50 results on '"Butterfield, Natalie C."'
Search Results
2. Publisher Correction: Accelerating functional gene discovery in osteoarthritis
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Butterfield, Natalie C., Curry, Katherine F., Steinberg, Julia, Dewhurst, Hannah, Komla-Ebri, Davide, Mannan, Naila S., Adoum, Anne-Tounsia, Leitch, Victoria D., Logan, John G., Waung, Julian A., Ghirardello, Elena, Southam, Lorraine, Youlten, Scott E., Wilkinson, J. Mark, McAninch, Elizabeth A., Vancollie, Valerie E., Kussy, Fiona, White, Jacqueline K., Lelliott, Christopher J., Adams, David J., Jacques, Richard, Bianco, Antonio C., Boyde, Alan, Zeggini, Eleftheria, Croucher, Peter I., Williams, Graham R., and Bassett, J. H. Duncan
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- 2021
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3. A molecular quantitative trait locus map for osteoarthritis
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Steinberg, Julia, Southam, Lorraine, Roumeliotis, Theodoros I., Clark, Matthew J., Jayasuriya, Raveen L., Swift, Diane, Shah, Karan M., Butterfield, Natalie C., Brooks, Roger A., McCaskie, Andrew W., Bassett, J. H. Duncan, Williams, Graham R., Choudhary, Jyoti S., Wilkinson, J. Mark, and Zeggini, Eleftheria
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- 2021
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4. Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease
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Youlten, Scott E., Kemp, John P., Logan, John G., Ghirardello, Elena J., Sergio, Claudio M., Dack, Michael R. G., Guilfoyle, Siobhan E., Leitch, Victoria D., Butterfield, Natalie C., Komla-Ebri, Davide, Chai, Ryan C., Corr, Alexander P., Smith, James T., Mohanty, Sindhu T., Morris, John A., McDonald, Michelle M., Quinn, Julian M. W., McGlade, Amelia R., Bartonicek, Nenad, Jansson, Matt, Hatzikotoulas, Konstantinos, Irving, Melita D., Beleza-Meireles, Ana, Rivadeneira, Fernando, Duncan, Emma, Richards, J. Brent, Adams, David J., Lelliott, Christopher J., Brink, Robert, Phan, Tri Giang, Eisman, John A., Evans, David M., Zeggini, Eleftheria, Baldock, Paul A., Bassett, J. H. Duncan, Williams, Graham R., and Croucher, Peter I.
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- 2021
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5. PYY is a negative regulator of bone mass and strength
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Leitch, Victoria D., Brassill, Mary Jane, Rahman, Sofia, Butterfield, Natalie C., Ma, Pattara, Logan, John G., Boyde, Alan, Evans, Holly, Croucher, Peter I., Batterham, Rachel L., Williams, Graham R., and Bassett, J.H. Duncan
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- 2019
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6. Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain
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Jo, Sungro, Fonseca, Tatiana L., Bocco, Barbara M.L.C., Fernandes, Gustavo W., McAninch, Elizabeth A., Bolin, Anaysa P., Da Conceicao, Rodrigo R., Werneck-de-Castro, Joao Pedro, Ignacio, Daniele L., Egri, Peter, Nemeth, Dorottya, Fekete, Csaba, Bernardi, Maria Martha, Leitch, Victoria D., Mannan, Naila S., Curry, Katharine F., Butterfield, Natalie C., Bassett, J.H. Duncan, Williams, Graham R., Gereben, Balazs, Ribeiro, Miriam O., and Bianco, Antonio C.
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Endoplasmic reticulum -- Health aspects ,Genetic polymorphisms -- Research ,Hypothyroidism -- Genetic aspects -- Care and treatment ,Thyroid hormones -- Usage ,Health care industry - Abstract
Levothyroxine (LT4) is a form of thyroid hormone used to treat hypothyroidism. In the brain, T4 is converted to the active form T3 by type 2 deiodinase (D2). Thus, it is intriguing that carriers of the Thr92Ala polymorphism in the D2 gene (DIO2) exhibit clinical improvement when liothyronine (LT3) is added to LT4 therapy. Here, we report that D2 is a cargo protein in ER Golgi intermediary compartment (ERGIC) vesicles, recycling between ER and Golgi. The Thr92-to-Ala substitution (Ala92- D2) caused ER stress and activated the unfolded protein response (UPR). Ala92-D2 accumulated in the trans-Golgi and generated less T3, which was restored by eliminating ER stress with the chemical chaperone 4-phenyl butyric acid (4-PBA). An Ala92-Dio2 polymorphism-carrying mouse exhibited UPR and hypothyroidism in distinct brain areas. The mouse refrained from physical activity, slept more, and required additional time to memorize objects. Enhancing T3 signaling in the brain with LT3 improved cognition, whereas restoring proteostasis with 4-PBA eliminated the Ala92-Dio2 phenotype. In contrast, primary hypothyroidism intensified the Ala92-Dio2 phenotype, with only partial response to LT4 therapy. Disruption of cellular proteostasis and reduced Ala92-D2 activity may explain the failure of LT4 therapy in carriers of Thr92Ala-DIO2., IntroductionHypothyroidism results from autoimmune destruction or surgical removal of the thyroid gland. Hence, symptoms are due to insufficient levels of thyroid hormones, which affects tens of millions worldwide (1). T4 [...]
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- 2019
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7. Quantitative X-Ray Imaging of Mouse Bone by Faxitron
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Butterfield, Natalie C., primary, Logan, John G., additional, Waung, Julian, additional, Williams, Graham R., additional, and Bassett, J. H. Duncan, additional
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- 2019
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8. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption
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McDonald, Michelle M, primary, Khoo, Weng Hua, additional, Ng, Pei Ying, additional, Xiao, Ya, additional, Zamerli, Jad, additional, Thatcher, Peter, additional, Kyaw, Wunna, additional, Pathmanandavel, Karrnan, additional, Grootveld, Abigail K, additional, Moran, Imogen, additional, Butt, Danyal, additional, Nguyen, Akira, additional, Corr, Alexander, additional, Warren, Sean, additional, Biro, Mate, additional, Butterfield, Natalie C, additional, Guilfoyle, Siobhan E, additional, Komla-Ebri, Davide, additional, Dack, Michael R G, additional, Dewhurst, Hannah F, additional, Logan, John G, additional, Li, Yongxiao, additional, Mohanty, Sindhu T, additional, Byrne, Niall, additional, Terry, Rachael L, additional, Simic, Marija K, additional, Chai, Ryan, additional, Quinn, Julian M W, additional, Youlten, Scott E, additional, Pettitt, Jessica A, additional, Abi-Hanna, David, additional, Jain, Rohit, additional, Weninger, Wolfgang, additional, Lundberg, Mischa, additional, Sun, Shuting, additional, Ebetino, Frank H, additional, Timpson, Paul, additional, Lee, Woei Ming, additional, Baldock, Paul A, additional, Rogers, Michael J, additional, Brink, Robert, additional, Williams, Graham R, additional, Bassett, J H Duncan, additional, Kemp, John P, additional, Pavlos, Nathan J, additional, Croucher, Peter I, additional, and Phan, Tri Giang, additional
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- 2021
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9. Correction: Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption
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McDonald, Michelle M, Khoo, Weng Hua, Ng, Pei Ying, Xiao, Ya, Zamerli, Jad, Thatcher, Peter, Kyaw, Wunna, Pathmanandavel, Karrnan, Grootveld, Abigail K, Moran, Imogen, Butt, Danyal, Nguyen, Akira, Corr, Alexander, Warren, Sean, Biro, Maté, Butterfield, Natalie C, Guilfoyle, Siobhan E, Komla-Ebri, Davide, Dack, Michael R G, Dewhurst, Hannah F, Logan, John G, Li, Yongxiao, Mohanty, Sindhu T, Byrne, Niall, Terry, Rachael L, Simic, Marija K, Chai, Ryan, Quinn, Julian M W, Youlten, Scott E, Pettitt, Jessica A, Abi-Hanna, David, Jain, Rohit, Weninger, Wolfgang, Lundberg, Mischa, Sun, Shuting, Timpson, Paul, Lee, Woei Ming, Baldock, Paul A, Rogers, Michael J, Brink, Robert, Williams, Graham R, Bassett, J H Duncan, Kemp, John P, Pavlos, Nathan J, Croucher, Peter I, and Phan, Tri Giang
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- 2021
10. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption
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McDonald, Michelle M., primary, Khoo, Weng Hua, additional, Ng, Pei Ying, additional, Xiao, Ya, additional, Zamerli, Jad, additional, Thatcher, Peter, additional, Kyaw, Wunna, additional, Pathmanandavel, Karrnan, additional, Grootveld, Abigail K., additional, Moran, Imogen, additional, Butt, Danyal, additional, Nguyen, Akira, additional, Corr, Alexander, additional, Warren, Sean, additional, Biro, Maté, additional, Butterfield, Natalie C., additional, Guilfoyle, Siobhan E., additional, Komla-Ebri, Davide, additional, Dack, Michael R.G., additional, Dewhurst, Hannah F., additional, Logan, John G., additional, Li, Yongxiao, additional, Mohanty, Sindhu T., additional, Byrne, Niall, additional, Terry, Rachael L., additional, Simic, Marija K., additional, Chai, Ryan, additional, Quinn, Julian M.W., additional, Youlten, Scott E., additional, Pettitt, Jessica A., additional, Abi-Hanna, David, additional, Jain, Rohit, additional, Weninger, Wolfgang, additional, Lundberg, Mischa, additional, Sun, Shuting, additional, Ebetino, Frank H., additional, Timpson, Paul, additional, Lee, Woei Ming, additional, Baldock, Paul A., additional, Rogers, Michael J., additional, Brink, Robert, additional, Williams, Graham R., additional, Bassett, J.H. Duncan, additional, Kemp, John P., additional, Pavlos, Nathan J., additional, Croucher, Peter I., additional, and Phan, Tri Giang, additional
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- 2021
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11. The Molecular Regulation of Vertebrate Limb Patterning
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Butterfield, Natalie C., primary, McGlinn, Edwina, additional, and Wicking, Carol, additional
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- 2010
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12. Mutations in mouse Ift144 model the craniofacial, limb and rib defects in skeletal ciliopathies
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Ashe, Alyson, Butterfield, Natalie C., Town, Liam, Courtney, Andrew D., Cooper, Ashley N., Ferguson, Charles, Barry, Rachael, Olsson, Fredrik, Liem, Karel F., Jr, Parton, Robert G., Wainwright, Brandon J., Anderson, Kathryn V., Whitelaw, Emma, and Wicking, Carol
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- 2012
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13. Functional validation of the osteoporosis GWAS candidate FUBP3 in knockout mice
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Watts, Laura, primary, Freudenthal, Bernard, additional, Butterfield, Natalie C., additional, Pollard, Andrea, additional, Komla-Ebri, Davide, additional, Leitch, Victoria, additional, Logan, John, additional, Mannan, Naila, additional, Bassett, J.H. Duncan, additional, and Williams, Graham R., additional
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- 2020
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14. Slc38a10 is a novel regulator of osteoblastic bone formation
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Pollard, Andrea S., primary, Ebri, Davide Komla, additional, Sparkes, Penny, additional, Gogakos, Apostolos, additional, Logan, John G., additional, Butterfield, Natalie C., additional, Leitch, Victoria, additional, Bassett, J.H. Duncan, additional, and Williams, Graham R., additional
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- 2020
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15. Osteocyte Transcriptome Mapping Identifies a Molecular Landscape Controlling Skeletal Homeostasis and Susceptibility to Skeletal Disease
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Youlten, Scott E., primary, Kemp, John P., additional, Logan, John G., additional, Ghirardello, Elena J., additional, Sergio, Claudio M., additional, Dack, Michael R. G., additional, Guilfoyle, Siobhan E., additional, Leitch, Victoria D., additional, Butterfield, Natalie C., additional, Komla-Ebri, Davide, additional, Chai, Ryan C., additional, Corr, Alexander P., additional, Smith, James T., additional, Mohanty, Sindhu, additional, Morris, John A., additional, McDonald, Michelle M., additional, Quinn, Julian M. W., additional, McGlade, Amelia R., additional, Bartonicek, Nenad, additional, Jansson, Matt, additional, Hatzikotoulas, Konstantinos, additional, Irving, Melita D., additional, Beleza-Meireles, Ana, additional, Rivadeneira, Fernando, additional, Duncan, Emma, additional, Richards, J. Brent, additional, Adams, David J., additional, Lelliott, Christopher J., additional, Brink, Robert, additional, Phan, Tri Giang, additional, Eisman, John A., additional, Evans, David M., additional, Zeggini, Eleftheria, additional, Baldock, Paul A., additional, Bassett, J. H. Duncan, additional, Williams, Graham R., additional, and Croucher, Peter I., additional
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- 2020
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16. Response to Letter to the Editor: “IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction”
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Joustra, Sjoerd D, primary, Roelfsema, Ferdinand, additional, van Trotsenburg, A S Paul, additional, Schneider, Harald J, additional, Kosilek, Robert P, additional, Kroon, Herman M, additional, Logan, John G, additional, Butterfield, Natalie C, additional, Zhou, Xiang, additional, Toufaily, Chirine, additional, Bak, Beata, additional, Turgeon, Marc-Olivier, additional, Brûlé, Emilie, additional, Steyn, Frederik J, additional, Gurnell, Mark, additional, Koulouri, Olympia, additional, Le Tissier, Paul, additional, Fontanaud, Pierre, additional, Bassett, J H Duncan, additional, Williams, Graham R, additional, Oostdijk, Wilma, additional, Wit, Jan M, additional, Pereira, Alberto M, additional, Biermasz, Nienke R, additional, Bernard, Daniel J, additional, and Schoenmakers, Nadia, additional
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- 2020
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17. Decoding the genomic basis of osteoarthritis
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Steinberg, Julia, primary, Southam, Lorraine, additional, Butterfield, Natalie C, additional, Roumeliotis, Theodoros I, additional, Fontalis, Andreas, additional, Clark, Matthew J, additional, Jayasuriya, Raveen L, additional, Swift, Diane, additional, Shah, Karan M, additional, Curry, Katherine F, additional, Brooks, Roger A, additional, McCaskie, Andrew W, additional, Lelliott, Christopher J., additional, Choudhary, Jyoti S, additional, Bassett, JH Duncan, additional, Williams, Graham R, additional, Wilkinson, J Mark, additional, and Zeggini, Eleftheria, additional
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- 2019
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18. Accelerating functional gene discovery in osteoarthritis
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Butterfield, Natalie C., primary, Curry, Katherine F., additional, Steinberg, Julia, additional, Dewhurst, Hannah, additional, Komla-Ebri, Davide, additional, Mannan, Naila S., additional, Adoum, Anne-Tounsia, additional, Leitch, Victoria D., additional, Logan, John G., additional, Waung, Julian A., additional, Ghirardello, Elena, additional, Southam, Lorraine, additional, Youlten, Scott E., additional, Mark Wilkinson, J, additional, McAninch, Elizabeth A., additional, Vancollie, Valerie E., additional, Kussy, Fiona, additional, White, Jacqueline K., additional, Lelliott, Christopher J., additional, Adams, David J., additional, Jacques, Richard, additional, Bianco, Antonio C., additional, Boyde, Alan, additional, Zeggini, Eleftheria, additional, Croucher, Peter I., additional, Williams, Graham R., additional, and Duncan Bassett, J. H., additional
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- 2019
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19. An atlas of genetic influences on osteoporosis in humans and mice
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Morris, John A, Kemp, John P, Youlten, Scott E, Laurent, Laetitia, Logan, John G, Chai, Ryan C, Vulpescu, Nicholas A, Forgetta, Vincenzo, Kleinman, Aaron, Mohanty, Sindhu T, Sergio, C Marcelo, Quinn, Julian, Nguyen-Yamamoto, Loan, Luco, Aimee-Lee, Vijay, Jinchu, Simon, Marie-Michelle, Pramatarova, Albena, Medina-Gomez, Carolina, Trajanoska, Katerina, Ghirardello, Elena J, Butterfield, Natalie C, Curry, Katharine F, Leitch, Victoria D, Sparkes, Penny C, Adoum, Anne-Tounsia, Mannan, Naila S, Komla-Ebri, Davide SK, Pollard, Andrea S, Dewhurst, Hannah F, Hassall, Thomas AD, Beltejar, Michael-John G, 23andMe Research Team, Adams, Douglas J, Vaillancourt, Suzanne M, Kaptoge, Stephen, Baldock, Paul, Cooper, Cyrus, Reeve, Jonathan, Ntzani, Evangelia E, Evangelou, Evangelos, Ohlsson, Claes, Karasik, David, Rivadeneira, Fernando, Kiel, Douglas P, Tobias, Jonathan H, Gregson, Celia L, Harvey, Nicholas C, Grundberg, Elin, Goltzman, David, Adams, David J, Lelliott, Christopher J, Hinds, David A, Ackert-Bicknell, Cheryl L, Hsu, Yi-Hsiang, Maurano, Matthew T, Croucher, Peter I, Williams, Graham R, Bassett, JH Duncan, Evans, David M, Richards, J Brent, Morris, John A [0000-0003-2769-8202], Kemp, John P [0000-0002-9105-2249], Youlten, Scott E [0000-0001-9314-2945], Vulpescu, Nicholas A [0000-0003-1310-0257], Sergio, C Marcelo [0000-0002-5426-0583], Medina-Gomez, Carolina [0000-0001-7999-5538], Reeve, Jonathan [0000-0002-4364-2682], Ntzani, Evangelia E [0000-0003-3712-4181], Rivadeneira, Fernando [0000-0001-9435-9441], Kiel, Douglas P [0000-0001-8474-0310], Gregson, Celia L [0000-0001-6414-0529], Harvey, Nicholas C [0000-0002-8194-2512], Lelliott, Christopher J [0000-0001-8087-4530], Hinds, David A [0000-0002-4911-803X], Williams, Graham R [0000-0002-8555-8219], Bassett, JH Duncan [0000-0003-0817-0082], Evans, David M [0000-0003-0663-4621], Richards, J Brent [0000-0002-3746-9086], and Apollo - University of Cambridge Repository
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Adult ,Male ,Mice, Knockout ,Middle Aged ,Polymorphism, Single Nucleotide ,Fractures, Bone ,Mice ,Phenotype ,Bone Density ,Animals ,Humans ,Osteoporosis ,Female ,Genetic Predisposition to Disease ,Aged ,Genome-Wide Association Study - Abstract
Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.
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- 2019
20. Slc20a2, encoding the phosphate transporter PiT2, is a novel genetic determinant of bone quality and strength
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Beck-Cormier, Sarah, Lelliott, Christopher J., Logan, John G., Lafont, David T., Leitch, Victoria D., Butterfield, Natalie C., Protheroe, Hayley J., Croucher, Peter I., Baldock, Paul A., Gaultier-Lintia, Alina, Nicolas, Gael, Bon, Nina, Sourice, Sophie, Jerome Guicheux, Beck, Laurent, Williams, Graham R., Bassett, J. H. Duncan, and Wellcome Trust
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EXPRESSION ,Science & Technology ,ROLES ,ANIMAL MODELS (GENETIC ANIMAL MODELS) ,IDENTIFICATION ,BIOGENESIS ,GENETIC RESEARCH (HUMAN ASSOCIATION STUDIES) ,06 Biological Sciences ,OSTEOPOROSIS ,Anatomy & Morphology ,DISORDERS OF CALCIUM ,CALCIFICATION ,09 Engineering ,Endocrinology & Metabolism ,MATRIX VESICLES ,CELLS ,DISORDERS OF CALCIUM/PHOSPHATE METABOLISM (OTHER) ,GROWTH ,BONE MATRIX (MATRIX MINERALIZATION) ,MINERAL DENSITY ,ORTHOPAEDICS (BIOMECHANICS) ,Life Sciences & Biomedicine ,PHOSPHATE METABOLISM (OTHER) ,11 Medical and Health Sciences - Abstract
Osteoporosis is characterized by low bone mineral density (BMD) and fragility fracture and affects over 200 million people worldwide. Bone quality describes the material properties that contribute to strength independently of BMD, and its quantitative analysis is a major priority in osteoporosis research. Tissue mineralization is a fundamental process requiring calcium and phosphate transporters. Here we identify impaired bone quality and strength in Slc20a2–/– mice lacking the phosphate transporter SLC20A2. Juveniles had abnormal endochondral and intramembranous ossification, decreased mineral accrual, and short stature. Adults exhibited only small reductions in bone mass and mineralization but a profound impairment of bone strength. Bone quality was severely impaired in Slc20a2–/– mice: yield load (–2.3 SD), maximum load (–1.7 SD), and stiffness (–2.7 SD) were all below values predicted from their bone mineral content as determined in a cohort of 320 wild‐type controls. These studies identify Slc20a2 as a physiological regulator of tissue mineralization and highlight its critical role in the determination of bone quality and strength.
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- 2019
21. IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction
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Joustra, Sjoerd D, primary, Roelfsema, Ferdinand, additional, van Trotsenburg, A S Paul, additional, Schneider, Harald J, additional, Kosilek, Robert P, additional, Kroon, Herman M, additional, Logan, John G, additional, Butterfield, Natalie C, additional, Zhou, Xiang, additional, Toufaily, Chirine, additional, Bak, Beata, additional, Turgeon, Marc-Olivier, additional, Brûlé, Emilie, additional, Steyn, Frederik J, additional, Gurnell, Mark, additional, Koulouri, Olympia, additional, Le Tissier, Paul, additional, Fontanaud, Pierre, additional, Duncan Bassett, J H, additional, Williams, Graham R, additional, Oostdijk, Wilma, additional, Wit, Jan M, additional, Pereira, Alberto M, additional, Biermasz, Nienke R, additional, Bernard, Daniel J, additional, and Schoenmakers, Nadia, additional
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- 2019
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22. Genetic and Pharmacological Targeting of Transcriptional Repression in Resistance to Thyroid Hormone Alpha
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Freudenthal, Bernard, primary, Shetty, Samiksha, additional, Butterfield, Natalie C., additional, Logan, John G., additional, Han, Cho Rong, additional, Zhu, Xuguang, additional, Astapova, Inna, additional, Hollenberg, Anthony N., additional, Cheng, Sheue-Yann, additional, Bassett, J.H. Duncan, additional, and Williams, Graham R., additional
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- 2019
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23. Slc20a2 , Encoding the Phosphate Transporter PiT2, Is an Important Genetic Determinant of Bone Quality and Strength
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Beck‐Cormier, Sarah, primary, Lelliott, Christopher J, additional, Logan, John G, additional, Lafont, David T, additional, Merametdjian, Laure, additional, Leitch, Victoria D, additional, Butterfield, Natalie C, additional, Protheroe, Hayley J, additional, Croucher, Peter I, additional, Baldock, Paul A, additional, Gaultier‐Lintia, Alina, additional, Maugars, Yves, additional, Nicolas, Gael, additional, Banse, Christopher, additional, Normant, Sébastien, additional, Magne, Nicolas, additional, Gérardin, Emmanuel, additional, Bon, Nina, additional, Sourice, Sophie, additional, Guicheux, Jérôme, additional, Beck, Laurent, additional, Williams, Graham R, additional, and Bassett, J H Duncan, additional
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- 2019
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24. Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain
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Jo, Sungro, primary, Fonseca, Tatiana L., additional, Bocco, Barbara M. L. C., additional, Fernandes, Gustavo W., additional, McAninch, Elizabeth A., additional, Bolin, Anaysa P., additional, Da Conceição, Rodrigo R., additional, Werneck-de-Castro, Joao Pedro, additional, Ignacio, Daniele L., additional, Egri, Péter, additional, Németh, Dorottya, additional, Fekete, Csaba, additional, Bernardi, Maria Martha, additional, Leitch, Victoria D., additional, Mannan, Naila S., additional, Curry, Katharine F., additional, Butterfield, Natalie C., additional, Bassett, J.H. Duncan, additional, Williams, Graham R., additional, Gereben, Balázs, additional, Ribeiro, Miriam O., additional, and Bianco, Antonio C., additional
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- 2018
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25. An Atlas of Human and Murine Genetic Influences on Osteoporosis
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Morris, John A., primary, Kemp, John P., additional, Youlten, Scott E., additional, Laurent, Laetitia, additional, Logan, John G., additional, Chai, Ryan, additional, Vulpescu, Nicholas A., additional, Forgetta, Vincenzo, additional, Kleinman, Aaron, additional, Mohanty, Sindhu, additional, Sergio, C. Marcelo, additional, Quinn, Julian, additional, Nguyen-Yamamoto, Loan, additional, Luco, Aimee Lee, additional, Vijay, Jinchu, additional, Simon, Marie-Michelle, additional, Pramatarova, Albena, additional, Medina-Gomez, Carolina, additional, Trajanoska, Katerina, additional, Ghirardello, Elena J., additional, Butterfield, Natalie C., additional, Curry, Katharine F., additional, Leitch, Victoria D., additional, Sparkes, Penny C., additional, Adoum, Anne-Tounsia, additional, Mannan, Naila S., additional, Komla-Ebri, Davide, additional, Pollard, Andrea S., additional, Dewhurst, Hannah F., additional, Hassall, Thomas, additional, Beltejar, Michael-John G, additional, Adams, Douglas J, additional, Vaillancourt, Suzanne M., additional, Kaptoge, Stephen, additional, Baldock, Paul, additional, Cooper, Cyrus, additional, Reeve, Jonathan, additional, Ntzani, Evangelia, additional, Evangelou, Evangelos, additional, Ohlsson, Claes, additional, Karasik, David, additional, Rivadeneira, Fernando, additional, Kiel, Douglas P., additional, Tobias, Jonathan H., additional, Gregson, Celia L., additional, Harvey, Nicholas C., additional, Grundberg, Elin, additional, Goltzman, David, additional, Adams, David J., additional, Lelliott, Christopher J., additional, Hinds, David A., additional, Ackert-Bicknell, Cheryl L., additional, Hsu, Yi-Hsiang, additional, Maurano, Matthew T., additional, Croucher, Peter I., additional, Williams, Graham R., additional, Bassett, J. H. Duncan, additional, Evans, David M., additional, and Richards, J. Brent, additional
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- 2018
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26. Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis
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Kemp, John P, primary, Morris, John A, additional, Medina-Gomez, Carolina, additional, Forgetta, Vincenzo, additional, Warrington, Nicole M, additional, Youlten, Scott E, additional, Zheng, Jie, additional, Gregson, Celia L, additional, Grundberg, Elin, additional, Trajanoska, Katerina, additional, Logan, John G, additional, Pollard, Andrea S, additional, Sparkes, Penny C, additional, Ghirardello, Elena J, additional, Allen, Rebecca, additional, Leitch, Victoria D, additional, Butterfield, Natalie C, additional, Komla-Ebri, Davide, additional, Adoum, Anne-Tounsia, additional, Curry, Katharine F, additional, White, Jacqueline K, additional, Kussy, Fiona, additional, Greenlaw, Keelin M, additional, Xu, Changjiang, additional, Harvey, Nicholas C, additional, Cooper, Cyrus, additional, Adams, David J, additional, Greenwood, Celia M T, additional, Maurano, Matthew T, additional, Kaptoge, Stephen, additional, Rivadeneira, Fernando, additional, Tobias, Jonathan H, additional, Croucher, Peter I, additional, Ackert-Bicknell, Cheryl L, additional, Bassett, J H Duncan, additional, Williams, Graham R, additional, Richards, J Brent, additional, and Evans, David M, additional
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- 2017
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27. Pitx1 determines characteristic hindlimb morphologies in cartilage micromass culture
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Butterfield, Natalie C., primary, Qian, Chen, additional, and Logan, Malcolm P. O., additional
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- 2017
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28. Tbx5 Buffers Inherent Left/Right Asymmetry Ensuring Symmetric Forelimb Formation
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Sulaiman, Fatima A., primary, Nishimoto, Satoko, additional, Murphy, George R. F., additional, Kucharska, Anna, additional, Butterfield, Natalie C., additional, Newbury-Ecob, Ruth, additional, and Logan, Malcolm P. O., additional
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- 2016
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29. IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction
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Joustra, Sjoerd D, Roelfsema, Ferdinand, van Trotsenburg, A S Paul, Schneider, Harald J, Kosilek, Robert P, Kroon, Herman M, Logan, John G, Butterfield, Natalie C, Zhou, Xiang, Toufaily, Chirine, Bak, Beata, Turgeon, Marc-Olivier, Brûlé, Emilie, Steyn, Frederik J, Gurnell, Mark, Koulouri, Olympia, Le Tissier, Paul, Fontanaud, Pierre, Duncan Bassett, J H, Williams, Graham R, Oostdijk, Wilma, Wit, Jan M, Pereira, Alberto M, Biermasz, Nienke R, Bernard, Daniel J, and Schoenmakers, Nadia
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- 2020
- Full Text
- View/download PDF
30. An atlas of genetic influences on osteoporosis in humans and mice
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Morris, John A., Kemp, John P., Youlten, Scott E., Laurent, Laetitia, Logan, John G., Chai, Ryan C., Vulpescu, Nicholas A., Forgetta, Vincenzo, Kleinman, Aaron, Mohanty, Sindhu T., Sergio, C. Marcelo, Quinn, Julian, Nguyen-Yamamoto, Loan, Luco, Aimee-Lee, Vijay, Jinchu, Simon, Marie-Michelle, Pramatarova, Albena, Medina-Gomez, Carolina, Trajanoska, Katerina, Ghirardello, Elena J., Butterfield, Natalie C., Curry, Katharine F., Leitch, Victoria D., Sparkes, Penny C., Adoum, Anne-Tounsia, Mannan, Naila S., Komla-Ebri, Davide S. K., Pollard, Andrea S., Dewhurst, Hannah F., Hassall, Thomas A. D., Beltejar, Michael-John G., Adams, Douglas J., Vaillancourt, Suzanne M., Kaptoge, Stephen, Baldock, Paul, Cooper, Cyrus, Reeve, Jonathan, Ntzani, Evangelia E., Evangelou, Evangelos, Ohlsson, Claes, Karasik, David, Rivadeneira, Fernando, Kiel, Douglas P., Tobias, Jonathan H., Gregson, Celia L., Harvey, Nicholas C., Grundberg, Elin, Goltzman, David, Adams, David J., Lelliott, Christopher J., Hinds, David A., Ackert-Bicknell, Cheryl L., Hsu, Yi-Hsiang, Maurano, Matthew T., Croucher, Peter I., Williams, Graham R., Bassett, J. H. Duncan, Evans, David M., and Richards, J. Brent
- Abstract
Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P= 1 × 10−75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P< 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.
- Published
- 2019
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- View/download PDF
31. Inactivation of Patched1 in the Mouse Limb Has Novel Inhibitory Effects on the Chondrogenic Program
- Author
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Bruce, Stephen J., primary, Butterfield, Natalie C., additional, Metzis, Vicki, additional, Town, Liam, additional, McGlinn, Edwina, additional, and Wicking, Carol, additional
- Published
- 2010
- Full Text
- View/download PDF
32. The metalloendopeptidase genePitrm1is regulated by hedgehog signaling in the developing mouse limb and is expressed in muscle progenitors
- Author
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Town, Liam, primary, McGlinn, Edwina, additional, Fiorenza, Salvatore, additional, Metzis, Vicki, additional, Butterfield, Natalie C., additional, Richman, Joy M., additional, and Wicking, Carol, additional
- Published
- 2009
- Full Text
- View/download PDF
33. Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb
- Author
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Butterfield, Natalie C., primary, Metzis, Vicki, additional, McGlinn, Edwina, additional, Bruce, Stephen J., additional, Wainwright, Brandon J., additional, and Wicking, Carol, additional
- Published
- 2009
- Full Text
- View/download PDF
34. Expression of the NET family memberZfp503is regulated by hedgehog and BMP signaling in the limb
- Author
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McGlinn, Edwina, primary, Richman, Joy M., additional, Metzis, Vicki, additional, Town, Liam, additional, Butterfield, Natalie C., additional, Wainwright, Brandon J., additional, and Wicking, Carol, additional
- Published
- 2008
- Full Text
- View/download PDF
35. A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development
- Author
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Ashe, Alyson, primary, Morgan, Daniel K, additional, Whitelaw, Nadia C, additional, Bruxner, Timothy J, additional, Vickaryous, Nicola K, additional, Cox, Liza L, additional, Butterfield, Natalie C, additional, Wicking, Carol, additional, Blewitt, Marnie E, additional, Wilkins, Sarah J, additional, Anderson, Gregory J, additional, Cox, Timothy C, additional, and Whitelaw, Emma, additional
- Published
- 2008
- Full Text
- View/download PDF
36. Expression of the NET family member Zfp503 is regulated by hedgehog and BMP signaling in the limb.
- Author
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McGlinn, Edwina, Richman, Joy M., Metzis, Vicki, Town, Liam, Butterfield, Natalie C., Wainwright, Brandon J., and Wicking, Carol
- Abstract
The NET/Nlz family of zinc finger transcription factors contribute to aspects of developmental growth and patterning across evolutionarily diverse species. To date, however, these molecules remain largely uncharacterized in mouse and chick. We previously reported that limb bud expression of Zfp503, the mouse orthologue of zebrafish nlz2/ znf503, is dependent on Gli3. Here, we show that Zfp503/ Znf503 is expressed in a restricted pattern during mouse and chick embryogenesis, with particularly dynamic expression in the developing limbs, face, somites, and brain. We also add to our previous data on Gli3 regulation by showing that the anterior domain of Zfp503 expression in the mouse limb is responsive to genetic and nongenetic manipulation of hedgehog signaling. Finally, we demonstrate that posterior expression of Znf503 in the chick limb is responsive to bone morphogenetic protein (BMP) signaling, indicating that Zfp503/ Znf503 may act at the nexus of multiple signaling pathways in development. Developmental Dynamics 237:1172-1182, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
37. Functional validation of the osteoporosis GWAS candidate FUBP3in knockout mice
- Author
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Watts, Laura, Freudenthal, Bernard, Butterfield, Natalie C., Pollard, Andrea, Komla-Ebri, Davide, Leitch, Victoria, Logan, John, Mannan, Naila, Bassett, J.H. Duncan, and Williams, Graham R.
- Published
- 2020
- Full Text
- View/download PDF
38. Slc38a10is a novel regulator of osteoblastic bone formation
- Author
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Pollard, Andrea S., Ebri, Davide Komla, Sparkes, Penny, Gogakos, Apostolos, Logan, John G., Butterfield, Natalie C., Leitch, Victoria, Bassett, J.H. Duncan, and Williams, Graham R.
- Published
- 2020
- Full Text
- View/download PDF
39. Accelerating functional gene discovery in osteoarthritis
- Author
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Butterfield, Natalie C, Curry, Katherine F, Steinberg, Julia, Dewhurst, Hannah, Komla-Ebri, Davide, Mannan, Naila S, Adoum, Anne-Tounsia, Leitch, Victoria D, Logan, John G, Waung, Julian A, Ghirardello, Elena, Southam, Lorraine, Youlten, Scott E, Wilkinson, J Mark, McAninch, Elizabeth A, Vancollie, Valerie E, Kussy, Fiona, White, Jacqueline K, Lelliott, Christopher J, Adams, David J, Jacques, Richard, Bianco, Antonio C, Boyde, Alan, Zeggini, Eleftheria, Croucher, Peter I, Williams, Graham R, and Bassett, JH Duncan
- Subjects
Gene Editing ,Mice, Knockout ,Iodide Peroxidase ,Bone and Bones ,3. Good health ,Gonadotropin-Releasing Hormone ,Disease Models, Animal ,Mice ,Cartilage ,Phenotype ,Drug Discovery ,Osteoarthritis ,Animals ,Paired Box Transcription Factors ,Clustered Regularly Interspaced Short Palindromic Repeats ,Genetic Predisposition to Disease ,CRISPR-Cas Systems ,Genetic Association Studies - Abstract
Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease.
40. A molecular quantitative trait locus map for osteoarthritis
- Author
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Steinberg, Julia, Southam, Lorraine, Roumeliotis, Theodoros I, Clark, Matthew J, Jayasuriya, Raveen L, Swift, Diane, Shah, Karan M, Butterfield, Natalie C, Brooks, Roger A, McCaskie, Andrew W, Bassett, JH Duncan, Williams, Graham R, Choudhary, Jyoti S, Wilkinson, J Mark, and Zeggini, Eleftheria
- Subjects
Phenotype ,Gene Expression Regulation ,Gene Expression Profiling ,Osteoarthritis ,Quantitative Trait Loci ,Humans ,Genetic Predisposition to Disease ,Transcriptome ,3. Good health ,Genome-Wide Association Study ,Transcription Factors - Abstract
Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis.
41. A molecular quantitative trait locus map for osteoarthritis
- Author
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Steinberg, Julia, Southam, Lorraine, Roumeliotis, Theodoros I., Clark, Matthew J., Jayasuriya, Raveen L., Swift, Diane, Shah, Karan M., Butterfield, Natalie C., Brooks, Roger A., McCaskie, Andrew W., Bassett, J. H. Duncan, Williams, Graham R., Choudhary, Jyoti S., Wilkinson, J. Mark, and Zeggini, Eleftheria
- Subjects
45/91 ,45 ,631/208/212/2019 ,education ,631/208/200 ,631/208/205/2138 ,article ,631/208/191/2018 ,humanities ,health care economics and organizations ,3. Good health - Abstract
Funder: Medical Research Council Centre for Integrated Research into Musculoskeletal Ageing grant (148985), Funder: Versus Arthritis; Tissue Engineering and Regenerative Therapies Centre (21156), Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis.
42. A molecular quantitative trait locus map for osteoarthritis
- Author
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Steinberg, Julia, Southam, Lorraine, Roumeliotis, Theodoros I., Clark, Matthew J., Jayasuriya, Raveen L., Swift, Diane, Shah, Karan M., Butterfield, Natalie C., Brooks, Roger A., McCaskie, Andrew W., Bassett, J. H. Duncan, Williams, Graham R., Choudhary, Jyoti S., Wilkinson, J. Mark, and Zeggini, Eleftheria
- Subjects
45/91 ,45 ,631/208/212/2019 ,education ,631/208/200 ,631/208/205/2138 ,article ,631/208/191/2018 ,humanities ,health care economics and organizations ,3. Good health - Abstract
Funder: Medical Research Council Centre for Integrated Research into Musculoskeletal Ageing grant (148985), Funder: Versus Arthritis; Tissue Engineering and Regenerative Therapies Centre (21156), Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis.
43. Author Correction: An atlas of genetic influences on osteoporosis in humans and mice
- Author
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Morris, John A., Kemp, John P., Youlten, Scott E., Laurent, Laetitia, Logan, John G., Chai, Ryan C., Vulpescu, Nicholas A., Forgetta, Vincenzo, Kleinman, Aaron, Mohanty, Sindhu T., Sergio, C. Marcelo, Quinn, Julian, Nguyen-Yamamoto, Loan, Luco, Aimee-Lee, Vijay, Jinchu, Simon, Marie-Michelle, Pramatarova, Albena, Medina-Gomez, Carolina, Trajanoska, Katerina, Ghirardello, Elena J., Butterfield, Natalie C., Curry, Katharine F., Leitch, Victoria D., Sparkes, Penny C., Adoum, Anne-Tounsia, Mannan, Naila S., Komla-Ebri, Davide S. K., Pollard, Andrea S., Dewhurst, Hannah F., Hassall, Thomas A. D., Beltejar, Michael-John G., Adams, Douglas J., Vaillancourt, Suzanne M., Kaptoge, Stephen, Baldock, Paul, Cooper, Cyrus, Reeve, Jonathan, Ntzani, Evangelia E., Evangelou, Evangelos, Ohlsson, Claes, Karasik, David, Rivadeneira, Fernando, Kiel, Douglas P., Tobias, Jonathan H., Gregson, Celia L., Harvey, Nicholas C., Grundberg, Elin, Goltzman, David, Adams, David J., Lelliott, Christopher J., Hinds, David A., Ackert-Bicknell, Cheryl L., Hsu, Yi-Hsiang, Maurano, Matthew T., Croucher, Peter I., Williams, Graham R., Bassett, J. H. Duncan, Evans, David M., and Richards, J. Brent
- Abstract
In the version of this article initially published, in Fig. 5a, the data in the right column of ‘DAAM2 gRNA1’ were incorrectly plotted as circles indicating ‘untreated’ rather than as squares indicating ‘treated’. The error has been corrected in the HTML and PDF versions of the article.
- Published
- 2019
- Full Text
- View/download PDF
44. A molecular quantitative trait locus map for osteoarthritis
- Author
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Raveen L Jayasuriya, D Swift, Karan M. Shah, Jyoti S. Choudhary, Lorraine Southam, Graham R. Williams, Eleftheria Zeggini, Andrew McCaskie, Theodoros I. Roumeliotis, Julia Steinberg, J. H. Duncan Bassett, Roger A. Brooks, M.J. Clark, J. Mark Wilkinson, Natalie C. Butterfield, Steinberg, Julia [0000-0002-0585-2312], Clark, Matthew J [0000-0003-2152-2257], Shah, Karan M [0000-0001-9909-6409], Butterfield, Natalie C [0000-0002-5209-7508], Bassett, JH Duncan [0000-0003-0817-0082], Williams, Graham R [0000-0002-8555-8219], Choudhary, Jyoti S [0000-0003-0881-5477], Wilkinson, J Mark [0000-0001-5577-3674], Zeggini, Eleftheria [0000-0003-4238-659X], Apollo - University of Cambridge Repository, Clark, Matthew J. [0000-0003-2152-2257], Shah, Karan M. [0000-0001-9909-6409], Butterfield, Natalie C. [0000-0002-5209-7508], Bassett, J. H. Duncan [0000-0003-0817-0082], Williams, Graham R. [0000-0002-8555-8219], Choudhary, Jyoti S. [0000-0003-0881-5477], and Wilkinson, J. Mark [0000-0001-5577-3674]
- Subjects
0301 basic medicine ,Article ,Gene expression profiling ,Gene regulation ,Genome-wide association studies ,Transcriptomics ,Science ,Quantitative Trait Loci ,631/208/205/2138 ,General Physics and Astronomy ,Genome-wide association study ,Computational biology ,Osteoarthritis ,Disease ,Biology ,Quantitative trait locus ,Proteomics ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,631/208/200 ,medicine ,Humans ,Genetic Predisposition to Disease ,Repurposing ,45/91 ,030203 arthritis & rheumatology ,Science & Technology ,Multidisciplinary ,45 ,631/208/212/2019 ,Gene Expression Profiling ,General Chemistry ,Omics ,medicine.disease ,ddc ,3. Good health ,Multidisciplinary Sciences ,030104 developmental biology ,Phenotype ,Drug development ,Gene Expression Regulation ,Science & Technology - Other Topics ,631/208/191/2018 ,Transcriptome ,Genome-Wide Association Study ,Transcription Factors - Abstract
Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis., Understanding the molecular effects of disease variants in relevant tissues is essential to understanding and treating disease. Here, the authors discover expression and protein quantitative trait loci in cartilage and synovium from 115 osteoarthritis patients to pinpoint genes of action and potential drug treatments.
- Published
- 2021
- Full Text
- View/download PDF
45. Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain.
- Author
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Sungro Jo, Fonseca, Tatiana L., Bocco, Barbara M. L. C., Fernandes, Gustavo W., McAninch, Elizabeth A., Bolin, Anaysa P., Da Conceição, Rodrigo R., Werneck-de-Castro, Joao Pedro, Ignacio, Daniele L., Egri, Péter, Németh, Dorottya, Fekete, Csaba, Bernardi, Maria Martha, Leitch, Victoria D., Mannan, Naila S., Curry, Katharine F., Butterfield, Natalie C., Bassett, J. H. Duncan, Williams, Graham R., and Gereben, Balázs
- Subjects
- *
HYPOTHYROIDISM , *THYROID hormones , *THYROID diseases , *LEVOTHYROXINE , *THYROTROPIN - Abstract
Levothyroxine (LT4) is a form of thyroid hormone used to treat hypothyroidism. In the brain, T4 is converted to the active form T3 by type 2 deiodinase (D2). Thus, it is intriguing that carriers of the Thr92Ala polymorphism in the D2 gene (DIO2) exhibit clinical improvement when liothyronine (LT3) is added to LT4 therapy. Here, we report that D2 is a cargo protein in ER Golgi intermediary compartment (ERGIC) vesicles, recycling between ER and Golgi. The Thr92-to-Ala substitution (Ala92-D2) caused ER stress and activated the unfolded protein response (UPR). Ala92-D2 accumulated in the trans-Golgi and generated less T3, which was restored by eliminating ER stress with the chemical chaperone 4-phenyl butyric acid (4-PBA). An Ala92-Dio2 polymorphism-carrying mouse exhibited UPR and hypothyroidism in distinct brain areas. The mouse refrained from physical activity, slept more, and required additional time to memorize objects. Enhancing T3 signaling in the brain with LT3 improved cognition, whereas restoring proteostasis with 4-PBA eliminated the Ala92-Dio2 phenotype. In contrast, primary hypothyroidism intensified the Ala92-Dio2 phenotype, with only partial response to LT4 therapy. Disruption of cellular proteostasis and reduced Ala92-D2 activity may explain the failure of LT4 therapy in carriers of Thr92Ala-DIO2. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
46. Accelerating functional gene discovery in osteoarthritis
- Author
-
Hannah F. Dewhurst, Peter I. Croucher, Julian A. Waung, Elena J. Ghirardello, Jacqueline K. White, Julia Steinberg, Anne-Tounsia Adoum, J. Mark Wilkinson, Graham R. Williams, Alan Boyde, John G. Logan, Valerie E. Vancollie, Naila S. Mannan, J. H. Duncan Bassett, Fiona Kussy, Natalie C. Butterfield, Davide Komla-Ebri, Lorraine Southam, Antonio C. Bianco, Scott E. Youlten, Victoria D. Leitch, Katherine F. Curry, Christopher J. Lelliott, David J. Adams, Elizabeth A. McAninch, Eleftheria Zeggini, Richard Jacques, Wellcome Trust, Commission of the European Communities, European Commission, Butterfield, Natalie C [0000-0002-5209-7508], Steinberg, Julia [0000-0002-0585-2312], Komla-Ebri, Davide [0000-0002-8381-5381], Leitch, Victoria D [0000-0001-5760-2887], Youlten, Scott E [0000-0001-9314-2945], Wilkinson, J Mark [0000-0001-5577-3674], McAninch, Elizabeth A [0000-0003-3993-4663], Vancollie, Valerie E [0000-0003-1547-1975], Lelliott, Christopher J [0000-0001-8087-4530], Adams, David J [0000-0001-9490-0306], Jacques, Richard [0000-0001-6710-5403], Boyde, Alan [0000-0002-9871-5498], Zeggini, Eleftheria [0000-0003-4238-659X], Croucher, Peter I [0000-0002-7102-2413], Williams, Graham R [0000-0002-8555-8219], Bassett, JH Duncan [0000-0003-0817-0082], and Apollo - University of Cambridge Repository
- Subjects
musculoskeletal diseases ,0301 basic medicine ,Science ,Mutant ,General Physics and Astronomy ,Osteoarthritis ,Bioinformatics ,Iodide Peroxidase ,Bone and Bones ,General Biochemistry, Genetics and Molecular Biology ,Article ,Gonadotropin-Releasing Hormone ,International Knockout Mouse Consortium ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Genome editing ,Drug Discovery ,medicine ,Animals ,Paired Box Transcription Factors ,CRISPR ,Clustered Regularly Interspaced Short Palindromic Repeats ,Genetic Predisposition to Disease ,Bone ,Gene ,Genetic Association Studies ,030304 developmental biology ,Gene Editing ,Mice, Knockout ,030203 arthritis & rheumatology ,0303 health sciences ,Multidisciplinary ,Drug discovery ,Cas9 ,business.industry ,General Chemistry ,medicine.disease ,Publisher Correction ,Phenotype ,3. Good health ,Disease Models, Animal ,030104 developmental biology ,Cartilage ,CRISPR-Cas Systems ,business - Abstract
Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease., Osteoarthritis is a chronic, heritable disease with no available treatment. Here, the authors show that a validated, rapid-throughput joint phenotyping pipeline detects osteoarthritis in the mouse knee following surgical provocation, in aging and after single gene deletion or point mutation.
- Published
- 2019
47. Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease
- Author
-
Siobhan E. Guilfoyle, John A. Morris, Scott E. Youlten, Graham R. Williams, Michael R.G. Dack, Elena J. Ghirardello, Amelia R. McGlade, Davide Komla-Ebri, John P. Kemp, Paul A. Baldock, David J. Adams, David M. Evans, J. H. Duncan Bassett, John G. Logan, Victoria D. Leitch, Fernando Rivadeneira, Eleftheria Zeggini, Michelle M. McDonald, Ryan C. Chai, Tri Giang Phan, Nenad Bartonicek, Melita Irving, Konstantinos Hatzikotoulas, Christopher J. Lelliott, Matt Jansson, Robert Brink, James T. Smith, Peter I. Croucher, Ana Beleza-Meireles, Claudio M Sergio, Sindhu T. Mohanty, J. Brent Richards, Alexander P. Corr, Natalie C. Butterfield, Emma L. Duncan, John A. Eisman, Julian M.W. Quinn, Youlten, Scott E [0000-0001-9314-2945], Kemp, John P [0000-0002-9105-2249], Sergio, Claudio M [0000-0002-5426-0583], Leitch, Victoria D [0000-0001-5760-2887], Butterfield, Natalie C [0000-0002-5209-7508], Komla-Ebri, Davide [0000-0002-8381-5381], Corr, Alexander P [0000-0002-8450-012X], Smith, James T [0000-0003-0528-0649], Mohanty, Sindhu T [0000-0001-7512-8808], Morris, John A [0000-0003-2769-8202], Quinn, Julian MW [0000-0001-9674-9646], Hatzikotoulas, Konstantinos [0000-0002-4699-3672], Rivadeneira, Fernando [0000-0001-9435-9441], Duncan, Emma [0000-0002-8143-4403], Richards, J Brent [0000-0002-3746-9086], Adams, David J [0000-0001-9490-0306], Lelliott, Christopher J [0000-0001-8087-4530], Phan, Tri Giang [0000-0002-4909-2984], Evans, David M [0000-0003-0663-4621], Zeggini, Eleftheria [0000-0003-4238-659X], Bassett, JH Duncan [0000-0003-0817-0082], Williams, Graham R [0000-0002-8555-8219], Croucher, Peter I [0000-0002-7102-2413], Apollo - University of Cambridge Repository, Wellcome Trust, and Internal Medicine
- Subjects
0301 basic medicine ,Male ,General Physics and Astronomy ,Transcriptome ,Mice ,0302 clinical medicine ,Skeletal disease ,Gene expression ,Homeostasis ,Mice, Knockout ,0303 health sciences ,Multidisciplinary ,Age Factors ,RNA sequencing ,Skeleton (computer programming) ,Cell biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Osteocyte ,Knockout mouse ,Female ,Bone Diseases ,Sequence analysis ,Bioinformatics ,Science ,Biology ,Osteocytes ,General Biochemistry, Genetics and Molecular Biology ,Article ,Bone and Bones ,03 medical and health sciences ,Gene expression analysis ,Sex Factors ,SDG 3 - Good Health and Well-being ,medicine ,Animals ,Humans ,Gene ,Skeleton ,030304 developmental biology ,Sequence Analysis, RNA ,Computational Biology ,General Chemistry ,030104 developmental biology ,Osteoporosis ,Bone structure ,030217 neurology & neurosurgery ,Function (biology) - Abstract
Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10−22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10−13) and osteoarthritis (P = 1.6 × 10−7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease., Osteocytes are the master regulatory cells within the skeleton. Here, the authors map the transcriptome of osteocytes from diverse skeletal sites, ages and between sexes and identify an osteocyte transcriptome signature associated with rare skeletal disorders and common complex skeletal diseases.
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48. Quantitative X-Ray Imaging of Mouse Bone by Faxitron.
- Author
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Butterfield NC, Logan JG, Waung J, Williams GR, and Bassett JHD
- Subjects
- Animals, Bone and Bones physiology, Image Processing, Computer-Assisted instrumentation, Mice, Microradiography instrumentation, Models, Animal, Software, Bone Density, Bone and Bones diagnostic imaging, Image Processing, Computer-Assisted methods, Microradiography methods
- Abstract
This chapter describes the use of point projection digital microradiography for rapid imaging and quantitation of bone mineral content in mice.
- Published
- 2019
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- View/download PDF
49. The metalloendopeptidase gene Pitrm1 is regulated by hedgehog signaling in the developing mouse limb and is expressed in muscle progenitors.
- Author
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Town L, McGlinn E, Fiorenza S, Metzis V, Butterfield NC, Richman JM, and Wicking C
- Subjects
- Animals, Embryo, Mammalian, Gene Expression Regulation, Developmental, Gene Expression Regulation, Enzymologic, Hedgehog Proteins genetics, Hedgehog Proteins metabolism, Metalloendopeptidases metabolism, Mice, Mice, Transgenic, Muscle, Skeletal metabolism, Myoblasts, Skeletal metabolism, PAX3 Transcription Factor, Paired Box Transcription Factors metabolism, Signal Transduction genetics, Tissue Distribution, Extremities embryology, Hedgehog Proteins physiology, Metalloendopeptidases genetics, Muscle, Skeletal embryology, Stem Cells metabolism
- Abstract
Pitrm1 is a zinc metalloendopeptidase that has been implicated in Alzheimer's disease and mitochondrial peptide degradation, but to date no major role in embryonic development has been documented. In a screen for genes regulated by hedgehog signaling in the mouse limb, we showed that expression of Pitrm1 is upregulated in response to loss of the Gli3 transcription factor. Here we confirm spatial changes in Pitrm1 expression in the Gli3 mutant mouse limb and examine Pitrm1 expression in Shh null and Ptch1 conditional deletion mouse mutants. In wild-type mice, Pitrm1 is expressed in a number of developing tissues known to be patterned by Sonic hedgehog, including the limbs, face, cortex, hippocampus, cerebellum, tectum, sub-mandibular gland, lung, genital tubercle, hair follicles, and the enamel knot of the teeth. Additionally, Pitrm1 is expressed in Pax3-expressing myoblast progenitors in the limb, the dermomyotome, and developing muscles of the face and torso., ((c) 2009 Wiley-Liss, Inc.)
- Published
- 2009
- Full Text
- View/download PDF
50. Identification and analysis of novel genes expressed in the mouse embryonic facial primordia.
- Author
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Bennetts JS, Fowles LF, Butterfield NC, Berkman JL, Teasdale RD, Simpson F, and Wicking C
- Subjects
- Animals, Computational Biology, Gene Expression Profiling, Genetic Vectors, HeLa Cells, Humans, In Situ Hybridization, Mice, Sequence Analysis, DNA, Transfection, Craniofacial Abnormalities genetics, Face embryology, Gene Expression Regulation, Developmental, Gene Library
- Abstract
Craniofacial anomalies are a common feature of human congenital dysmorphology syndromes, suggesting that genes expressed in the developing face are likely to play a wider role in embryonic development. To facilitate the identification of genes involved in embryogenesis, we previously constructed an enriched cDNA library by subtracting adult mouse liver cDNA from that of embryonic day (E)10.5 mouse pharyngeal arch cDNA. From this library, 273 unique clones were sequenced and known proteins binned into functional categories in order to assess enrichment of the library (1). We have now selected 31 novel and poorly characterised genes from this library and present bioinformatic analysis to predict proteins encoded by these genes, and to detect evolutionary conservation. Of these genes 61% (19/31) showed restricted expression in the developing embryo, and a subset of these was chosen for further in silico characterisation as well as experimental determination of subcellular localisation based on transient transfection of predicted full-length coding sequences into mammalian cell lines. Where a human orthologue of these genes was detected, chromosomal localisation was determined relative to known loci for human congenital disease.
- Published
- 2006
- Full Text
- View/download PDF
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