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1. Accelerating functional gene discovery in osteoarthritis

Author

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

Published
2021
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2. Publisher Correction: Accelerating functional gene discovery in osteoarthritis

Author

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

Published
2021
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3. A molecular quantitative trait locus map for osteoarthritis

Author

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

Published
2021
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4. Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease

Author

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.

Published
2021
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5. Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain

Author

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.

Subjects
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 [...]

Published
2019
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6. Correction: Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption

Author

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

Published
2021

7. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption

Author

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

Published
2021
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10. Slc38a10 is a novel regulator of osteoblastic bone formation

Author

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

Published
2020
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11. Response to Letter to the Editor: “IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction”

Author

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

Published
2020
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12. PYY is a negative regulator of bone mass and strength

Author

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., Bassett, J.H. Duncan, Wellcome Trust, Commission of the European Communities, and European Commission

Subjects
Endocrinology & Metabolism, digestive, oral, and skin physiology, 06 Biological Sciences, hormones, hormone substitutes, and hormone antagonists, 11 Medical and Health Sciences, 09 Engineering
Abstract

Objective Bone loss in anorexia nervosa and following bariatric surgery is associated with an elevated circulating concentration of the gastrointestinal, anorexigenic hormone, peptide YY (PYY). Selective deletion of the PYY receptor Y1R in osteoblasts or Y2R in the hypothalamus results in high bone mass, but deletion of PYY in mice has resulted in conflicting skeletal phenotypes leading to uncertainty regarding its role in the regulation of bone mass. As PYY analogs are under development for treatment of obesity, we aimed to clarify the relationship between PYY and bone mass. Methods The skeletal phenotype of Pyy knockout (KO) mice was investigated during growth (postnatal day P14) and adulthood (P70 and P186) using X-ray microradiography, micro-CT, back-scattered electron scanning electron microscopy (BSE-SEM), histomorphometry and biomechanical testing. Results Bones from juvenile and Pyy KO mice were longer (P

Published
2019

13. Slc20a2, encoding the phosphate transporter PiT2, is a novel genetic determinant of bone quality and strength

Author

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

Subjects
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.

Published
2019

14. IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction

Author

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

Published
2019
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15. Slc20a2 , Encoding the Phosphate Transporter PiT2, Is an Important Genetic Determinant of Bone Quality and Strength

Author

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

Published
2019
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16. Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain

Author

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

Published
2018
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19. IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction

Author

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

Published
2020
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24. A molecular quantitative trait locus map for osteoarthritis

Author

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
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25. Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain.

Author

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
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26. 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

27. 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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28. A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development.

Author

Ashe A, Morgan DK, Whitelaw NC, Bruxner TJ, Vickaryous NK, Cox LL, Butterfield NC, Wicking C, Blewitt ME, Wilkins SJ, Anderson GJ, Cox TC, and Whitelaw E

Subjects
Animals, Female, Genes, Lethal, Genome, Heterozygote, Histone Deacetylase 1, Histone Deacetylases metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Transgenic, Transcription Factors metabolism, Williams Syndrome physiopathology, Embryonic Development, Epigenesis, Genetic
Abstract

Background: Some years ago we established an N-ethyl-N-nitrosourea screen for modifiers of transgene variegation in the mouse and a preliminary description of the first six mutant lines, named MommeD1-D6, has been published. We have reported the underlying genes in three cases: MommeD1 is a mutation in SMC hinge domain containing 1 (Smchd1), a novel modifier of epigenetic gene silencing; MommeD2 is a mutation in DNA methyltransferase 1 (Dnmt1); and MommeD4 is a mutation in Smarca 5 (Snf2h), a known chromatin remodeler. The identification of Dnmt1 and Smarca5 attest to the effectiveness of the screen design., Results: We have now extended the screen and have identified four new modifiers, MommeD7-D10. Here we show that all ten MommeDs link to unique sites in the genome, that homozygosity for the mutations is associated with severe developmental abnormalities and that heterozygosity results in phenotypic abnormalities and reduced reproductive fitness in some cases. In addition, we have now identified the underlying genes for MommeD5 and MommeD10. MommeD5 is a mutation in Hdac1, which encodes histone deacetylase 1, and MommeD10 is a mutation in Baz1b (also known as Williams syndrome transcription factor), which encodes a transcription factor containing a PHD-type zinc finger and a bromodomain. We show that reduction in the level of Baz1b in the mouse results in craniofacial features reminiscent of Williams syndrome., Conclusions: These results demonstrate the importance of dosage-dependent epigenetic reprogramming in the development of the embryo and the power of the screen to provide mouse models to study this process.

Published
2008
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