Search

Your search keyword '"Trembath, R.C."' showing total 107 results
Start Over Author "Trembath, R.C."
107 results on '"Trembath, R.C."'

5. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia

Author

Harrison, R.E., Flanagan, J.A., Sankelo, M., Abdalla, S.A., Rowell, J., Machado, R.D., Elliott, C.G., Robbins, I.M., Olschewski, H., McLaughlin, V., Gruenig, E., Kermeen, F., Laitinen, T., Morrell, N.W., and Trembath, R.C.

Subjects
Nucleotide sequence -- Research -- Case studies, Telangiectasia, Hereditary Hemorrhagic -- Research -- Case studies -- Care and treatment, Mutation (Biology) -- Case studies, Transforming growth factors -- Case studies, Pulmonary hypertension -- Care and treatment -- Research -- Case studies, Health, Care and treatment, Research, Case studies
Abstract

Background: Mutations of the transforming growth factor β (TGFβ) receptor components ENDOGLIN and ALK-1 cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). Heterozygous mutations of the type II [...]

Published
2003

6. A locus for asphyxiating thoracic dystrophy, ATD, maps to chromosome 15q 13. (Short Report)

Author

Morgan, N.V., Bacchelli, C., Gissen, P., Morton, J., Ferrero, G.B., Silengo, M., Labrune, P., Casteels, I., Hall, C., Cox, P., Kelly, D.A., Trembath, R.C., Scambler, P.J., Maher, E.R., Goodman, F.R., and Johnson, C.A.

Subjects
Genetic disorders -- Research -- Genetic aspects, Musculoskeletal diseases -- Genetic aspects -- Research, Chest -- Abnormalities -- Genetic aspects -- Research -- Diseases, Health
Abstract

Asphyxiating thoracic dystrophy (ATD), or Jeune syndrome, is a multisystem autosomal recessive disorder associated with a characteristic skeletal dysplasia and variable renal, hepatic, pancreatic, and retinal abnormalities. We have performed [...]

Published
2003

7. Haplotype analysis of distantly related populations implicates corneodesmosin in psoriasis susceptibility. (Letter to JMG)

Author

Capon, F., Toal, I.K., Evans, J.C., Allen, M.H., Patel, S., Tillman, D., Burden, D., Barker, J.N.W.N., and Trembath, R.C.

Subjects
Psoriasis -- Genetic aspects, Desmosomes -- Physiological aspects -- Genetic aspects, Haplotypes -- Physiological aspects -- Genetic aspects, Health, Physiological aspects, Genetic aspects
Abstract

Psoriasis (MIM * 177900) is a hyperproliferative skin disorder, characterised by inflammatory cell dermal infiltration, disruption of keratinocyte terminal differentiation, and premature desquamation of the stratum corneum. (1) Although the [...]

Published
2003

8. Mapping of a novel locus for achromatopsia (ACHM4) to 1p and identification of a germline mutation in the α subunit of cone transducin (GNAT2). (Short Report)

Author

Aligianis, I.A., Forshew, T., Johnson, S., Michaelides, M., Johnson, C.A., Trembath, R.C., Hunt, D.M., Moore, A.T., and Maher, E.R.

Subjects
Consanguinity -- Research -- Health aspects -- Genetic aspects, Familial diseases -- Research -- Genetic aspects, Dysplasia -- Genetic aspects -- Research, Color blindness -- Genetic aspects -- Research, Pakistanis -- Health aspects -- Research, Medical genetics -- Research -- Health aspects, Chromosome mapping -- Research -- Health aspects -- Genetic aspects, Health
Abstract

Objective: To determine the molecular basis for achromatopsia using autozygosity mapping and positional candidate gene analysis. Design and methods: A large consanguineous Pakistani family containing six subjects with autosomal recessive [...]

Published
2002

9. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author

Iglesias, A.I. (Adriana I.), Mishra, A. (Aniket), Vitart, V. (Veronique), Bykhovskaya, Y. (Yelena), Höhn, R. (René), Springelkamp, H. (Henriët), Cuellar-Partida, G. (Gabriel), Gharahkhani, P. (Puya), Bailey, J.N.C. (Jessica N. Cooke), Willoughby, C.E. (Colin E.), Li, X. (Xiaohui), Yazar, S. (Seyhan), Nag, A. (Abhishek), Khawaja, A.P. (Anthony), Polasek, O. (Ozren), Siscovick, D.S. (David), Mitchell, P. (Paul), Tham, Y.C. (Yih Chung), Haines, J.L. (Jonathan), Kearns, L.S. (Lisa S.), Hayward, C. (Caroline), Shi, Y. (Yuan), Van Leeuwen, E.M. (Elisabeth M.), Taylor, K.D. (Kent), Wang, J.J. (Jie Jin), Rochtchina, E. (Elena), Attia, J. (John), Scott, R. (Rodney), Holliday, E.G. (Elizabeth), Baird, P.N. (Paul), Xie, J. (Jing), Inouye, M. (Michael), Viswanathan, A. (Ananth), Sim, X. (Xueling), Bonnemaijer, P.W.M. (Pieter), Rotter, J.I. (Jerome I.), Martin, N.G. (Nicholas G.), Zeller, T. (Tanja), Mills, R.A. (Richard), Staffieri, S.E. (Sandra E.), Jonas, J.B. (Jost B.), Schmidtmann, I. (Irene), Boutin, T. (Thibaud), Kang, J.H. (Jae H.), Lucas, S.E.M. (Sionne E.M.), Wong, T.Y. (Tien Yin), Beutel, M.E. (Manfred E.), Wilson, J.F. (James F.), Allingham, R.R. (R Rand), Brilliant, M.H. (Murray H.), Budenz, D.L. (Donald L.), Christen, W.G. (William G.), Fingert, J. (John), Friedman, D.S. (David), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Hauser, M.A. (Michael), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Loomis, S.J. (Stephanie J.), Moroi, S.E. (Sayoko), Pericak-Vance, M.A. (Margaret), Realini, A. (Anthony), Richards, J.E. (Julia E.), Schuman, J.S. (Joel S.), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Weinreb, R.N. (Robert N.), Wollstein, G. (Gadi), Zack, D.J. (Donald), Zhang, K. (Kang), Donnelly, P. (Peter), Barroso, I.E. (Inês), Blackwell, J.M. (Jenefer M.), Bramon, E. (Elvira), Brown, M.A. (Matthew), Casas, J.P. (Juan), Corvin, A. (Aiden), Deloukas, P. (Panos), Duncanson, A. (Audrey), Jankowski, J. (Janusz), Markus, H.S. (Hugh), Mathew, J. (Joseph), Palmer, C.N.A. (Colin), Plomin, R. (Robert), Rautanen, A. (Anna), Sawcer, S.J. (Stephen), Trembath, R.C. (Richard), Wood, N.W. (Nicholas W.), Spencer, C.C.A. (Chris C.), Band, G. (Gavin), Bellenguez, C. (Céline), Freeman, C. (Colin), Hellenthal, F.A., Giannoulatou, E. (Eleni), Pirinen, M. (Matti), Pearson, R. (Ruth), Strange, A. (Amy), Su, Z. (Zhan), Vukcevic, D. (Damjan), Langford, C. (Cordelia), Hunt, S.E. (Sarah E.), Edkins, T. (Ted), Gwilliam, R. (Rhian), Blackburn, H. (Hannah), Bumpstead, S. (Suzannah), Dronov, S. (Serge), Gillman, M. (Matthew), Gray, E. (Emma), Hammond, N. (Naomi), Jayakumar, A. (Alagurevathi), McCann, O.T. (Owen), Liddle, J. (Jennifer), Potter, S.C. (Simon), Ravindrarajah, R. (Radhi), Ricketts, M. (Michelle), Waller, P. (Patrick), Weston, P. (Paul), Widaa, S. (Sara), Whittaker, P. (Pamela), Uitterlinden, A.G. (André), Vithana, E.N. (Eranga), Foster, P.J. (Paul), Hysi, P.G. (Pirro), Hewitt, A.W. (Alex W.), Khor, C.C., Pasquale, L.R. (Louis), Montgomery, G.W. (Grant W.), Klaver, C.C.W. (Caroline), Aung, T. (Tin), Pfeiffer, A.F.H. (Andreas), Mackey, D.A. (David), Hammond, C.J. (Christopher), Cheng, C.-Y. (Ching-Yu), Craig, J.E. (Jamie), Rabinowitz, Y.S. (Yaron), Wiggs, J.L. (Janey L.), Burdon, K.P. (Kathryn), Duijn, C.M. (Cornelia) van, MacGregor, S. (Stuart), Iglesias, A.I. (Adriana I.), Mishra, A. (Aniket), Vitart, V. (Veronique), Bykhovskaya, Y. (Yelena), Höhn, R. (René), Springelkamp, H. (Henriët), Cuellar-Partida, G. (Gabriel), Gharahkhani, P. (Puya), Bailey, J.N.C. (Jessica N. Cooke), Willoughby, C.E. (Colin E.), Li, X. (Xiaohui), Yazar, S. (Seyhan), Nag, A. (Abhishek), Khawaja, A.P. (Anthony), Polasek, O. (Ozren), Siscovick, D.S. (David), Mitchell, P. (Paul), Tham, Y.C. (Yih Chung), Haines, J.L. (Jonathan), Kearns, L.S. (Lisa S.), Hayward, C. (Caroline), Shi, Y. (Yuan), Van Leeuwen, E.M. (Elisabeth M.), Taylor, K.D. (Kent), Wang, J.J. (Jie Jin), Rochtchina, E. (Elena), Attia, J. (John), Scott, R. (Rodney), Holliday, E.G. (Elizabeth), Baird, P.N. (Paul), Xie, J. (Jing), Inouye, M. (Michael), Viswanathan, A. (Ananth), Sim, X. (Xueling), Bonnemaijer, P.W.M. (Pieter), Rotter, J.I. (Jerome I.), Martin, N.G. (Nicholas G.), Zeller, T. (Tanja), Mills, R.A. (Richard), Staffieri, S.E. (Sandra E.), Jonas, J.B. (Jost B.), Schmidtmann, I. (Irene), Boutin, T. (Thibaud), Kang, J.H. (Jae H.), Lucas, S.E.M. (Sionne E.M.), Wong, T.Y. (Tien Yin), Beutel, M.E. (Manfred E.), Wilson, J.F. (James F.), Allingham, R.R. (R Rand), Brilliant, M.H. (Murray H.), Budenz, D.L. (Donald L.), Christen, W.G. (William G.), Fingert, J. (John), Friedman, D.S. (David), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Hauser, M.A. (Michael), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Loomis, S.J. (Stephanie J.), Moroi, S.E. (Sayoko), Pericak-Vance, M.A. (Margaret), Realini, A. (Anthony), Richards, J.E. (Julia E.), Schuman, J.S. (Joel S.), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Weinreb, R.N. (Robert N.), Wollstein, G. (Gadi), Zack, D.J. (Donald), Zhang, K. (Kang), Donnelly, P. (Peter), Barroso, I.E. (Inês), Blackwell, J.M. (Jenefer M.), Bramon, E. (Elvira), Brown, M.A. (Matthew), Casas, J.P. (Juan), Corvin, A. (Aiden), Deloukas, P. (Panos), Duncanson, A. (Audrey), Jankowski, J. (Janusz), Markus, H.S. (Hugh), Mathew, J. (Joseph), Palmer, C.N.A. (Colin), Plomin, R. (Robert), Rautanen, A. (Anna), Sawcer, S.J. (Stephen), Trembath, R.C. (Richard), Wood, N.W. (Nicholas W.), Spencer, C.C.A. (Chris C.), Band, G. (Gavin), Bellenguez, C. (Céline), Freeman, C. (Colin), Hellenthal, F.A., Giannoulatou, E. (Eleni), Pirinen, M. (Matti), Pearson, R. (Ruth), Strange, A. (Amy), Su, Z. (Zhan), Vukcevic, D. (Damjan), Langford, C. (Cordelia), Hunt, S.E. (Sarah E.), Edkins, T. (Ted), Gwilliam, R. (Rhian), Blackburn, H. (Hannah), Bumpstead, S. (Suzannah), Dronov, S. (Serge), Gillman, M. (Matthew), Gray, E. (Emma), Hammond, N. (Naomi), Jayakumar, A. (Alagurevathi), McCann, O.T. (Owen), Liddle, J. (Jennifer), Potter, S.C. (Simon), Ravindrarajah, R. (Radhi), Ricketts, M. (Michelle), Waller, P. (Patrick), Weston, P. (Paul), Widaa, S. (Sara), Whittaker, P. (Pamela), Uitterlinden, A.G. (André), Vithana, E.N. (Eranga), Foster, P.J. (Paul), Hysi, P.G. (Pirro), Hewitt, A.W. (Alex W.), Khor, C.C., Pasquale, L.R. (Louis), Montgomery, G.W. (Grant W.), Klaver, C.C.W. (Caroline), Aung, T. (Tin), Pfeiffer, A.F.H. (Andreas), Mackey, D.A. (David), Hammond, C.J. (Christopher), Cheng, C.-Y. (Ching-Yu), Craig, J.E. (Jamie), Rabinowitz, Y.S. (Yaron), Wiggs, J.L. (Janey L.), Burdon, K.P. (Kathryn), Duijn, C.M. (Cornelia) van, and MacGregor, S. (Stuart)

Abstract

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

Published
2018
Full Text
View/download PDF

10. Psoriasis is associated with pleiotropic susceptibility loci identified in type II diabetes and Crohn disease

Author

Wolf, N., Quaranta, M., Prescott, N.J., Allen, M., Smith, R., Burden, A.D., Worthington, J., Griffiths, C.E.M., Mathew, C.G., Barker, J.N., Capon, F., and Trembath, R.C.

Subjects
Psoriasis -- Genetic aspects, Psoriasis -- Development and progression, Quantitative trait loci -- Research, Type 2 diabetes -- Genetic aspects, Crohn's disease -- Genetic aspects, Health
Published
2008

11. AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production

Author

Mahil, S.K., Twelves, S., Farkas, K., Setta-Kaffetzi, N., Burden, A.D., Gach, J.E., Irvine, A.D., Kepiro, L., Mockenhaupt, M., Oon, H.H., Pinner, J., Ranki, A., Seyger, M.M.B., Soler-Palacin, P., Storan, E.R., Tan, E.S., Valeyrie-Allanore, L., Young, H.S., Trembath, R.C., Choon, S.E., Szell, M., Bata-Csorgo, Z., Smith, C.H., Meglio, P. Di, Barker, J.N., Capon, F., Mahil, S.K., Twelves, S., Farkas, K., Setta-Kaffetzi, N., Burden, A.D., Gach, J.E., Irvine, A.D., Kepiro, L., Mockenhaupt, M., Oon, H.H., Pinner, J., Ranki, A., Seyger, M.M.B., Soler-Palacin, P., Storan, E.R., Tan, E.S., Valeyrie-Allanore, L., Young, H.S., Trembath, R.C., Choon, S.E., Szell, M., Bata-Csorgo, Z., Smith, C.H., Meglio, P. Di, Barker, J.N., and Capon, F.

Abstract

Contains fulltext : 172588.pdf (publisher's version ) (Open Access), Prominent skin involvement is a defining characteristic of autoinflammatory disorders caused by abnormal IL-1 signaling. However, the pathways and cell types that drive cutaneous autoinflammatory features remain poorly understood. We sought to address this issue by investigating the pathogenesis of pustular psoriasis, a model of autoinflammatory disorders with predominant cutaneous manifestations. We specifically characterized the impact of mutations affecting AP1S3, a disease gene previously identified by our group and validated here in a newly ascertained patient resource. We first showed that AP1S3 expression is distinctively elevated in keratinocytes. Because AP1S3 encodes a protein implicated in autophagosome formation, we next investigated the effects of gene silencing on this pathway. We found that AP1S3 knockout disrupts keratinocyte autophagy, causing abnormal accumulation of p62, an adaptor protein mediating NF-kappaB activation. We showed that as a consequence, AP1S3-deficient cells up-regulate IL-1 signaling and overexpress IL-36alpha, a cytokine that is emerging as an important mediator of skin inflammation. These abnormal immune profiles were recapitulated by pharmacological inhibition of autophagy and verified in patient keratinocytes, where they were reversed by IL-36 blockade. These findings show that keratinocytes play a key role in skin autoinflammation and identify autophagy modulation of IL-36 signaling as a therapeutic target.

Published
2016

19. IL36RN mutations define a severe autoinflammatory phenotype of generalized pustular psoriasis

Author

Hussain, S., Berki, D.M., Choon, S.E., Burden, A.D., Allen, M.H., Arostegui, J.I., Chaves, A., Duckworth, M., Irvine, A.D., Mockenhaupt, M., Navarini, A.A., Seyger, M.M.B., Soler-Palacin, P., Prins, C., Valeyrie-Allanore, L., Vicente, M.A., Trembath, R.C., Smith, C.H., Barker, J.N., Capon, F., Hussain, S., Berki, D.M., Choon, S.E., Burden, A.D., Allen, M.H., Arostegui, J.I., Chaves, A., Duckworth, M., Irvine, A.D., Mockenhaupt, M., Navarini, A.A., Seyger, M.M.B., Soler-Palacin, P., Prins, C., Valeyrie-Allanore, L., Vicente, M.A., Trembath, R.C., Smith, C.H., Barker, J.N., and Capon, F.

Abstract

Contains fulltext : 153039.pdf (publisher's version ) (Closed access)

Published
2015

20. Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci

Author

Tsoi, L.C., Spain, S.L., Ellinghaus, E., Stuart, P.E., Capon, F., Knight, J., Tejasvi, T., Kang, H.M., Allen, M.H., Lambert, S., Stoll, S.W., Weidinger, S., Gudjonsson, J.E., Kõks, S., Kingo, K., Esko, T., Das, S., Metspalu, A., Weichenthal, M., Enerbäck, C., Krueger, G.G., Voorhees, J.J., Chandran, V., Rosen, C.F., Rahman, P., Gladman, D.D., Reis, A., Nair, R.P., Franke, A., Barker, J.N.W.N., Abecasis, G.R., Trembath, R.C., Elder, J.T., Tsoi, L.C., Spain, S.L., Ellinghaus, E., Stuart, P.E., Capon, F., Knight, J., Tejasvi, T., Kang, H.M., Allen, M.H., Lambert, S., Stoll, S.W., Weidinger, S., Gudjonsson, J.E., Kõks, S., Kingo, K., Esko, T., Das, S., Metspalu, A., Weichenthal, M., Enerbäck, C., Krueger, G.G., Voorhees, J.J., Chandran, V., Rosen, C.F., Rahman, P., Gladman, D.D., Reis, A., Nair, R.P., Franke, A., Barker, J.N.W.N., Abecasis, G.R., Trembath, R.C., and Elder, J.T.

Abstract

Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (P<5 × 10−8). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies.

Published
2015

21. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus

Author

Su, Z., Gay, L.J., Strange, A., Palles, C., Band, G., Whiteman, D.C., Lescai, F., Langford, C., Nanji, M., Edkins, S., van der Winkel, A., Levine, D., Sasieni, P., Bellenguez, C., Howarth, K., Freeman, C., Trudgill, N., Tucker, A.T., Pirinen, M., Peppelenbosch, M.P., van der Laan, L.J.W., Kuipers, E.J., Drenth, J.P.H., Peters, W.H., Reynolds, J.V., Kelleher, D.P., McManus, R., Grabsch, H., Prenen, H., Bisschops, R., Krishnadath, K., Siersema, P.D., van Baal, J.W.P.M., Middleton, M., Petty, R., Gillies, R., Burch, N., Bhandari, P., Paterson, S., Edwards, C., Penman, I., Vaidya, K., Ang, Y., Murray, I., Patel, P., Ye, W., Mullins, P., Wu, A.H., Bird, N.C., Dallal, H., Shaheen, N.J., Murray, L.J., Koss, K., Bernstein, L., Romero, Y., Hardie, L.J., Zhang, R., Winter, H., Corley, D.A., Panter, S., Risch, H.A., Reid, B.J., Sargeant, I., Gammon, M.D., Smart, H., Dhar, A., McMurtry, H., Ali, H., Liu, G., Casson, A.G., Chow, W.-H., Rutter, M., Tawil, A., Morris, D., Nwokolo, C., Isaacs, P., Rodgers, C., Ragunath, K., MacDonald, C., Haigh, C., Monk, D., Davies, G., Wajed, S., Johnston, D., Gibbons, M., Cullen, S., Church, N., Langley, R., Griffin, M., Alderson, D., Deloukas, P., Hunt, S.E., Gray, E., Dronov, S., Potter, S.C., Tashakkori-Ghanbaria, A., Anderson, M., Brooks, C., Blackwell, J.M., Bramon, E., Brown, M.A., Casas, J.P., Corvin, A., Duncanson, A., Markus, H.S., Mathew, C.G., Palmer, C.N.A., Plomin, R., Rautanen, A., Sawcer, S.J., Trembath, R.C., Viswanathan, A.C., Wood, N., Trynka, G., Wijmenga, C., Cazier, J.-B., Atherfold, P., Nicholson, A.M., Gellatly, N.L., Glancy, D., Cooper, S.C., Cunningham, D., Lind, T., Hapeshi, J., Ferry, D., Rathbone, B., Brown, J., Love, S., Attwood, S., MacGregor, S., Watson, P., Sanders, S., Ek, W., Harrison, R.F., Moayyedi, P., de Caestecker, J., Barr, H., Stupka, E., Vaughan, T.L., Peltonen, L., Spencer, C.C.A., Tomlinson, I., Donnelly, P., Jankowski, J.A.Z., Genetics, E.A., and Consor, W.T.C.C.

Subjects
digestive system diseases
Abstract

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined = 4.09 × 10−9; odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13–1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined = 2.74 × 10−10; OR = 1.14, 95% CI = 1.10–1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

Published
2012

22. AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking

Author

Setta-Kaffetzi, N., Simpson, M.A., Navarini, A.A., Patel, V.M., Lu, H.C., Allen, M.H., Duckworth, M., Bachelez, H., Burden, A.D., Choon, S.E., Griffiths, C.E., Kirby, B., Kolios, A., Seyger, M.M.B., Prins, C., Smahi, A., Trembath, R.C., Fraternali, F., Smith, C.H., Barker, J.N., Capon, F., Setta-Kaffetzi, N., Simpson, M.A., Navarini, A.A., Patel, V.M., Lu, H.C., Allen, M.H., Duckworth, M., Bachelez, H., Burden, A.D., Choon, S.E., Griffiths, C.E., Kirby, B., Kolios, A., Seyger, M.M.B., Prins, C., Smahi, A., Trembath, R.C., Fraternali, F., Smith, C.H., Barker, J.N., and Capon, F.

Abstract

Contains fulltext : 138240.pdf (publisher's version ) (Closed access), Adaptor protein complex 1 (AP-1) is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes. The knockout of most murine AP-1 complex subunits is embryonically lethal, so the identification of human disease-associated alleles has the unique potential to deliver insights into gene function. Here, we report two founder mutations (c.11T>G [p.Phe4Cys] and c.97C>T [p.Arg33Trp]) in AP1S3, the gene encoding AP-1 complex subunit sigma1C, in 15 unrelated individuals with a severe autoinflammatory skin disorder known as pustular psoriasis. Because the variants are predicted to destabilize the 3D structure of the AP-1 complex, we generated AP1S3-knockdown cell lines to investigate the consequences of AP-1 deficiency in skin keratinocytes. We found that AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like receptor 3) and resulted in a marked inhibition of downstream signaling. These findings identify pustular psoriasis as an autoinflammatory phenotype caused by defects in vesicular trafficking and demonstrate a requirement of AP-1 for Toll-like receptor homeostasis.

Published
2014

23. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Author

Postmus, D. (Douwe), Trompet, S. (Stella), Deshmukh, H. (Harshal), Barnes, M.J. (Michael), Li, X. (Xiaohui), Warren, H. (Helen), Chasman, D.I. (Daniel), Zhou, K. (Kaixin), Arsenault, B.J. (Benoit J.), Donnelly, L.A. (Louise), Wiggins, K.L. (Kerri), Avery, C.L., Griffin, P. (Paula), Feng, Q. (Qiping), Taylor, K.D. (Kent), Li, G. (Guo), Evans, D.S. (Daniel), Smith, A.V. (Davey), Keyser, C.E. (Catherina Elisabeth) de, Johnson, A.D. (Andrew), Craen, A.J. (Anton) de, Stott, D.J. (David. J.), Buckley, B.M. (Brendan M.), Ford, I., Westendorp, R.G.J. (Rudi), Slagboom, P.E. (Eline), Sattar, N. (Naveed), Munroe, P. (Patricia), Sever, P. (Peter), Poulter, N.R. (Neil), Stanton, A. (Alice), Shields, D.C. (Denis C.), O'Brien, E. (Eoin), Shaw-Hawkins, S. (Sue), Chen, Y.-D.I. (Ida), Nickerson, D.A. (Deborah), Smith, J.D. (Joshua D.), Dubé, G.P. (Gregory), Boekholdt, S.M. (Matthijs), Hovingh, G.K. (Kees), Kastelein, J.J.P. (John), Mckeigue, P.M. (Paul), Betteridge, J. (John), Neil, A. (Andrew), Durrington, P.N. (Paul), Doney, A.S.F. (Alex), Carr, F. (Fiona), Morris, A.D. (Andrew), McCarthy, M.I. (Mark), Groop, L. (Leif), Ahlqvist, E. (Emma), Barroso, I.E. (Inês), Blackwell, K.L. (Kimberly), Bramon, E. (Elvira), Brown, M.A. (Matthew), Casas, J.P. (Juan), Corvin, A. (Aiden), Deloukas, P. (Panagiotis), Duncanson, A. (Audrey), Jankowski, J.A. (Janusz Antoni), Markus, H.S. (Hugh), Mathew, C.G. (Christopher G.), Palmer, C.N.A. (Colin), Plomin, R. (Robert), Rautanen, A. (Anna), Sawcer, S.J. (Stephen), Trembath, R.C. (Richard), Viswanathan, A.C. (Ananth), Wood, N.W. (Nicholas), Spencer, C.C.A. (Chris C.), Band, G. (Gavin), Bellenguez, C. (Céline), Freeman, C. (Colin), Hellenthal, F.A., Giannoulatou, E. (Eleni), Pirinen, M. (Matti), Pearson, R. (Ruth), Strange, A. (Amy), Su, Z. (Zhan), Vukcevic, D. (Damjan), Donnelly, P. (Peter), Langford, C. (Cordelia), Hunt, S.E. (Sarah), Edkins, T. (Ted), Gwilliam, R. (Rhian), Blackburn, H. (Hannah), Bumpstead, S. (Suzannah), Dronov, S. (Serge), Gillman, M. (Matthew), Gray, E. (Emma), Hammond, N. (Naomi), Jayakumar, A. (Alagurevathi), McCann, O.T. (Owen), Liddle, J. (Jennifer), Potter, S.C. (Simon), Ravindrarajah, R. (Radhi), Ricketts, M. (Michelle), Waller, M. (Matthew), Weston, P. (Paul), Widaa, S. (Sara), Whittaker, P. (Pamela), Bis, J.C. (Joshua), Rice, K.M. (Kenneth), Smith, N.L. (Nicholas), Lumley, T. (Thomas), Whitsel, E.A. (Eric), Stürmer, T., Boerwinkle, E.A. (Eric), Ngwa, J.S., O'Donnell, C.J. (Christopher J.), Vasan, R.S. (Ramachandran Srini), Wei, W.-Q. (Wei-Qi), Wilke, R.A. (Russell A.), Liu, C.-T. (Ching-Ti), Sun, F. (Fangui), Guo, X. (Xiuqing), Heckbert, S.R. (Susan), Post, W. (Wendy), Sotoodehnia, N. (Nona), Arnold, A.M. (Alice), Stafford, J.M. (Jeanette M.), Ding, J. (Jingzhong), Herrington, D.M. (David), Kritchevsky, S.B. (Stephen), Eiriksdottir, G. (Gudny), Launer, L.J. (Lenore), Harris, T.B. (Tamara), Chu, A.Y. (Audrey), Giulianini, F. (Franco), MacFadyen, J.G. (Jean G.), Barratt, B.J. (Bryan J.), Nyberg, F. (Fredrik), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Hofman, A. (Albert), Rivadeneira Ramirez, F. (Fernando), Emilsson, V. (Valur), Franco, O.H. (Oscar), Ridker, P.M. (Paul), Gudnason, V. (Vilmundur), Liu, Y. (YongMei), Denny, J.C. (Joshua C.), Ballantyne, C. (Christie), Rotter, J.I. (Jerome I.), Cupples, L.A. (Adrienne), Psaty, B.M. (Bruce), Tardif, J.-C. (Jean-Claude), Colhoun, H.M. (H.), Hitman, G.A. (Graham), Krauss, R.M. (Ronald), Jukema, J.W. (Jan Wouter), Caulfield, M. (Mark), Postmus, D. (Douwe), Trompet, S. (Stella), Deshmukh, H. (Harshal), Barnes, M.J. (Michael), Li, X. (Xiaohui), Warren, H. (Helen), Chasman, D.I. (Daniel), Zhou, K. (Kaixin), Arsenault, B.J. (Benoit J.), Donnelly, L.A. (Louise), Wiggins, K.L. (Kerri), Avery, C.L., Griffin, P. (Paula), Feng, Q. (Qiping), Taylor, K.D. (Kent), Li, G. (Guo), Evans, D.S. (Daniel), Smith, A.V. (Davey), Keyser, C.E. (Catherina Elisabeth) de, Johnson, A.D. (Andrew), Craen, A.J. (Anton) de, Stott, D.J. (David. J.), Buckley, B.M. (Brendan M.), Ford, I., Westendorp, R.G.J. (Rudi), Slagboom, P.E. (Eline), Sattar, N. (Naveed), Munroe, P. (Patricia), Sever, P. (Peter), Poulter, N.R. (Neil), Stanton, A. (Alice), Shields, D.C. (Denis C.), O'Brien, E. (Eoin), Shaw-Hawkins, S. (Sue), Chen, Y.-D.I. (Ida), Nickerson, D.A. (Deborah), Smith, J.D. (Joshua D.), Dubé, G.P. (Gregory), Boekholdt, S.M. (Matthijs), Hovingh, G.K. (Kees), Kastelein, J.J.P. (John), Mckeigue, P.M. (Paul), Betteridge, J. (John), Neil, A. (Andrew), Durrington, P.N. (Paul), Doney, A.S.F. (Alex), Carr, F. (Fiona), Morris, A.D. (Andrew), McCarthy, M.I. (Mark), Groop, L. (Leif), Ahlqvist, E. (Emma), Barroso, I.E. (Inês), Blackwell, K.L. (Kimberly), Bramon, E. (Elvira), Brown, M.A. (Matthew), Casas, J.P. (Juan), Corvin, A. (Aiden), Deloukas, P. (Panagiotis), Duncanson, A. (Audrey), Jankowski, J.A. (Janusz Antoni), Markus, H.S. (Hugh), Mathew, C.G. (Christopher G.), Palmer, C.N.A. (Colin), Plomin, R. (Robert), Rautanen, A. (Anna), Sawcer, S.J. (Stephen), Trembath, R.C. (Richard), Viswanathan, A.C. (Ananth), Wood, N.W. (Nicholas), Spencer, C.C.A. (Chris C.), Band, G. (Gavin), Bellenguez, C. (Céline), Freeman, C. (Colin), Hellenthal, F.A., Giannoulatou, E. (Eleni), Pirinen, M. (Matti), Pearson, R. (Ruth), Strange, A. (Amy), Su, Z. (Zhan), Vukcevic, D. (Damjan), Donnelly, P. (Peter), Langford, C. (Cordelia), Hunt, S.E. (Sarah), Edkins, T. (Ted), Gwilliam, R. (Rhian), Blackburn, H. (Hannah), Bumpstead, S. (Suzannah), Dronov, S. (Serge), Gillman, M. (Matthew), Gray, E. (Emma), Hammond, N. (Naomi), Jayakumar, A. (Alagurevathi), McCann, O.T. (Owen), Liddle, J. (Jennifer), Potter, S.C. (Simon), Ravindrarajah, R. (Radhi), Ricketts, M. (Michelle), Waller, M. (Matthew), Weston, P. (Paul), Widaa, S. (Sara), Whittaker, P. (Pamela), Bis, J.C. (Joshua), Rice, K.M. (Kenneth), Smith, N.L. (Nicholas), Lumley, T. (Thomas), Whitsel, E.A. (Eric), Stürmer, T., Boerwinkle, E.A. (Eric), Ngwa, J.S., O'Donnell, C.J. (Christopher J.), Vasan, R.S. (Ramachandran Srini), Wei, W.-Q. (Wei-Qi), Wilke, R.A. (Russell A.), Liu, C.-T. (Ching-Ti), Sun, F. (Fangui), Guo, X. (Xiuqing), Heckbert, S.R. (Susan), Post, W. (Wendy), Sotoodehnia, N. (Nona), Arnold, A.M. (Alice), Stafford, J.M. (Jeanette M.), Ding, J. (Jingzhong), Herrington, D.M. (David), Kritchevsky, S.B. (Stephen), Eiriksdottir, G. (Gudny), Launer, L.J. (Lenore), Harris, T.B. (Tamara), Chu, A.Y. (Audrey), Giulianini, F. (Franco), MacFadyen, J.G. (Jean G.), Barratt, B.J. (Bryan J.), Nyberg, F. (Fredrik), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Hofman, A. (Albert), Rivadeneira Ramirez, F. (Fernando), Emilsson, V. (Valur), Franco, O.H. (Oscar), Ridker, P.M. (Paul), Gudnason, V. (Vilmundur), Liu, Y. (YongMei), Denny, J.C. (Joshua C.), Ballantyne, C. (Christie), Rotter, J.I. (Jerome I.), Cupples, L.A. (Adrienne), Psaty, B.M. (Bruce), Tardif, J.-C. (Jean-Claude), Colhoun, H.M. (H.), Hitman, G.A. (Graham), Krauss, R.M. (Ronald), Jukema, J.W. (Jan Wouter), and Caulfield, M. (Mark)

Published
2014
Full Text
View/download PDF

25. Rare Pathogenic Variants in IL36RN Underlie a Spectrum of Psoriasis-Associated Pustular Phenotypes

Author

Setta-Kaffetzi, N., Navarini, A.A., Patel, V.M., Pullabhatla, V., Pink, A.E., Choon, S.E., Allen, M.A., Burden, A.D., Griffiths, C.E., Seijger, M.M.B., Kirby, B., Trembath, R.C., Simpson, M.A., Smith, C.H., Capon, F., Barker, J.N., Setta-Kaffetzi, N., Navarini, A.A., Patel, V.M., Pullabhatla, V., Pink, A.E., Choon, S.E., Allen, M.A., Burden, A.D., Griffiths, C.E., Seijger, M.M.B., Kirby, B., Trembath, R.C., Simpson, M.A., Smith, C.H., Capon, F., and Barker, J.N.

Abstract

Item does not contain fulltext

Published
2013

26. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

Author

Tsoi, L.C., Spain, S.L., Knight, J., Ellinghaus, E., Stuart, P.E., Capon, F., Ding, J., Li, Y., Tejasvi, T., Gudjonsson, J.E., Kang, H.M., Allen, M.H., McManus, R., Novelli, G., Samuelsson, L., Schalkwijk, J., Ståhle, M., Burden, A.D., Smith, C.H., Cork, M.J., Estivill, X., Bowcock, A.M., Krueger, G.G., Weger, W., Worthington, J., Tazi-Ahnini, R., Nestle, F.O., Hayday, A., Hoffmann, P., Winkelmann, J., Wijmenga, C., Langford, C., Edkins, S., Andrews, R., Blackburn, H., Strange, A., Band, G., Pearson, R.D., Vukcevic, D., Spencer, C.C.A., Deloukas, P., Mrowietz, U., Schreiber, S., Weidinger, S., Kõks, S., Kingo, K., Esko, T., Metspalu, A., Lim, H.W., Voorhees, J.J., Weichenthal, M., Wichmann, H.E., Chandran, V., Rosen, C.F., Rahman, P., Gladman, D.D., Griffiths, C.E.M., Reis, A., Kere, J., Nair, R.P., Franke, A., Barker, J.N.W.N., Abecasis, G.R., Elder, J.T., Trembath, R.C., Tsoi, L.C., Spain, S.L., Knight, J., Ellinghaus, E., Stuart, P.E., Capon, F., Ding, J., Li, Y., Tejasvi, T., Gudjonsson, J.E., Kang, H.M., Allen, M.H., McManus, R., Novelli, G., Samuelsson, L., Schalkwijk, J., Ståhle, M., Burden, A.D., Smith, C.H., Cork, M.J., Estivill, X., Bowcock, A.M., Krueger, G.G., Weger, W., Worthington, J., Tazi-Ahnini, R., Nestle, F.O., Hayday, A., Hoffmann, P., Winkelmann, J., Wijmenga, C., Langford, C., Edkins, S., Andrews, R., Blackburn, H., Strange, A., Band, G., Pearson, R.D., Vukcevic, D., Spencer, C.C.A., Deloukas, P., Mrowietz, U., Schreiber, S., Weidinger, S., Kõks, S., Kingo, K., Esko, T., Metspalu, A., Lim, H.W., Voorhees, J.J., Weichenthal, M., Wichmann, H.E., Chandran, V., Rosen, C.F., Rahman, P., Gladman, D.D., Griffiths, C.E.M., Reis, A., Kere, J., Nair, R.P., Franke, A., Barker, J.N.W.N., Abecasis, G.R., Elder, J.T., and Trembath, R.C.

Abstract

To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.

Published
2012

27. Conditional analysis identifies three novel major histocompatibility complex loci associated with psoriasis

Author

Knight, J., Spain, S.L., Capon, F., Hayday, A., Nestle, F.O., Clop, A., Barker, J.N., Weale, M.E., Trembath, R.C., Donnelly, P., Bergboer, J.G.M., et al., Knight, J., Spain, S.L., Capon, F., Hayday, A., Nestle, F.O., Clop, A., Barker, J.N., Weale, M.E., Trembath, R.C., Donnelly, P., Bergboer, J.G.M., and et al.

Abstract

Item does not contain fulltext, Psoriasis is a common, chronic, inflammatory skin disorder. A number of genetic loci have been shown to confer risk for psoriasis. Collectively, these offer an integrated model for the inherited basis for susceptibility to psoriasis that combines altered skin barrier function together with the dysregulation of innate immune pathogen sensing and adap-tive immunity. The major histocompatibility complex (MHC) harbours the psoriasis susceptibility region which exhibits the largest effect size, driven in part by variation contained on the HLA-Cw*0602 allele. However, the resolution of the number and genomic location of potential independent risk loci are hampered by extensive linkage disequilibrium across the region. We leveraged the power of large psoriasis case and control data sets and the statistical approach of conditional analysis to identify potential further association signals distributed across the MHC. In addition to the major loci at HLA-C (P = 2.20 × 10(-236)), we observed and replicated four additional independent signals for disease association, three of which are novel. We detected evidence for association at SNPs rs2507971 (P = 6.73 × 10(-14)), rs9260313 (P = 7.93 × 10(-09)), rs66609536 (P = 3.54 × 10(-07)) and rs380924 (P = 6.24 × 10(-06)), located within the class I region of the MHC, with each observation replicated in an independent sample (P ≤ 0.01). The previously identified locus is close to MICA, the other three lie near MICB, HLA-A and HCG9 (a non-coding RNA gene). The identification of disease associations with both MICA and MICB is particularly intriguing, since each encodes an MHC class I-related protein with potent immunological function.

Published
2012

28. De novo mutations of the gene encoding the histone acetyltransferase KAT6B cause Genitopatellar syndrome

Author

Simpson, M.A., Deshpande, C., Dafou, D., Peart-Vissers, L.E.L.M., Woollard, W.J., Holder, S.E., Gillessen-Kaesbach, G., Derks, R., White, S.M., Cohen-Snuijf, R., Kant, S.G., Hoefsloot, L.H., Reardon, W., Brunner, H.G., Bongers, E.M., Trembath, R.C., Simpson, M.A., Deshpande, C., Dafou, D., Peart-Vissers, L.E.L.M., Woollard, W.J., Holder, S.E., Gillessen-Kaesbach, G., Derks, R., White, S.M., Cohen-Snuijf, R., Kant, S.G., Hoefsloot, L.H., Reardon, W., Brunner, H.G., Bongers, E.M., and Trembath, R.C.

Abstract

Item does not contain fulltext, Genitopatellar syndrome (GPS) is a rare disorder in which patellar aplasia or hypoplasia is associated with external genital anomalies and severe intellectual disability. Using an exome-sequencing approach, we identified de novo mutations of KAT6B in five individuals with GPS; a single nonsense variant and three frameshift indels, including a 4 bp deletion observed in two cases. All identified mutations are located within the terminal exon of the gene and are predicted to generate a truncated protein product lacking evolutionarily conserved domains. KAT6B encodes a member of the MYST family of histone acetyltranferases. We demonstrate a reduced level of both histone H3 and H4 acetylation in patient-derived cells suggesting that dysregulation of histone acetylation is a direct functional consequence of GPS alleles. These findings define the genetic basis of GPS and illustrate the complex role of the regulation of histone acetylation during development.

Published
2012

29. Combined analysis of Genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci

Author

Ellinghaus, D., Ellinghaus, E., Nair, R.P., Stuart, P.E., Esko, T., Metspalu, A., Debrus, S., Raelson, J.V., Tejasvi, T., Belouchi, M., West, S.L., Barker, J.N., Kõks, S., Kingo, K., Balschun, T., Palmieri, O., Annese, V., Gieger, C., Wichmann, H.E., Kabesch, M., Trembath, R.C., Mathew, C.G., Abecasis, G.R., Weidinger, S., Nikolaus, S., Schreiber, S., Elder, J.T., Weichenthal, M., Nothnagel, M., Franke, A., Ellinghaus, D., Ellinghaus, E., Nair, R.P., Stuart, P.E., Esko, T., Metspalu, A., Debrus, S., Raelson, J.V., Tejasvi, T., Belouchi, M., West, S.L., Barker, J.N., Kõks, S., Kingo, K., Balschun, T., Palmieri, O., Annese, V., Gieger, C., Wichmann, H.E., Kabesch, M., Trembath, R.C., Mathew, C.G., Abecasis, G.R., Weidinger, S., Nikolaus, S., Schreiber, S., Elder, J.T., Weichenthal, M., Nothnagel, M., and Franke, A.

Abstract

Psoriasis (PS) and Crohn disease (CD) have been shown to be epidemiologically, pathologically, and therapeutically connected, but little is known about their shared genetic causes. We performed meta-analyses of five published genome-wide association studies on PS (2,529 cases and 4,955 controls) and CD (2,142 cases and 5,505 controls), followed up 20 loci that showed strongest evidence for shared disease association and, furthermore, tested cross-disease associations for previously reported PS and CD risk alleles in additional 6,115 PS cases, 4,073 CD cases, and 10,100 controls. We identified seven susceptibility loci outside the human leukocyte antigen region (9p24 near JAK2, 10q22 at ZMIZ1, 11q13 near PRDX5, 16p13 near SOCS1, 17q21 at STAT3, 19p13 near FUT2, and 22q11 at YDJC) shared between PS and CD with genome-wide significance (p < 5 × 10−8) and confirmed four already established PS and CD risk loci (IL23R, IL12B, REL, and TYK2). Three of the shared loci are also genome-wide significantly associated with PS alone (10q22 at ZMIZ1, prs1250544 = 3.53 × 10−8, 11q13 near PRDX5, prs694739 = 3.71 × 10−09, 22q11 at YDJC, prs181359 = 8.02 × 10−10). In addition, we identified one susceptibility locus for CD (16p13 near SOCS1, prs4780355 = 4.99 × 10−8). Refinement of association signals identified shared genome-wide significant associations for exonic SNPs at 10q22 (ZMIZ1) and in silico expression quantitative trait locus analyses revealed that the associations at ZMIZ1 and near SOCS1 have a potential functional effect on gene expression. Our results show the usefulness of joint analyses of clinically distinct immune-mediated diseases and enlarge the map of shared genetic risk loci.

Published
2012

30. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy

Author

Ostergaard, P., Simpson, M.A., Mendola, A., Vasudevan, P., Connell, F.C., van Impel, A., Moore, A.T., Loeys, B.L., Ghalamkarpour, A., Onoufriadis, A., Martinez-Corral, I., Devery, S., Leroy, J.G., Van Laer, L., Singer, A., Bialer, M.G., McEntagart, M., Quarrell, O., Brice, G., Trembath, R.C., Schulte-Merker, S., Makinen, T., Vikkula, M., Mortimer, P.S., Mansour, S., Jeffery, S., Ostergaard, P., Simpson, M.A., Mendola, A., Vasudevan, P., Connell, F.C., van Impel, A., Moore, A.T., Loeys, B.L., Ghalamkarpour, A., Onoufriadis, A., Martinez-Corral, I., Devery, S., Leroy, J.G., Van Laer, L., Singer, A., Bialer, M.G., McEntagart, M., Quarrell, O., Brice, G., Trembath, R.C., Schulte-Merker, S., Makinen, T., Vikkula, M., Mortimer, P.S., Mansour, S., and Jeffery, S.

Abstract

Item does not contain fulltext, We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a microcephaly-lymphedema-chorioretinal-dysplasia cohort. Subsequent Sanger sequencing of KIF11 in a further 15 unrelated microcephalic probands with lymphedema and/or chorioretinopathy identified additional heterozygous mutations in 12 of them. KIF11 encodes EG5, a homotetramer kinesin motor. The variety of mutations we have found (two nonsense, two splice site, four missense, and six indels causing frameshifts) are all predicted to have an impact on protein function. EG5 has previously been shown to play a role in spindle assembly and function, and these findings highlight the critical role of proteins necessary for spindle formation in CNS development. Moreover, identification of KIF11 mutations in patients with chorioretinopathy and lymphedema suggests that EG5 is involved in the development and maintenance of retinal and lymphatic structures.

Published
2012

31. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Author

Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C.C.A., Patsopoulos, N.A., Moutsianas, L., Dilthey, A., Su, Z., Freeman, C., Hunt, S.E., Edkins, S., Gray, E., Booth, D.R., Potter, S.C., Goris, A., Band, G., Bang Oturai, A., Strange, A., Saarela, J., Bellenguez, C., Fontaine, B., Gillman, M., Hemmer, B., Gwilliam, R., Zipp, F., Jayakumar, A., Martin, R., Leslie, S., Hawkins, S., Giannoulatou, E., D’alfonso, S., Blackburn, H., Martinelli Boneschi, F., Liddle, J., Harbo, H.F., Perez, M.L., Spurkland, A., Waller, M.J., Mycko, M.P., Ricketts, M., Comabella, M., Hammond, N., Kockum, I., McCann, O.T., Ban, M., Whittaker, P., Kemppinen, A., Weston, P., Hawkins, C., Widaa, S., Zajicek, J., Dronov, S., Robertson, N., Bumpstead, S.J., Barcellos, L.F., Ravindrarajah, R., Abraham, R., Alfredsson, L., Ardlie, K., Aubin, C., Baker, A., Baker, K., Baranzini, S.E., Bergamaschi, L., Bergamaschi, R., Bernstein, A., Berthele, A., Boggild, M., Bradfield, J.P., Brassat, D., Broadley, S.A., Buck, D., Butzkueven, H., Capra, R., Carroll, W.M., Cavalla, P., Celius, E.G., Cepok, S., Chiavacci, R., Clerget-Darpoux, F., Clysters, K., Comi, G., Cossburn, M., Cournu-Rebeix, I., Cox, M.B., Cozen, W., Cree, B.A.C., Cross, A.H., Cusi, D., Daly, M.J., Davis, E., de Bakker, P.I.W., Debouverie, M., D’hooghe, M.B., Dixon, K., Dobosi, R., Dubois, B., Ellinghaus, D., Elovaara, I., Esposito, F., Fontenille, C., Foote, S., Franke, A., Galimberti, D., Ghezzi, A., Glessner, J., Gomez, R., Gout, O., Graham, C., Grant, S.F.A., Rosa Guerini, F., Hakonarson, H., Hall, P., Hamsten, A., Hartung, H-P, Heard, R.N., Heath, S., Hobart, J., Hoshi, M., Infante-Duarte, C., Ingram, G., Ingram, W., Islam, T., Jagodic, M., Kabesch, M., Kermode, A.G., Kilpatrick, T.J., Kim, C., Klopp, N., Koivisto, K., Larsson, M., Lathrop, M., Lechner-Scott, J.S., Leone, M.A., Leppä, V., Liljedahl, U., Lima Bomfim, I., Lincoln, R.R., Link, J., Liu, J., Lorentzen, Å.R., Lupoli, S., Macciardi, F., Mack, T., Marriott, M., Martinelli, V., Mason, D., McCauley, J.L., Mentch, F., Mero, I-L, Mihalova, T., Montalban, X., Mottershead, J., Myhr, K-M, Naldi, P., Ollier, W., Page, A., Palotie, A., Pelletier, J., Piccio, L., Pickersgill, T., Piehl, F., Pobywajlo, S., Quach, H.L., Ramsay, P.P., Reunanen, M., Reynolds, R., Rioux, J.D., Rodegher, M., Roesner, S., Rubio, J.P., Rückert, I-M, Salvetti, M., Salvi, E., Santaniello, A., Schaefer, C.A., Schreiber, S., Schulze, C., Scott, R.J., Sellebjerg, F., Selmaj, K.W., Sexton, D., Shen, L., Simms-Acuna, B., Skidmore, S., Sleiman, P.M.A., Smestad, C., Sørensen, P.S., Søndergaard, H.B., Stankovich, J., Strange, R.C., Sulonen, A-M, Sundqvist, E., Syvänen, A-C, Taddeo, F., Taylor, B., Blackwell, J.M., Tienari, P., Bramon, E., Tourbah, A., Brown, M.A., Tronczynska, E., Casas, J.P., Tubridy, N., Corvin, A., Vickery, J., Jankowski, J., Villoslada, P., Markus, H.S., Wang, K., Mathew, C.G., Wason, J., Palmer, C.N.A., Wichmann, H-E, Plomin, R., Willoughby, E., Rautanen, A., Winkelmann, J., Wittig, M., Trembath, R.C., Yaouanq, J., Viswanathan, A.C., Zhang, H., Wood, N.W., Zuvich, R., Deloukas, P., Langford, C., Duncanson, A., Oksenberg, J.R., Pericak-Vance, M.A., Haines, J.L., Olsson, T., Hillert, J., Ivinson, A.J., De Jager, P.L., Peltonen, L., Stewart, G.J., Hafler, D.A., Hauser, S.L., McVean, G., Donnelly, P., Compston, A., Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C.C.A., Patsopoulos, N.A., Moutsianas, L., Dilthey, A., Su, Z., Freeman, C., Hunt, S.E., Edkins, S., Gray, E., Booth, D.R., Potter, S.C., Goris, A., Band, G., Bang Oturai, A., Strange, A., Saarela, J., Bellenguez, C., Fontaine, B., Gillman, M., Hemmer, B., Gwilliam, R., Zipp, F., Jayakumar, A., Martin, R., Leslie, S., Hawkins, S., Giannoulatou, E., D’alfonso, S., Blackburn, H., Martinelli Boneschi, F., Liddle, J., Harbo, H.F., Perez, M.L., Spurkland, A., Waller, M.J., Mycko, M.P., Ricketts, M., Comabella, M., Hammond, N., Kockum, I., McCann, O.T., Ban, M., Whittaker, P., Kemppinen, A., Weston, P., Hawkins, C., Widaa, S., Zajicek, J., Dronov, S., Robertson, N., Bumpstead, S.J., Barcellos, L.F., Ravindrarajah, R., Abraham, R., Alfredsson, L., Ardlie, K., Aubin, C., Baker, A., Baker, K., Baranzini, S.E., Bergamaschi, L., Bergamaschi, R., Bernstein, A., Berthele, A., Boggild, M., Bradfield, J.P., Brassat, D., Broadley, S.A., Buck, D., Butzkueven, H., Capra, R., Carroll, W.M., Cavalla, P., Celius, E.G., Cepok, S., Chiavacci, R., Clerget-Darpoux, F., Clysters, K., Comi, G., Cossburn, M., Cournu-Rebeix, I., Cox, M.B., Cozen, W., Cree, B.A.C., Cross, A.H., Cusi, D., Daly, M.J., Davis, E., de Bakker, P.I.W., Debouverie, M., D’hooghe, M.B., Dixon, K., Dobosi, R., Dubois, B., Ellinghaus, D., Elovaara, I., Esposito, F., Fontenille, C., Foote, S., Franke, A., Galimberti, D., Ghezzi, A., Glessner, J., Gomez, R., Gout, O., Graham, C., Grant, S.F.A., Rosa Guerini, F., Hakonarson, H., Hall, P., Hamsten, A., Hartung, H-P, Heard, R.N., Heath, S., Hobart, J., Hoshi, M., Infante-Duarte, C., Ingram, G., Ingram, W., Islam, T., Jagodic, M., Kabesch, M., Kermode, A.G., Kilpatrick, T.J., Kim, C., Klopp, N., Koivisto, K., Larsson, M., Lathrop, M., Lechner-Scott, J.S., Leone, M.A., Leppä, V., Liljedahl, U., Lima Bomfim, I., Lincoln, R.R., Link, J., Liu, J., Lorentzen, Å.R., Lupoli, S., Macciardi, F., Mack, T., Marriott, M., Martinelli, V., Mason, D., McCauley, J.L., Mentch, F., Mero, I-L, Mihalova, T., Montalban, X., Mottershead, J., Myhr, K-M, Naldi, P., Ollier, W., Page, A., Palotie, A., Pelletier, J., Piccio, L., Pickersgill, T., Piehl, F., Pobywajlo, S., Quach, H.L., Ramsay, P.P., Reunanen, M., Reynolds, R., Rioux, J.D., Rodegher, M., Roesner, S., Rubio, J.P., Rückert, I-M, Salvetti, M., Salvi, E., Santaniello, A., Schaefer, C.A., Schreiber, S., Schulze, C., Scott, R.J., Sellebjerg, F., Selmaj, K.W., Sexton, D., Shen, L., Simms-Acuna, B., Skidmore, S., Sleiman, P.M.A., Smestad, C., Sørensen, P.S., Søndergaard, H.B., Stankovich, J., Strange, R.C., Sulonen, A-M, Sundqvist, E., Syvänen, A-C, Taddeo, F., Taylor, B., Blackwell, J.M., Tienari, P., Bramon, E., Tourbah, A., Brown, M.A., Tronczynska, E., Casas, J.P., Tubridy, N., Corvin, A., Vickery, J., Jankowski, J., Villoslada, P., Markus, H.S., Wang, K., Mathew, C.G., Wason, J., Palmer, C.N.A., Wichmann, H-E, Plomin, R., Willoughby, E., Rautanen, A., Winkelmann, J., Wittig, M., Trembath, R.C., Yaouanq, J., Viswanathan, A.C., Zhang, H., Wood, N.W., Zuvich, R., Deloukas, P., Langford, C., Duncanson, A., Oksenberg, J.R., Pericak-Vance, M.A., Haines, J.L., Olsson, T., Hillert, J., Ivinson, A.J., De Jager, P.L., Peltonen, L., Stewart, G.J., Hafler, D.A., Hauser, S.L., McVean, G., Donnelly, P., and Compston, A.

Abstract

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability1. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals2, 3, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk4. Modestly powered genome-wide association studies (GWAS)5, 6, 7, 8, 9, 10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility11. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Published
2011

32. Meta-analysis confirms the LCE3C_LCE3B deletion as a risk factor for psoriasis in several ethnic groups and finds interaction with HLA-Cw6

Author

Riveira-Munoz, E., He, S.M., Escaramis, G., Stuart, P.E., Huffmeier, U., Lee, C., Kirby, B., Oka, A., Giardina, E., Liao, W., Bergboer, J.G.M., Kainu, K., Cid, R. de, Munkhbat, B., Zeeuwen, P.L.J.M., Armour, J.A., Poon, A., Mabuchi, T., Ozawa, A., Zawirska, A., Burden, A.D., Barker, J.N., Capon, F., Traupe, H., Sun, L.D., Cui, Y., Yin, X.Y., Chen, G., Lim, H.W., Nair, R.P., Voorhees, J.J., Tejasvi, T., Pujol, R., Munkhtuvshin, N., Fischer, J., Kere, J., Schalkwijk, J., Bowcock, A., Kwok, P.Y., Novelli, G., Inoko, H., Ryan, A.W., Trembath, R.C., Reis, A., Zhang, X.J., Elder, J.T., Estivill, X., Riveira-Munoz, E., He, S.M., Escaramis, G., Stuart, P.E., Huffmeier, U., Lee, C., Kirby, B., Oka, A., Giardina, E., Liao, W., Bergboer, J.G.M., Kainu, K., Cid, R. de, Munkhbat, B., Zeeuwen, P.L.J.M., Armour, J.A., Poon, A., Mabuchi, T., Ozawa, A., Zawirska, A., Burden, A.D., Barker, J.N., Capon, F., Traupe, H., Sun, L.D., Cui, Y., Yin, X.Y., Chen, G., Lim, H.W., Nair, R.P., Voorhees, J.J., Tejasvi, T., Pujol, R., Munkhtuvshin, N., Fischer, J., Kere, J., Schalkwijk, J., Bowcock, A., Kwok, P.Y., Novelli, G., Inoko, H., Ryan, A.W., Trembath, R.C., Reis, A., Zhang, X.J., Elder, J.T., and Estivill, X.

Abstract

Contains fulltext : 96094.pdf (publisher's version ) (Closed access), A multicenter meta-analysis including data from 9,389 psoriasis patients and 9,477 control subjects was performed to investigate the contribution of the deletion of genes LCE3C and LCE3B, involved in skin barrier defense, to psoriasis susceptibility in different populations. The study confirms that the deletion of LCE3C and LCE3B is a common genetic factor for susceptibility to psoriasis in the European populations (OR(Overall) = 1.21 (1.15-1.27)), and for the first time directly demonstrates the deletion's association with psoriasis in the Chinese (OR = 1.27 (1.16-1.34)) and Mongolian (OR = 2.08 (1.44-2.99)) populations. The analysis of the HLA-Cw6 locus showed significant differences in the epistatic interaction with the LCE3C and LCE3B deletion in at least some European populations, indicating epistatic effects between these two major genetic contributors to psoriasis. The study highlights the value of examining genetic risk factors in multiple populations to identify genetic interactions, and indicates the need of further studies to understand the interaction of the skin barrier and the immune system in susceptibility to psoriasis.

Published
2011

34. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.

Author

Strange, A., Capon, F., Spencer, C.C., Knight, J., Weale, M.E., Allen, M.H., Barton, A., Band, G., Bellenguez, C., Bergboer, J.G.M., Blackwell, J.M., Bramon, E., Bumpstead, S.J., Casas, J.P., Cork, M.J., Corvin, A., Deloukas, P., Dilthey, A., Duncanson, A., Edkins, S., Estivill, X., Fitzgerald, O., Freeman, C., Giardina, E., Gray, E., Hofer, A., Huffmeier, U., Hunt, S.E., Irvine, A.D., Jankowski, J., Kirby, B., Langford, C., Lascorz, J., Leman, J., Leslie, S., Mallbris, L., Markus, H.S., Mathew, C.G., McLean, W.H.I., McManus, R., Mossner, R., Moutsianas, L., Naluai, A.T., Nestle, F.O., Novelli, G., Onoufriadis, A., Palmer, C.N., Perricone, C., Pirinen, M., Plomin, R., Potter, S.C., Pujol, R.M., Rautanen, A., Riveira-Munoz, E., Ryan, A.W., Salmhofer, W., Samuelsson, L., Sawcer, S.J., Schalkwijk, J., Smith, C.H., Stahle, M., Su, Z., Tazi-Ahnini, R., Traupe, H., Viswanathan, A.C., Warren, R.B., Weger, W., Wolk, K., Wood, N., Worthington, J., Young, H.S., Zeeuwen, P.L.J.M., Hayday, A., Burden, A.D., Griffiths, C.E., Kere, J., Reis, A., McVean, G., Evans, D.M., Brown, M.A., Barker, J.N., Peltonen, L., Donnelly, P., Trembath, R.C., Strange, A., Capon, F., Spencer, C.C., Knight, J., Weale, M.E., Allen, M.H., Barton, A., Band, G., Bellenguez, C., Bergboer, J.G.M., Blackwell, J.M., Bramon, E., Bumpstead, S.J., Casas, J.P., Cork, M.J., Corvin, A., Deloukas, P., Dilthey, A., Duncanson, A., Edkins, S., Estivill, X., Fitzgerald, O., Freeman, C., Giardina, E., Gray, E., Hofer, A., Huffmeier, U., Hunt, S.E., Irvine, A.D., Jankowski, J., Kirby, B., Langford, C., Lascorz, J., Leman, J., Leslie, S., Mallbris, L., Markus, H.S., Mathew, C.G., McLean, W.H.I., McManus, R., Mossner, R., Moutsianas, L., Naluai, A.T., Nestle, F.O., Novelli, G., Onoufriadis, A., Palmer, C.N., Perricone, C., Pirinen, M., Plomin, R., Potter, S.C., Pujol, R.M., Rautanen, A., Riveira-Munoz, E., Ryan, A.W., Salmhofer, W., Samuelsson, L., Sawcer, S.J., Schalkwijk, J., Smith, C.H., Stahle, M., Su, Z., Tazi-Ahnini, R., Traupe, H., Viswanathan, A.C., Warren, R.B., Weger, W., Wolk, K., Wood, N., Worthington, J., Young, H.S., Zeeuwen, P.L.J.M., Hayday, A., Burden, A.D., Griffiths, C.E., Kere, J., Reis, A., McVean, G., Evans, D.M., Brown, M.A., Barker, J.N., Peltonen, L., Donnelly, P., and Trembath, R.C.

Abstract

1 november 2010, Contains fulltext : 89179.pdf (publisher's version ) (Closed access), To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 x 10 and two loci with a combined P < 5 x 10). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 x 10). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.

Published
2010

35. Mutations in the pericentrin (PCNT) gene cause primordial dwarfism.

Author

Rauch, A., Thiel, C.T., Schindler, D., Wick, U., Crow, Y.J., Ekici, A.B., Essen, A.J. van, Goecke, T.O., Al-Gazali, L., Chrzanowska, K.H., Zweier, C., Brunner, H.G., Becker, K., Curry, C.J., Dallapiccola, B., Devriendt, K., Dorfler, A., Kinning, E., Megarbane, A., Meinecke, P., Semple, R.K., Spranger, S., Toutain, A., Trembath, R.C., Voss, E., Wilson, L., Hennekam, R.C.M., Zegher, F. de, Dorr, H.G., Reis, A., Rauch, A., Thiel, C.T., Schindler, D., Wick, U., Crow, Y.J., Ekici, A.B., Essen, A.J. van, Goecke, T.O., Al-Gazali, L., Chrzanowska, K.H., Zweier, C., Brunner, H.G., Becker, K., Curry, C.J., Dallapiccola, B., Devriendt, K., Dorfler, A., Kinning, E., Megarbane, A., Meinecke, P., Semple, R.K., Spranger, S., Toutain, A., Trembath, R.C., Voss, E., Wilson, L., Hennekam, R.C.M., Zegher, F. de, Dorr, H.G., and Reis, A.

Abstract

Contains fulltext : 70830.pdf (publisher's version ) (Closed access), Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin (PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism type II (MOPD II) in 25 patients. Adults with this rare inherited condition have an average height of 100 centimeters and a brain size comparable to that of a 3-month-old baby, but are of near-normal intelligence. Absence of PCNT results in disorganized mitotic spindles and missegregation of chromosomes. Mutations in related genes are known to cause primary microcephaly (MCPH1, CDK5RAP2, ASPM, and CENPJ).

Published
2008

36. Hidradenitis suppurativa: haploinsufficiency of gamma-secretase components does not affect gamma-secretase enzyme activity in vitro.

Author

Pink, A.E., Dafou, D., Desai, N., Holmes, O., Hobbs, C., Smith, C.H., Mortimer, P., Simpson, M.A, Trembath, R.C., and Barker, J.N.

Subjects
HIDRADENITIS suppurativa, SECRETASES, IN vitro studies, GENETICS
Abstract

A letter to the editor is presented which discusses a study regarding Hidradenitis suppurativa (HS), a chronic inflammatory dermatosis, and the effect of haploinsufficiency of gamma-secretase components in gamma-secretase enzyme activity in vitro.

Published
2016
Full Text
View/download PDF

37. Mutations in the embryonal subunit of the acetylcholine receptor (CHRNG) cause lethal and Escobar variants of multiple pterygium syndrome.

Author

Morgan, N.V., Brueton, L., Cox, P., Greally, M.T., Tolmie, J.L., Pasha, S., Aligianis, I.A., Bokhoven, J.H.L.M. van, Marton, T., Al-Gazali, L., Morton, J.E., Oley, C.A., Johnson, C.A., Trembath, R.C., Brunner, H.G., Maher, E.R., Morgan, N.V., Brueton, L., Cox, P., Greally, M.T., Tolmie, J.L., Pasha, S., Aligianis, I.A., Bokhoven, J.H.L.M. van, Marton, T., Al-Gazali, L., Morton, J.E., Oley, C.A., Johnson, C.A., Trembath, R.C., Brunner, H.G., and Maher, E.R.

Abstract

Contains fulltext : 50026.pdf (publisher's version ) (Closed access), Multiple pterygium syndromes (MPSs) comprise a group of multiple-congenital-anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis). In addition, a variety of developmental defects (e.g., vertebral anomalies) may occur. MPSs are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. To elucidate the pathogenesis of MPS, we undertook a genomewide linkage scan of a large consanguineous family and mapped a locus to 2q36-37. We then identified germline-inactivating mutations in the embryonal acetylcholine receptor gamma subunit (CHRNG) in families with both lethal and nonlethal MPSs. These findings extend the role of acetylcholine receptor dysfunction in human disease and provide new insights into the pathogenesis and management of fetal akinesia syndromes.

Published
2006

46. Radiological malformations of the ear in pendred syndrome

Author

Phelps, P.D., primary, Coffey, R.A., additional, Trembath, R.C., additional, Luxon, L.M., additional, Grossman, A.B., additional, Britton, K.E., additional, Kendall-Taylor, P., additional, Graham, J.M., additional, Cadge, B.C., additional, Stephens, S.G.D., additional, Pembrey, M.E., additional, and Reardon, W., additional

Published
1998
Full Text
View/download PDF

47. Genetics of Silver-Russell Syndrome

Author

Wakeling, E.L., primary, Abu-Amero, S., additional, Price, S.M., additional, Stanier, P., additional, Trembath, R.C., additional, Moore, G.E., additional, and Preece, M.A., additional

Published
1998
Full Text
View/download PDF

50. Does BMPR2 mutation disrupt pulmonary vasculogenesis? *

Author

Jeffery, Trina K., Upton, Paul D., Yang, X., Southwood, M., Long, L., Trembath, R.C., and Morrell, Nicholas W.

Subjects
Gene mutations -- Research -- Health aspects -- Genetic aspects, Endothelial growth factors -- Genetic aspects -- Research -- Health aspects, Bone morphogenetic proteins -- Health aspects -- Research -- Genetic aspects, Health, Research, Genetic aspects, Health aspects
Abstract

Abbreviations: BMP = bone morphogenetic protein; BMPR2 =bone morphogenetic protein type II receptor; HPAEC = human pulmonary artery endothelial cell ********** Mutations in the gene encoding the bone morphogenetic protein [...]

Published
2005

Catalog

Books, media, physical & digital resources
See catalog results