Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 315 (5816): 1278-1282

Copyright © 2007 by the American Association for the Advancement of Science

LRP6 Mutation in a Family with Early Coronary Disease and Metabolic Risk Factors

Arya Mani,1* Jayaram Radhakrishnan,1 He Wang,2 Alaleh Mani,3 Mohammad-Ali Mani,4 Carol Nelson-Williams,1 Khary S. Carew,1 Shrikant Mane,1 Hossein Najmabadi,5 Dan Wu,2 Richard P. Lifton1*

Abstract: Coronary artery disease (CAD) is the leading cause of death worldwide and is commonly caused by a constellation of risk factors called the metabolic syndrome. We characterized a family with autosomal dominant early CAD, features of the metabolic syndrome (hyperlipidemia, hypertension, and diabetes), and osteoporosis. These traits showed genetic linkage to a short segment of chromosome 12p, in which we identified a missense mutation in LRP6, which encodes a co-receptor in the Wnt signaling pathway. The mutation, which substitutes cysteine for arginine at a highly conserved residue of an epidermal growth factor–like domain, impairs Wnt signaling in vitro. These results link a single gene defect in Wnt signaling to CAD and multiple cardiovascular risk factors.

1 Departments of Internal Medicine, Genetics and Molecular Biophysics, and Biochemistry, Howard Hughes Medical Institute and Yale University School of Medicine, New Haven, CT 06510, USA.
2 Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA.
3 Department of Material Science, Amir Kabir University of Technology, Tehran 15875/4413, Iran.
4 Department of Human Sciences, Azad University of Tehran, Tehran 13185/786, Iran.
5 Genetics Research Center, The Social Welfare and Rehabilitation Sciences University, Tehran 19875/383, Iran.

* To whom correspondence should be addressed. E-mail: arya.mani{at}yale.edu (A.M.); richard.lifton{at}yale.edu (R.P.L.)


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway.
R. Allache, S. Lachance, M. C. Guyot, P. De Marco, E. Merello, M. J. Justice, V. Capra, and Z. Kibar (2014)
Hum. Mol. Genet. 23, 1687-1699
   Abstract »    Full Text »    PDF »
Genome-Wide Linkage Approach Yields Novel Early Onset Myocardial Infarction Locus in East Asians.
C. D. Anderson and J. Rosand (2013)
Circ Cardiovasc Genet 6, 531-532
   Full Text »    PDF »
Lipoprotein Receptor-Related Protein-6 Protects the Brain From Ischemic Injury.
T. Abe, P. Zhou, K. Jackman, C. Capone, B. Casolla, K. Hochrainer, T. Kahles, M. E. Ross, J. Anrather, and C. Iadecola (2013)
Stroke 44, 2284-2291
   Abstract »    Full Text »    PDF »
Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies.
J. Bollerslev, K. Henriksen, M. Frost Nielsen, K. Brixen, and W. Van Hul (2013)
Eur. J. Endocrinol. 169, R39-R57
   Abstract »    Full Text »    PDF »
Molecular Biology of Atherosclerosis.
P. N. Hopkins (2013)
Physiol Rev 93, 1317-1542
   Abstract »    Full Text »    PDF »
Atherosclerotic Disease in Type 2 Diabetes Is Associated With an Increase in Sclerostin Levels.
S. Morales-Santana, B. Garcia-Fontana, A. Garcia-Martin, P. Rozas-Moreno, J. A. Garcia-Salcedo, R. Reyes-Garcia, and M. Munoz-Torres (2013)
Diabetes Care 36, 1667-1674
   Abstract »    Full Text »    PDF »
Wnt signaling in bone formation and its therapeutic potential for bone diseases.
J. H. Kim, X. Liu, J. Wang, X. Chen, H. Zhang, S. H. Kim, J. Cui, R. Li, W. Zhang, Y. Kong, et al. (2013)
Therapeutic Advances in Musculoskeletal Diseases 5, 13-31
   Abstract »    PDF »
Endocytic receptor-mediated control of morphogen signaling.
T. E. Willnow, A. Christ, and A. Hammes (2012)
Development 139, 4311-4319
   Abstract »    Full Text »    PDF »
Wnt Signaling in Bone Development and Disease: Making Stronger Bone with Wnts.
J. B. Regard, Z. Zhong, B. O. Williams, and Y. Yang (2012)
Cold Spring Harb Perspect Biol 4, a007997
   Abstract »    Full Text »    PDF »
Wnt signalling in smooth muscle cells and its role in cardiovascular disorders.
C. Mill and S. J. George (2012)
Cardiovasc Res 95, 233-240
   Abstract »    Full Text »    PDF »
Chemical and genetic evidence for the involvement of Wnt antagonist Dickkopf2 in regulation of glucose metabolism.
X. Li, J. Shan, W. Chang, I. Kim, J. Bao, H.-J. Lee, X. Zhang, V. T. Samuel, G. I. Shulman, D. Liu, et al. (2012)
PNAS 109, 11402-11407
   Abstract »    Full Text »    PDF »
Cross-talk between Insulin and Wnt Signaling in Preadipocytes: ROLE OF WNT CO-RECEPTOR LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN-5 (LRP5).
J. Palsgaard, B. Emanuelli, J. N. Winnay, G. Sumara, G. Karsenty, and C. R. Kahn (2012)
J. Biol. Chem. 287, 12016-12026
   Abstract »    Full Text »    PDF »
Genetic Analysis of Atherosclerosis and Glucose Homeostasis in an Intercross Between C57BL/6 and BALB/cJ Apolipoprotein E-Deficient Mice.
Z. Zhang, J. S. Rowlan, Q. Wang, and W. Shi (2012)
Circ Cardiovasc Genet 5, 190-201
   Abstract »    Full Text »    PDF »
Low Density Lipoprotein (LDL) Receptor-related Protein 6 (LRP6) Regulates Body Fat and Glucose Homeostasis by Modulating Nutrient Sensing Pathways and Mitochondrial Energy Expenditure.
W. Liu, R. Singh, C. S. Choi, H.-Y. Lee, A. R. Keramati, V. T. Samuel, R. P. Lifton, G. I. Shulman, and A. Mani (2012)
J. Biol. Chem. 287, 7213-7223
   Abstract »    Full Text »    PDF »
Genetic Basis of Atherosclerosis: Insights From Mice and Humans.
I. M. Stylianou, R. C. Bauer, M. P. Reilly, and D. J. Rader (2012)
Circ. Res. 110, 337-355
   Abstract »    Full Text »    PDF »
LRP6 Protein Regulates Low Density Lipoprotein (LDL) Receptor-mediated LDL Uptake.
Z.-j. Ye, G.-W. Go, R. Singh, W. Liu, A. R. Keramati, and A. Mani (2012)
J. Biol. Chem. 287, 1335-1344
   Abstract »    Full Text »    PDF »
Response to Letter by Tsuda Regarding Article, "Vitamin D Deficiency Is Associated With Subclinical Carotid Atherosclerosis: The Northern Manhattan Study".
M. D. Walker and S. J. Silverberg (2011)
Stroke 42, e640
   Full Text »    PDF »
Fibroblast Growth Factor 2 Stimulation of Osteoblast Differentiation and Bone Formation Is Mediated by Modulation of the Wnt Signaling Pathway.
Y. Fei, L. Xiao, T. Doetschman, D. J. Coffin, and M. M. Hurley (2011)
J. Biol. Chem. 286, 40575-40583
   Abstract »    Full Text »    PDF »
Modulation of canonical Wnt signaling by the extracellular matrix component biglycan.
A. D. Berendsen, L. W. Fisher, T. M. Kilts, R. T. Owens, P. G. Robey, J. S. Gutkind, and M. F. Young (2011)
PNAS 108, 17022-17027
   Abstract »    Full Text »    PDF »
A Rate-Limiting Role for Dickkopf-1 in Bone Formation and the Remediation of Bone Loss in Mouse and Primate Models of Postmenopausal Osteoporosis by an Experimental Therapeutic Antibody.
H. Glantschnig, K. Scott, R. Hampton, N. Wei, P. McCracken, P. Nantermet, J. Z. Zhao, S. Vitelli, L. Huang, P. Haytko, et al. (2011)
J. Pharmacol. Exp. Ther. 338, 568-578
   Abstract »    Full Text »    PDF »
Bone Overgrowth-associated Mutations in the LRP4 Gene Impair Sclerostin Facilitator Function.
O. Leupin, E. Piters, C. Halleux, S. Hu, I. Kramer, F. Morvan, T. Bouwmeester, M. Schirle, M. Bueno-Lozano, F. J. Ramos Fuentes, et al. (2011)
J. Biol. Chem. 286, 19489-19500
   Abstract »    Full Text »    PDF »
SMAD4-mediated WNT signaling controls the fate of cranial neural crest cells during tooth morphogenesis.
J. Li, X. Huang, X. Xu, J. Mayo, P. Bringas Jr, R. Jiang, S. Wang, and Y. Chai (2011)
Development 138, 1977-1989
   Abstract »    Full Text »    PDF »
Wnt Signaling Regulates Hepatic Metabolism.
H. Liu, M. M. Fergusson, J. J. Wu, I. I. Rovira, J. Liu, O. Gavrilova, T. Lu, J. Bao, D. Han, M. N. Sack, et al. (2011)
Science Signaling 4, ra6
   Abstract »    Full Text »    PDF »
Wild-type LRP6 inhibits, whereas atherosclerosis-linked LRP6R611C increases PDGF-dependent vascular smooth muscle cell proliferation.
A. R. Keramati, R. Singh, A. Lin, S. Faramarzi, Z.-j. Ye, S. Mane, G. Tellides, R. P. Lifton, and A. Mani (2011)
PNAS 108, 1914-1918
   Abstract »    Full Text »    PDF »
Mapping the Epistatic Network Underlying Murine Reproductive Fatpad Variation.
J. P. Jarvis and J. M. Cheverud (2011)
Genetics 187, 597-610
   Abstract »    Full Text »    PDF »
Wnt receptors, bone mass, and fractures: gene-wide association analysis of LRP5 and LRP6 polymorphisms with replication.
J. A. Riancho, J. M. Olmos, B. Pineda, C. Garcia-Ibarbia, M. I. Perez-Nunez, D. N. Nan, J. Velasco, A. Cano, M. A. Garcia-Perez, M. T. Zarrabeitia, et al. (2011)
Eur. J. Endocrinol. 164, 123-131
   Abstract »    Full Text »    PDF »
Generation and Selection of Novel Fully Human Monoclonal Antibodies That Neutralize Dickkopf-1 (DKK1) Inhibitory Function in Vitro and Increase Bone Mass in Vivo.
H. Glantschnig, R. A. Hampton, P. Lu, J. Z. Zhao, S. Vitelli, L. Huang, P. Haytko, T. Cusick, C. Ireland, S. W. Jarantow, et al. (2010)
J. Biol. Chem. 285, 40135-40147
   Abstract »    Full Text »    PDF »
Inhibition of tumorigenesis driven by different Wnt proteins requires blockade of distinct ligand-binding regions by LRP6 antibodies.
S. A. Ettenberg, O. Charlat, M. P. Daley, S. Liu, K. J. Vincent, D. D. Stuart, A. G. Schuller, J. Yuan, B. Ospina, J. Green, et al. (2010)
PNAS 107, 15473-15478
   Abstract »    Full Text »    PDF »
Activation of Canonical Wingless-type MMTV Integration Site Family (Wnt) Signaling in Mature Adipocytes Increases {beta}-Catenin Levels and Leads to Cell Dedifferentiation and Insulin Resistance.
B. Gustafson and U. Smith (2010)
J. Biol. Chem. 285, 14031-14041
   Abstract »    Full Text »    PDF »
Gene Variants of TCF7L2 Influence Weight Loss and Body Composition During Lifestyle Intervention in a Population at Risk for Type 2 Diabetes.
A. Haupt, C. Thamer, M. Heni, C. Ketterer, J. Machann, F. Schick, F. Machicao, N. Stefan, C. D. Claussen, H.-U. Haring, et al. (2010)
Diabetes 59, 747-750
   Abstract »    Full Text »    PDF »
Increased Lipid Oxidation Causes Oxidative Stress, Increased Peroxisome Proliferator-activated Receptor-{gamma} Expression, and Diminished Pro-osteogenic Wnt Signaling in the Skeleton.
M. Almeida, E. Ambrogini, L. Han, S. C. Manolagas, and R. L. Jilka (2009)
J. Biol. Chem. 284, 27438-27448
   Abstract »    Full Text »    PDF »
The ClinSeq Project: Piloting large-scale genome sequencing for research in genomic medicine.
L. G. Biesecker, J. C. Mullikin, F. M. Facio, C. Turner, P. F. Cherukuri, R. W. Blakesley, G. G. Bouffard, P. S. Chines, P. Cruz, N. F. Hansen, et al. (2009)
Genome Res. 19, 1665-1674
   Abstract »    Full Text »    PDF »
A Common Variant in Low-Density Lipoprotein Receptor-Related Protein 6 Gene (LRP6) Is Associated With LDL-Cholesterol.
M. Tomaszewski, F. J. Charchar, T. Barnes, M. Gawron-Kiszka, A. Sedkowska, E. Podolecka, J. Kowalczyk, W. Rathbone, Z. Kalarus, W. Grzeszczak, et al. (2009)
Arterioscler Thromb Vasc Biol 29, 1316-1321
   Abstract »    Full Text »    PDF »
Regulation of Phosphatidylinositol Kinases and Metabolism by Wnt3a and Dvl.
Y. Qin, L. Li, W. Pan, and D. Wu (2009)
J. Biol. Chem. 284, 22544-22548
   Abstract »    Full Text »    PDF »
Cooperative Folding and Ligand-binding Properties of LRP6 {beta}-Propeller Domains.
C.-C. Liu, C. Pearson, and G. Bu (2009)
J. Biol. Chem. 284, 15299-15307
   Abstract »    Full Text »    PDF »
Polyunsaturated Fatty Acids Modulate the Effect of TCF7L2 Gene Variants on Postprandial Lipemia.
D. Warodomwichit, D. K. Arnett, E. K. Kabagambe, M. Y. Tsai, J. E. Hixson, R. J. Straka, M. Province, P. An, C.-Q. Lai, I. Borecki, et al. (2009)
J. Nutr. 139, 439-446
   Abstract »    Full Text »    PDF »
Mutation in EGFP Domain of LDL Receptor-Related Protein 6 Impairs Cellular LDL Clearance.
W. Liu, S. Mani, N. R. Davis, N. Sarrafzadegan, P. B. Kavathas, and A. Mani (2008)
Circ. Res. 103, 1280-1288
   Abstract »    Full Text »    PDF »
TCF7L2 Variants Associate with CKD Progression and Renal Function in Population-Based Cohorts.
A. Kottgen, S.-J. Hwang, E. Rampersaud, J. Coresh, K. E. North, J. S. Pankow, J. B. Meigs, J. C. Florez, A. Parsa, D. Levy, et al. (2008)
J. Am. Soc. Nephrol. 19, 1989-1999
   Abstract »    Full Text »    PDF »
Wnt3a-Mediated Formation of Phosphatidylinositol 4,5-Bisphosphate Regulates LRP6 Phosphorylation.
W. Pan, S.-C. Choi, H. Wang, Y. Qin, L. Volpicelli-Daley, L. Swan, L. Lucast, C. Khoo, X. Zhang, L. Li, et al. (2008)
Science 321, 1350-1353
   Abstract »    Full Text »    PDF »
Genetic and Genomic Discovery Using Family Studies.
I. B. Borecki and M. A. Province (2008)
Circulation 118, 1057-1063
   Full Text »    PDF »
Msx2 Exerts Bone Anabolism via Canonical Wnt Signaling.
S.-L. Cheng, J.-S. Shao, J. Cai, O. L. Sierra, and D. A. Towler (2008)
J. Biol. Chem. 283, 20505-20522
   Abstract »    Full Text »    PDF »
Wnt Signal Amplification via Activity, Cooperativity, and Regulation of Multiple Intracellular PPPSP Motifs in the Wnt Co-receptor LRP6.
B. T. MacDonald, C. Yokota, K. Tamai, X. Zeng, and X. He (2008)
J. Biol. Chem. 283, 16115-16123
   Abstract »    Full Text »    PDF »
UniPrime: a workflow-based platform for improved universal primer design.
M. Bekaert and E. C. Teeling (2008)
Nucleic Acids Res. 36, e56
   Abstract »    Full Text »    PDF »
Epicardium-derived progenitor cells require {beta}-catenin for coronary artery formation.
M. Zamora, J. Manner, and P. Ruiz-Lozano (2007)
PNAS 104, 18109-18114
   Abstract »    Full Text »    PDF »
The Fructose Nation.
E. G. Neilson (2007)
J. Am. Soc. Nephrol. 18, 2619-2621
   Full Text »    PDF »
Lipoproteins and their receptors in embryonic development: more than cholesterol clearance.
T. E. Willnow, A. Hammes, and S. Eaton (2007)
Development 134, 3239-3249
   Abstract »    Full Text »    PDF »
Oxidative Stress Antagonizes Wnt Signaling in Osteoblast Precursors by Diverting beta-Catenin from T Cell Factor- to Forkhead Box O-mediated Transcription.
M. Almeida, L. Han, M. Martin-Millan, C. A. O'Brien, and S. C. Manolagas (2007)
J. Biol. Chem. 282, 27298-27305
   Abstract »    Full Text »    PDF »
Highlights From The Literature.
(2007)
Physiology 22, 158-160
   Full Text »    PDF »
Metabolic Syndrome--What We Know and What We Don't Know: LPR6 Mutation in a Family with Early Coronary Disease and Metabolic Risk Factors. Science 315: 1278-1282, 2007.
Ar. Mani, J. Radhakrishnan, H. Wang, Al. Mani, M.A. Mani, C. Nelson-Williams, K.S. Carew, S. Mane, H. Najmabadi, D. Wu, et al. (2007)
J. Am. Soc. Nephrol. 18, 1619-1623
   Full Text »    PDF »
Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease.
G. V. De Ferrari, A. Papassotiropoulos, T. Biechele, F. Wavrant De-Vrieze, M. E. Avila, M. B. Major, A. Myers, K. Saez, J. P. Henriquez, A. Zhao, et al. (2007)
PNAS 104, 9434-9439
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882