arrow) was also characteristic of all affected kindred members. Characteristic radiographic findings included an abnormally thick mandibular ramus (arrow, Panel D); a markedly thickened cortex and narrowed medullary cavity (arrow) in the femur (Panel E), which was otherwise normal; and dense but otherwise normal-appearing vertebrae (Panel F).
Bone Density
A total of seven members of the kindred had strikingly elevatedage- and sex-adjusted bone mineral density in the lumbar spine,femoral neck, and total body, whereas nine had normal bone densityat all sites (Table 1). Phenotypic classification of bone densityas either very high (indicating affected subjects) or normal(indicating unaffected subjects) was unambiguous. In affectedsubjects, age- and sex-adjusted bone density of the lumbar spinewas at least 5 SD above the population mean, and the mean zscores for bone density in the lumbar spine, femoral neck, andtotal body were 6.83, 4.42, and 4.78, respectively. In contrast,none of the unaffected subjects had a z score at any site thatwas greater than 2.71, and the mean z scores for bone densityin the lumbar spine, femoral neck, and total body were 0.40,–0.61, and –0.08, respectively. All affected subjectshad torus palatinus and the striking square jaw; none of theunaffected subjects had either of these features. None of theaffected subjects had a history of bone fracture.
The pattern of elevated bone density with torus palatinus anda square jaw was characteristic of autosomal dominant transmissionwith high penetrance (Figure 2). The trait was present in successivegenerations, affected or obligate-carrier parents had approximatelyequal numbers of affected and unaffected offspring overall,and there was male-to-male transmission. There were four deceasedobligate gene carriers, one of whom (Subject 16) was examinedbefore death and found to have torus palatinus and the characteristicmandible. Three living family members (Subjects 17, 18, and19) did not undergo bone-density measurements, but they didnot have torus palatinus or the characteristic facies.
Figure 2. Pedigree of the Kindred Showing the Linkage of Bone Density to 11q12–13.
Solid symbols indicate affected members of the kindred, open symbols unaffected members, shaded symbols obligate carriers, symbols with dots members who were not evaluated, squares male members, circles female members, and slashes deceased members. The members are numbered in the order in which blood samples were received at the laboratory. Below each symbol, the genotypes for a subgroup of genetic markers at 11q12–13 are shown in their chromosomal order. Chromosome segments that cosegregate with the affected status are enclosed by boxes. All affected members shared a chromosome segment extending from locus D11S1765 to D11S4184.
Biochemical Findings
The mean serum calcium and phosphate levels were normal in theaffected subjects; the urinary calcium level was at the highend of the normal range (Table 2). Serum levels of parathyroidhormone and vitamin D metabolites were also normal. In addition,the mean serum level of tartrate-resistant acid phosphatasewas normal (1.2±2 U per liter), and serum levels of thebrain isoform of creatine kinase were undetectable; these twobiochemical markers may be elevated in patients with osteopetrosis.24,25
Table 2. Indexes of Mineral Metabolism and Markers of Bone Turnover in Four Affected Subjects and Nine Controls.
The mean level of urinary N-telopeptide of type 1 collagen,a marker of bone resorption, was normal in the affected subjects(Table 2). Circulating levels of the receptor for activationof nuclear factor-B ligand and osteoprotegerin, cytokines thatregulate rates of bone resorption,26 were also normal. As notedabove, the level of tartrate-resistant acid phosphatase, a markerof osteoclast activity, was normal. In contrast, the mean levelof serum osteocalcin, a marker of bone formation, was markedlyelevated — more than three times the value in the controls.The values for bone-specific alkaline phosphatase were not elevatedin the affected subjects (mean value, 25±6 U per liter;normal range, 15 to 41). The levels of TGF-1 were markedly elevated.These findings suggested that increased bone formation withunaltered bone resorption was the mechanism of high bone densityin affected members of this family.
Point Mutation in LRP5
Because of prior reports of linkage of both high-bone-densityand low-bone-density phenotypes to 11q12–13,16,17,27,28we performed genotyping for 37 polymorphic genetic markers acrossa 40-cM segment of this interval (Figure 2). Analysis of therelation between inheritance of this chromosome segment andhigh bone density provided strong evidence of linkage, witha multipoint lod score of 5.30. When the three subjects in whombone density was not measured but who did not have torus palatinusor a square jaw were included in the analysis as unaffectedsubjects, the lod score was 6.21 (odds of linkage to 11q12–13,>1 million to 1). Meiotic recombination events in affectedsubjects localized the disease gene to the 16-cM interval flankedby loci D11S4191 and D11S4207. This linked interval containsLRP5, the gene for osteoporosis–pseudoglioma.18
The protein encoded by LRP5 spans the plasma membrane once andcontains a large extracellular segment with four domains thatare each predicted to form a structure resembling a propellerwith six blades (Figure 3A). The amino acid sequence YWTD ora variant of this sequence is found as a conserved element (aYWTD repeat) in each propeller blade.29,30
Panel A is a schematic of the structure of LRP5. A number of motifs are identified by their homology to other proteins, although the precise function of each is uncertain. There is an amino-terminal signal sequence for targeting the protein to the membrane (black), with four propeller structures (shown as hexagons), each followed by an epidermal-growth-factor–like repeat (purple); three low-density lipoprotein (LDL) receptor–like ligand binding domains (gray); a single transmembrane domain (black); and a C-terminal cytoplasmic tail (black). The location of the G171V mutation identified in the kindred is shown. Panel B shows the novel LRP5 variant in the kindred. A segment of exon 3 was amplified from kindred members by polymerase-chain-reaction assay, fractionated by electrophoresis under nondenaturing conditions, and exposed to x-ray film. Kindred members are numbered as in Figure 2, and affected members are indicated by asterisks. Affected members had a novel fragment not found in unaffected members, located below the common fragment (arrow). Panel C shows the sequence of the variant in the kindred. The normal DNA sequence of a segment of LRP5 spanning codons 169 through 172 is shown at the left; the encoded amino acids are indicated by the single letters above. The sequence of the same segment from the novel variant in affected members of the kindred is shown at the right. There is a single base substitution (G to T) (asterisks), resulting in the substitution of valine for glycine at codon 171. Panel D shows the conservation of glycine in propeller structures. A partial amino acid sequence of the fourth blade of a number of propellers of the YWTD family is shown. Glycine is highly conserved at this position in the first three propellers of LRP5 and LRP6 in humans (h) and mice (m), as well as in the only YWTD propeller of the LDL receptor (LDLR) and the first propeller of the Drosophila melanogaster (Dm) homologue, arrow (red).
We examined the coding sequence of LRP5 for DNA-sequence variantsand identified one variant in all the affected subjects (Figure 3B).This variant introduced a single base substitution thatresulted in a missense mutation, with valine substituted forglycine at residue 171 (LRP5V171) (Figure 3C). The residue liesin the fourth blade of the first propeller, two amino acidsbeyond the aspartate residue of the YWTD sequence (Figure 3Aand Figure 3D).
The heterozygous LRP5V171 mutation precisely cosegregated withhigh bone density in the kindred (Figure 3B); LRP5V171 is nota simple polymorphism, since it was absent in 420 control chromosomesfrom unrelated, unaffected subjects. The normal glycine residueshows extraordinary evolutionary conservation (Figure 3D). Glycineis found at the same position in the fourth blade of the firstthree propellers of LRP5 and LRP6 in humans and mice, as wellas in the single propeller of the low-density lipoprotein (LDL)receptor in humans, mice, rats, pigs, hamsters, and rabbits.Moreover, glycine is also found at this position in the firstpropeller of the Drosophila melanogaster LDL-receptor–relatedprotein homologue, arrow. In addition, glycine is present atthis position in a wide range of other YWTD propellers, includingthose in other LDL-receptor–related proteins, as wellas those in the epidermal growth factor precursor, the very-low-densitylipoprotein receptor, and the vitellogenin receptor in fruitflies and mosquitos (protein sequences are available at http://www.ncbi.nlm.nih.gov/entrez).The evolutionary conservation of this glycine residue is strongevidence of the functional importance of its mutation in ourkindred.
Molecular Studies
If this mutation indeed causes gain of LRP5 function and increasedWnt signaling, downstream target genes in the Wnt signalingpathway should show increased expression in vivo. A direct transcriptionaltarget of Wnt signaling is the extracellular matrix proteinfibronectin.31 Fibronectin levels were markedly elevated inthe affected members of our kindred, with a mean level thatwas more than 3 SD above the mean level in controls (Table 2).
Possible mechanisms of increased Wnt signaling include constitutivesignaling in the absence of a ligand, increased signaling inresponse to a ligand, or loss of action of a normal inhibitorof signaling. To identify the mechanism, we performed in vitrostudies using the mouse fibroblast NIH3T3 cell line, in whichthe expression of normal LRP5 potentiates Wnt signaling.19 Wefound that the expression of LRP5V171 did not activate signalingin the absence of Wnt-1, a finding that ruled out constitutivesignaling as the mechanism (Figure 4A). Activation of the signalingpathway in response to Wnt-1 was the same with normal and mutantLRP5; this finding ruled out increased activation by a ligandas the mechanism (Figure 4A). Finally, we tested the actionof the endogenous antagonist of Wnt signaling, Dkk-1. AlthoughDkk-1 inhibited Wnt signaling in conjunction with wild-typeLRP5, Dkk-1 inhibition of Wnt signaling was virtually abolishedin cells expressing LRP5V171 (Figure 4B). These findings indicatedthat LRP5V171 results in increased Wnt signaling because ofloss of Dkk antagonism.
Figure 4. Level of Wnt Signaling with Normal and Mutant LRP5.
DNA encoding the indicated proteins was introduced (transfected) into the mouse fibroblast NIH3T3 cell line. The level of Wnt signaling was determined by measuring the activity of the luciferase enzyme expressed under control of a promoter specifically activated by Wnt signaling. Panel A shows the potentiation of Wnt signaling by normal and mutant LRP5. In the absence of Wnt-1, neither normal LRP5 nor LRP5V171 activated Wnt signaling above the level of that with a control protein, -galactosidase (LacZ), demonstrating that LRP5V171 does not result in constitutive Wnt signaling. In the presence of Wnt-1, signaling was potentiated to an equal degree with normal LRP5 and LRP5V171, indicating that LRP5V171 does not simply increase signaling in response to Wnt-1. Wnt signaling in each experiment is represented as the relative level compared with the expression of the -galactosidase control in the absence of LRP5 and Wnt-1. The control value was arbitrarily defined as 1. Panel B shows the level of Dkk-1 inhibition of Wnt signaling. The inhibition of Wnt signaling was expressed as the percent reduction in signaling in the presence of Dkk-1 as compared with signaling in its absence. Whereas Dkk-1 inhibited Wnt signaling in the presence of normal LRP5, this inhibition was almost lost in the presence of LRP5V171. The T bars indicate standard deviations.
Discussion
Recent work has established that loss of function of LRP5 leadsto reduced bone mass.18 Our study shows that a gain-of-functionmutation in LRP5 causes an autosomal dominant disorder characterizedby high bone density, torus palatinus, and a wide, deep mandible.
Our in vitro and in vivo studies show that the LRP5V171 mutationincreases Wnt signaling. The mutation impairs antagonism ofWnt signaling by Dkk-1 in vitro, and the levels of fibronectin,a downstream target of Wnt signaling, are increased in vivoin patients with this mutation. These findings indicate thatunopposed Wnt signaling due to loss of action of a normal antagonistis the molecular mechanism that accounts for the effect of themutation.
Nonsyndromic high bone mass has been linked to 11q12–13in another kindred.16 While we were preparing this report, Littleet al. identified an LRP5 mutation in the other kindred.32 Remarkably,this mutation is identical to the LRP5V171 mutation in our kindred.To our knowledge, these families do not share a common ancestor,suggesting that the mutations have arisen independently; however,the possibility of a very remote common ancestor cannot be excluded.It is striking that the same mutation is associated with nonsyndromichigh bone mass in one family and syndromic high bone mass inthe other. These findings suggest that alleles of other genesor environmental factors influence phenotypic manifestationsof the mutation and that other phenotypes in kindreds with autosomaldominant high bone mass may also arise from the same mutation.If this is correct, all these disorders could be diagnosed withthe use of a simple genetic test. The findings also suggestthat the target for gain-of-function mutations in LRP5 is verysmall, possibly indicating a site critical for Dkk binding oraction.
Our findings provide evidence that the Wnt signaling pathwayalters bone mass through a primary effect on bone formation.Biochemical markers of bone resorption were unaltered in affectedmembers of our kindred, whereas levels of specific markers ofosteoblast activity were strikingly elevated. These findingsindicate an uncoupling of bone turnover in favor of increasedbone formation. The observation that LRP5 is expressed at highlevels in osteoblasts is consistent with its having a role inthis axis.33 The elevated fibronectin levels are also consistentwith an effect on bone formation, since fibronectin is an earlyscaffolding protein in osteoid formation and enhances the survivaland differentiation of osteoblasts.34,35,36,37 Finally, theobserved elevation in TGF-1 levels is noteworthy. TGF-1 hasstimulatory effects on osteoblasts, and targeted disruptionin mice results in reduced bone mass.38,39,40
Given the established role of rare LRP5 mutations in abnormalbone density, it is of particular interest that variation inbone density in the general population may be linked to thechromosome segment containing LRP5.28 This finding raises thepossibility that common variants that alter the expression orfunction of LRP5 will be found to have a role in the risk ofosteoporosis in the general population. Further studies willbe required to investigate this possibility. Finally, the observationthat the impaired action of Dkk at LRP5 increases bone densitysuggests that pharmacologic antagonism of Dkk action, eitherat the prereceptor level or through the inhibition of bindingor action at LRP5, may have a role in the prevention or treatmentof osteoporosis.
Supported by grants from the National Institutes of Health (AG15345,to Dr. Insogna, and CA85420, to Dr. Wu), the Danbury HospitalMedical Education Center, the Yale Core Center for MusculoskeletalDisorders (AR46032, to Dr. Insogna), the Yale Bone Center, andthe Yale General Clinical Research Center (National Center forResearch Resources grant RR00125). Dr. Lifton is an Investigatorof the Howard Hughes Medical Institute.
We are indebted to the members of the kindred who participatedin the study for making this work possible, and to Carol Nelson-Williams,Ana Quinones, Diane Wall, and the staff of the Yale GeneralClinical Research Center, for technical assistance and helpfuldiscussions.
Source Information
From the Departments of Genetics (L.M.B., A.F., R.P.L.) and Medicine (J.B., L.M., M.A.M., K.I., R.P.L.), Yale University School of Medicine, New Haven; and the Department of Genetics and Developmental Biology (J.M., D.W.), University of Connecticut Health Center, Farmington — both in Connecticut.
Address reprint requests to Dr. Lifton at the Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Ave., New Haven, CT 06510, or at richard.lifton{at}yale.edu.
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