Search

Your search keyword '"Lapi, E"' showing total 154 results
Start Over Author "Lapi, E"
154 results on '"Lapi, E"'

1. MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype

Author

Smol, T., Petit, F., Piton, A., Keren, B., Sanlaville, D., Afenjar, A., Baker, S., Bedoukian, E. C., Bhoj, E. J., Bonneau, D., Boudry-Labis, E., Bouquillon, S., Boute-Benejean, O., Caumes, R., Chatron, N., Colson, C., Coubes, C., Coutton, C., Devillard, F., Dieux-Coeslier, A., Doco-Fenzy, M., Ewans, L. J., Faivre, L., Fassi, E., Field, M., Fournier, C., Francannet, C., Genevieve, D., Giurgea, I., Goldenberg, A., Green, A. K., Guerrot, A. M., Heron, D., Isidor, B., Keena, B. A., Krock, B. L., Kuentz, P., Lapi, E., Le Meur, N., Lesca, G., Li, D., Marey, I., Mignot, C., Nava, C., Nesbitt, A., Nicolas, G., Roche-Lestienne, C., Roscioli, T., Satre, V., Santani, A., Stefanova, M., Steinwall Larsen, S., Saugier-Veber, P., Picker-Minh, S., Thuillier, C., Verloes, A., Vieville, G., Wenzel, M., Willems, M., Whalen, S., Zarate, Y. A., Ziegler, A., Manouvrier-Hanu, S., Kalscheuer, V. M., Gerard, B., and Ghoumid, Jamal

Published
2018
Full Text
View/download PDF

8. Synpolydactyly phenotypes correlate with size of expansions in HOXD 13 polyalanine tract

Author

Goodman, F.R., Mundlos, S., Muragaki, Y., Donnai, D., Giovannucci-Uzielli, M.L., Lapi, E., Majewski, F., McGaughran, J., McKeown, C., Reardon, W., Upton, J., Winter, R.M., Olsen, B.R., and Scambler, P.J.

Subjects
Birth defects -- Genetic aspects, Mutation (Biology) -- Genetic aspects, Genetic disorders -- Research, Genetic transcription -- Regulation, Science and technology
Abstract

Synpolydactyly (SPD) is a dominantly inherited congenital limb malformation. Typical cases have 3/4 finger and 4/5 toe syndactyly, with a duplicated digit in the syndactylous web, but incomplete penetrance and variable expressivity are common. The condition has recently been shown to be caused by expansions of an imperfect trinucleotide repeat sequence encoding a 15-residue polyalanine tract in HOXD13. We have studied 16 new and 4 previously published SPD families, with between 7 and 14 extra residues in the tract, to analyze the molecular basis for the observed variation in phenotype. Although there is no evidence of change in expansion size within families, even over six generations, there is a highly significant increase in the penetrance and severity of phenotype with increasing expansion size, affecting both hands (P = 0.012) and feet (P < 0.00005). Affected individuals from a family with a 14-alanine expansion, the largest so far reported, all have a strikingly similar and unusually severe limb phenotype, involving the first digits and distal carpals. Affected males from this family also have hypospadias, not previously described in SPD, but consistent with HOXD13 expression in the developing genital tubercle. The remarkable correlation between phenotype and expansion size suggests that expansion of the tract leads to a specific gain of function in the mutant HOXD13 protein, and has interesting implications for the role of polyalanine tracts in the control of transcription.

Published
1997

9. STAG2 cohesin is essential for heart morphogenesis

Author

De Koninck, M., primary, Lapi, E., additional, Badia-Careaga, C., additional, Cossio, I., additional, Giménez-Llorente, D., additional, Rodríguez-Corsino, M., additional, Andrada, E., additional, Hidalgo, A., additional, Manzanares, M., additional, Real, F. X., additional, and Losada, A., additional

Published
2019
Full Text
View/download PDF

10. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author

Acuna Hidalgo, R., Deriziotis, P., Steehouwer, M., Gilissen, C.F., Graham, S.A., Dam, S van, Hoover-Fong, J., Telegrafi, A.B., Destree, A., Smigiel, R., Lambie, L.A., Kayserili, H., Altunoglu, U., Lapi, E., Uzielli, M.L., Aracena, M., Nur, B.G., Mihci, E., Moreira, L.M., Borges Ferreira, V., Horovitz, D.D., Rocha, K.M., Jezela-Stanek, A., Brooks, A.S., Reutter, H., Cohen, J.S., Fatemi, A., Smitka, M., Grebe, T.A., Donato, N. Di, Deshpande, C., Vandersteen, A., Lourenco, C., Dufke, A., Rossier, E., Andre, G., Baumer, A., Spencer, C., McGaughran, J., Franke, L., Veltman, J.A., Vries, B.B. de, Schinzel, A., Fisher, S.E., Hoischen, A., Bon, B.W.M. van, Acuna Hidalgo, R., Deriziotis, P., Steehouwer, M., Gilissen, C.F., Graham, S.A., Dam, S van, Hoover-Fong, J., Telegrafi, A.B., Destree, A., Smigiel, R., Lambie, L.A., Kayserili, H., Altunoglu, U., Lapi, E., Uzielli, M.L., Aracena, M., Nur, B.G., Mihci, E., Moreira, L.M., Borges Ferreira, V., Horovitz, D.D., Rocha, K.M., Jezela-Stanek, A., Brooks, A.S., Reutter, H., Cohen, J.S., Fatemi, A., Smitka, M., Grebe, T.A., Donato, N. Di, Deshpande, C., Vandersteen, A., Lourenco, C., Dufke, A., Rossier, E., Andre, G., Baumer, A., Spencer, C., McGaughran, J., Franke, L., Veltman, J.A., Vries, B.B. de, Schinzel, A., Fisher, S.E., Hoischen, A., and Bon, B.W.M. van

Abstract

Contains fulltext : 174787.pdf (publisher's version ) (Open Access), Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.

Published
2017

11. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author

Acuna-Hidalgo, R. (Rocio), Deriziotis, P. (Pelagia), Steehouwer, M. (Marloes), Gilissen, C. (Christian), Graham, S.A. (Sarah A.), van Dam, S. (Sipko), Hoover-Fong, J. (Julie), Telegrafi, A.B. (Aida B.), Destrée, A. (Anne), Smigiel, R. (Robert), Lambie, L.A. (Lindsday A.), Kayserili, H. (Hülya), Altunoglu, U. (Umut), Lapi, E. (Elisabetta), Uzielli, M.L. (Maria Luisa), Aracena, M. (Mariana), Nur, B.G. (Banu G.), Mihci, E. (Ercan), Moreira, L.M.A. (Lilia M. A.), Borges Ferreira, V. (Viviane), Horovitz, D.D.G. (Dafne D. G.), da Rocha, K.M. (Katia M.), Jezela-Stanek, A. (Aleksandra), Brooks, A.S. (Alice), Reutter, H. (Heiko), Cohen, J.S. (Julie S.), Fatemi, A. (Ali), Smitka, M. (Martin), Grebe, T.A. (Theresa A.), Di Donato, N. (Nataliya), Deshpande, C. (Charu), Vandersteen, A.M. (Anthony M.), Marques Lourenço, C. (Charles), Dufke, A. (Andreas), Rossier, E. (Eva), Andre, G. (Gwenaelle), Baumer, A. (Alessandra), Spencer, C. (Careni), McGaughran, J., Franke, L. (Lude), Veltman, J.A. (Joris), Vries, B. (Boukje) de, Schinzel, A. (Albert), Fisher, S.E. (Simon), Hoischen, A. (Alex), Bon, B. (Bregje) van, Acuna-Hidalgo, R. (Rocio), Deriziotis, P. (Pelagia), Steehouwer, M. (Marloes), Gilissen, C. (Christian), Graham, S.A. (Sarah A.), van Dam, S. (Sipko), Hoover-Fong, J. (Julie), Telegrafi, A.B. (Aida B.), Destrée, A. (Anne), Smigiel, R. (Robert), Lambie, L.A. (Lindsday A.), Kayserili, H. (Hülya), Altunoglu, U. (Umut), Lapi, E. (Elisabetta), Uzielli, M.L. (Maria Luisa), Aracena, M. (Mariana), Nur, B.G. (Banu G.), Mihci, E. (Ercan), Moreira, L.M.A. (Lilia M. A.), Borges Ferreira, V. (Viviane), Horovitz, D.D.G. (Dafne D. G.), da Rocha, K.M. (Katia M.), Jezela-Stanek, A. (Aleksandra), Brooks, A.S. (Alice), Reutter, H. (Heiko), Cohen, J.S. (Julie S.), Fatemi, A. (Ali), Smitka, M. (Martin), Grebe, T.A. (Theresa A.), Di Donato, N. (Nataliya), Deshpande, C. (Charu), Vandersteen, A.M. (Anthony M.), Marques Lourenço, C. (Charles), Dufke, A. (Andreas), Rossier, E. (Eva), Andre, G. (Gwenaelle), Baumer, A. (Alessandra), Spencer, C. (Careni), McGaughran, J., Franke, L. (Lude), Veltman, J.A. (Joris), Vries, B. (Boukje) de, Schinzel, A. (Albert), Fisher, S.E. (Simon), Hoischen, A. (Alex), and Bon, B. (Bregje) van

Abstract

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.

Published
2017
Full Text
View/download PDF

12. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author

Acuna-Hidalgo, R, Deriziotis, P, Steehouwer, M, Gilissen, C, Graham, SA, van Dam, S, Hoover-Fong, J, Telegrafi, AB, Destree, A, Smigiel, R, Lambie, LA, Kayserili, H, Altunoglu, U, Lapi, E, Uzielli, ML, Aracena, M, Nur, BG, Mihci, E, Moreira, LMA, Ferreira, VB, Horovitz, D D G, da Rocha, KM, Jezela-Stanek, A, Brooks, Alice, Reutter, H, Cohen, JS, Fatemi, A, Smitka, M, Grebe, TA, Di Donato, N, Deshpande, C, Vandersteen, A, Lourenco, CM, Dufke, A, Rossier, E, Andre, G, Baumer, A, Spencer, C, McGaughran, J, Franke, L, Veltman, JA, de Vries, BBA, Schinzel, A, Fisher, SE, Hoischen, A, van Bon, BW, Acuna-Hidalgo, R, Deriziotis, P, Steehouwer, M, Gilissen, C, Graham, SA, van Dam, S, Hoover-Fong, J, Telegrafi, AB, Destree, A, Smigiel, R, Lambie, LA, Kayserili, H, Altunoglu, U, Lapi, E, Uzielli, ML, Aracena, M, Nur, BG, Mihci, E, Moreira, LMA, Ferreira, VB, Horovitz, D D G, da Rocha, KM, Jezela-Stanek, A, Brooks, Alice, Reutter, H, Cohen, JS, Fatemi, A, Smitka, M, Grebe, TA, Di Donato, N, Deshpande, C, Vandersteen, A, Lourenco, CM, Dufke, A, Rossier, E, Andre, G, Baumer, A, Spencer, C, McGaughran, J, Franke, L, Veltman, JA, de Vries, BBA, Schinzel, A, Fisher, SE, Hoischen, A, and van Bon, BW

Published
2017

16. Otopalatodigital Type ll in a female: clinical and laboratory studies

Author

Guarducci, S., Cecconi, A., Lapi, E., Ricotti, G., Ricci, U., Lapini, M., Ombroni, L., Andreucci, E., Pelagatti, S., Lazzerini, V., Sani, I., Brusaferri, A., and Uzielli, Giovannucci M.L.

Subjects
Genetic research -- Analysis, Human genetics -- Research, Genetic disorders -- Research, Biological sciences
Published
2000

20. Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome

Author

Cantagrel, V, Silhavy, Jl, Bielas, S, Swistun, D, Marsh, Se, Bertrand, J, Audollent, S, Attié Bitach, T, Holden, Kr, Dobyns, Wb, Traver, D, Al Gazali, L, Ali, Br, Lindner, Th, Caspary, T, Otto, Ea, Hildebrandt, F, Glass, Ia, Logan, Cv, Johnson, Ca, Bennett, C, Brancati, F, Grattan Smith, P, Leventer, J, Van Coster, R, Dias, K, Moco, C, Moreira, Ae Kim, C, Akiss, A, Maegawa, G, Abdel Salam GMH, Abdel Aleem, A, Zaki, Ms, Marti, I, Quijano Roy, S, de Lonlay, P, Verloes A, A., Touraine, R, Koenig, M, Lagier Tourenne, C, Messer, J, Philippi, H, Tzeli, Sk, Halldorsson, S, Johannsdottir, J, Ludvigsson, P, Magee, A, Stuart, B, Lev, D, Michelson, M, Ben Zeev, B, Fischetto, R, Gentile, M, Battaglia, Giordano, L, Boccone, L, Ruggieri, M, Bigoni, S, Ferlini, A, Donati, Ma, Procopio, E, Lapi, E, Genuardi, M, Caridi, G, Faravelli, F, Ghiggeri, G, Briuglia, Silvana, Tortorella, Gaetano, Rigoli, Luciana Concetta, SALPIETRO DAMIANO, Carmelo, D’Arrigo, S, Pantaleoni, C, Riva, D, Uziel, G, Laverda, Am, Permunian, A, Bova, S, Fazz, Ei, Sabrina, S, Battini, R, Bertini, E, Dallapiccola, B, Cilio, Mr, Di Sabato, M, Emma, F, Leuzzi, V, Parisi, P, Simonati, A, Al Tawari AA, Bastaki, L, Ahmad Aqueel, A, Jong, Mm, Koul, R, Rajab, A, Sztriha, L, Azam, M, Barbot, C, Rodriguez, B, Pascual Castroviejo, I, Eugen Boltshauser, E, Hulya, H, Comu, S, Akcakus, M, Sahin, Y, Phadke, Sr, Melick, N, Mikati, M, Nicholl, D, Hurst, J, Hennekam, Rcm, Bernes, S, Sanchez, H, Clark, Ae, Wynshaw Boris, A, Donahue, C, Sherr, Eh, Barkovich, Aj, Hahn, D., Sanger, Td, Gallager, Te, Daugherty, C, Krishnamoorthy, Ks, Sarco, D, Walsh CA, Soul, Jmckanna, T, Joanne Milisa, J, Chung, Wk, De Vivo DC, Raynes, H, Schubert, R, Seward, A, Brooks, Dg, Amy Goldstein, A, Caldwell, J, Finsecke, E, Maria, Bl, Cruse, Rp, Lotzete, Swoboda, Kj, Viskochil, Dh, Valente, Em, Woods, Cg, and Gleeson, Jg

Subjects
Cerebellum, Ataxia, TMEM67, Molecular Sequence Data, Biology, Joubert Syndrome, Joubert syndrome, Article, cilia gene ARL13B, mutation, 03 medical and health sciences, 0302 clinical medicine, Ciliogenesis, INPP5E, medicine, Genetics, Animals, Humans, Genetics(clinical), Abnormalities, Multiple, Genetic Predisposition to Disease, Cilia, Genetics (clinical), Conserved Sequence, Zebrafish, 030304 developmental biology, Neurons, 0303 health sciences, Brain Diseases, ADP-Ribosylation Factors, Cilium, Chromosome Mapping, Computational Biology, Syndrome, Mutation, medicine.disease, Cell biology, medicine.anatomical_structure, RPGRIP1L, medicine.symptom, Abnormalities, Multiple, 030217 neurology & neurosurgery
Abstract

Joubert syndrome (JS) and related disorders are a group of autosomal-recessive conditions sharing the “molar tooth sign” on axial brain MRI, together with cerebellar vermis hypoplasia, ataxia, and psychomotor delay. JS is suggested to be a disorder of cilia function and is part of a spectrum of disorders involving retinal, renal, digital, oral, hepatic, and cerebral organs. We identified mutations in ARL13B in two families with the classical form of JS. ARL13B belongs to the Ras GTPase family, and in other species is required for ciliogenesis, body axis formation, and renal function. The encoded Arl13b protein was expressed in developing murine cerebellum and localized to the cilia in primary neurons. Overexpression of human wild-type but not patient mutant ARL13B rescued the Arl13b scorpion zebrafish mutant. Thus, ARL13B has an evolutionarily conserved role mediating cilia function in multiple organs.

Published
2008

21. Bone density and metabolism in subjects with microdeletion of chromosome 22q11 (del22q11)

Author

Stagi, S, Lapi, E, Gambineri, E, Manoni, C, Genuardi, Maurizio, Colarusso, G, Conti, C, Chiarelli, F, De Martino, M, Azzari, C., Genuardi, Maurizio (ORCID:0000-0002-7410-8351), Stagi, S, Lapi, E, Gambineri, E, Manoni, C, Genuardi, Maurizio, Colarusso, G, Conti, C, Chiarelli, F, De Martino, M, Azzari, C., and Genuardi, Maurizio (ORCID:0000-0002-7410-8351)

Abstract

Although hypoparathyroidism with hypocalcaemia is one of the most frequent clinical features of monoallelic microdeletion of chromosome 22q11 (22q11DS), bone mass and metabolism have not yet been assessed in these patients. DESIGN: This study aimed to evaluate bone mass and metabolism in a cohort of patients, both children and adults, with 22q11DS. METHODS: In twenty-eight patients with 22q11DS (median age 12.5, range 6.1-42.8 years), serum levels of ionised and total calcium, phosphate, parathyroid hormone (PTH), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, osteocalcin and bone-specific alkaline phosphatase (BSAP), and urinary deoxypyridinoline concentrations were evaluated. In these patients, bone mineral density (BMD) was evaluated by dual-energy X-ray absorptiometry (DXA) examination, and volumetric BMD (bone mineral apparent density (BMAD)) was calculated. The data obtained from paediatric and adult patients were compared with two age-, sex- and body size-matched healthy subject control groups. RESULTS: Patients with 22q11DS showed a reduced BMAD Z-score compared with controls (P<0.001). These patients also had significantly lower ionised (P<0.001) and total calcium (P<0.05) levels as well as lower PTH levels (P<0.05), compared with the controls. In particular, children and young patients with 22q11DS had significantly lower serum osteocalcin levels (P<0.001), BSAP levels (P<0.001) and urinary deoxypyridinoline concentrations (P<0.001) than controls. These results were not confirmed in adults. Finally, patients with hypoparathyroidism and/or hypocalcaemia at the time of the study showed significantly lower ionised (P<0.001) and total calcium levels (P<0.001), PTH levels (P<0.05), BSAP levels (P<0.001), osteocalcin levels (P<0.001) and urinary deoxypyridinoline concentrations (P<0.001), compared with patients without hypoparathyroidism and/or hypocalcaemia. Nonetheless, the BMAD Z-score did not show substantial differences

Published
2010

23. Mutations in the nebulin gene can cause severe congenital nemaline myopathy.

Author

Wallgren-Pettersson, C., Donner, K., Sewry, C.A., Bijlsma, E., Lammens, M.M.Y., Bushby, K., Giovannucci Uzielli, M.L., Lapi, E., Odent, S., Akcoren, Z., Topaloglu, H., Pelin, K., Wallgren-Pettersson, C., Donner, K., Sewry, C.A., Bijlsma, E., Lammens, M.M.Y., Bushby, K., Giovannucci Uzielli, M.L., Lapi, E., Odent, S., Akcoren, Z., Topaloglu, H., and Pelin, K.

Abstract

Item does not contain fulltext, Previously, we reported results indicating that nebulin was the gene causing the typical form of autosomal recessive nemaline (rod) myopathy. Here we describe the identification of mutations in the nebulin gene in seven offspring of five families affected by the severe congenital form of nemaline myopathy. One pregnancy was terminated on the grounds of foetal abnormality, while six affected infants died at ages ranging from the first day of life to 19 months. Only three of the six neonates were able to establish spontaneous respiration. Three had arthrogryposis. In three of the five families, the mutations were located in exon 184. These mutations are predicted to cause absence of the C-terminal part of nebulin.

Published
2002

28. 13q Deletion and central nervous system anomalies: further insights from karyotype-phenotype analyses of 14 patients

Author

Ballarati, L., primary, Rossi, E., additional, Bonati, M. T., additional, Gimelli, S., additional, Maraschio, P., additional, Finelli, P., additional, Giglio, S., additional, Lapi, E., additional, Bedeschi, M. F., additional, Guerneri, S., additional, Arrigo, G., additional, Patricelli, M. G., additional, Mattina, T., additional, Guzzardi, O., additional, Pecile, V., additional, Police, A., additional, Scarano, G., additional, Larizza, L., additional, Zuffardi, O., additional, and Giardino, D., additional

Published
2006
Full Text
View/download PDF

31. Spectrum and distribution of MECP2 mutations in 64 Italian Rett syndrome girls: tentative genotype/phenotype correlation

Author

Giunti, L., primary, Pelagatti, S., additional, Lazzerini, V., additional, Guarducci, S., additional, Lapi, E., additional, Coviello, S., additional, Cecconi, A., additional, Ombroni, L., additional, Andreucci, E., additional, Sani, I., additional, Brusaferri, A., additional, Lasagni, A., additional, Ricotti, G., additional, Giometto, B., additional, Nicolao, P., additional, Gasparini, P., additional, Granatiero, M., additional, and Giovannucci Uzielli, M.L., additional

Published
2001
Full Text
View/download PDF

32. Premature ovarian failure (POF) and fragile X premutation females: From POF to fragile X carrier identification, from fragile X carrier diagnosis to POF association data

Author

Uzielli, M.L. Giovannucci, primary, Guarducci, S., additional, Lapi, E., additional, Cecconi, A., additional, Ricci, U., additional, Ricotti, G., additional, Biondi, C., additional, Scarselli, B., additional, Vieri, F., additional, Scarnato, P., additional, Gori, F., additional, and Sereni, A., additional

Published
1999
Full Text
View/download PDF

33. Fragile X premutation is a significant risk factor for premature ovarian failure: The international collaborative POF in fragile X study?preliminary data

Author

Allingham-Hawkins, Diane J., primary, Babul-Hirji, Riyana, additional, Chitayat, David, additional, Holden, Jeanette J.A., additional, Yang, Kathy T., additional, Lee, C., additional, Hudson, R., additional, Gorwill, H., additional, Nolin, Sarah L., additional, Glicksman, Anne, additional, Jenkins, Edmund C., additional, Brown, W. Ted, additional, Howard-Peebles, Patricia N., additional, Becchi, Cindy, additional, Cummings, Emilie, additional, Fallon, Lee, additional, Seitz, Suzanne, additional, Black, Susan H., additional, Vianna-Morgante, Angela M., additional, Costa, Silvia S., additional, Otto, Paulo A., additional, Mingroni-Netto, Regina C., additional, Murray, Anna, additional, Webb, J., additional, MacSwinney, F., additional, Dennis, N., additional, Jacobs, Patricia A., additional, Syrrou, Maria, additional, Georgiou, Ioannis, additional, Patsalis, Phillipos C., additional, Giovannucci Uzielli, Maria L., additional, Guarducci, S., additional, Lapi, E., additional, Cecconi, A., additional, Ricci, U., additional, Ricotti, G., additional, Biondi, C., additional, Scarselli, B., additional, and Vieri, F., additional

Published
1999
Full Text
View/download PDF

37. SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence.

Author

Wang, X. D., Lapi, E., Sullivan, A., Ratnayaka, I., Goldin, R., Hay, R., and Lu, X.

Subjects
*CYCLIN-dependent kinases, *APOPTOSIS, *RETINOBLASTOMA, *TUMOR suppressor proteins, *TUMOR suppressor genes, *PHOSPHORYLATION, *CELL cycle, *TUMOR growth
Abstract

Oncogene-induced senescence represents a key tumor suppressive mechanism. Here, we show that Ras oncogene-induced senescence can be mediated by the recently identified haploinsufficient tumor suppressor apoptosis-stimulating protein of p53 (ASPP) 2 through a novel and p53/p19Arf/p21waf1/cip1-independent pathway. ASPP2 suppresses Ras-induced small ubiquitin-like modifier (SUMO)-modified nuclear cyclin D1 and inhibits retinoblastoma protein (Rb) phosphorylation. The lysine residue, K33, of cyclin D1 is a key site for this newly identified regulation. In agreement with the fact that its nuclear localization is required for its oncogenic activity, we show that nuclear cyclin D1 is far more potent than wild-type (WT) cyclin D1 in bypassing Ras-induced senescence. Thus, this study identifies SUMO modification as a positive regulator of nuclear cyclin D1, and reveals a new way by which cell cycle entry and senescence are regulated. [ABSTRACT FROM AUTHOR]

Published
2011
Full Text
View/download PDF

40. Novel multimodal molecular imaging of Vitamin H (Biotin) transporter activity in the murine placenta.

Author

Noam, Ben Eliezer, Marina, Lysenko, Inbal, Biton E., Ofra, Golani, Jennifer, Bartels L., Solana, Fernandez R., Tolulope, Aweda A., Nicholas, Clanton A., Rebecca, Beacham, Suzanne, Lapi E., Joel, Garbow R., and Michal, Neeman

Subjects
BIOTIN, PLACENTA, MAGNETIC resonance imaging, TROPHOBLAST, LABORATORY mice
Abstract

Vitamin H (biotin) is delivered to the fetus transplacentally by an active biotin-transport mechanism and is critical for fetal development. Our objective was to develop a comprehensive MRI technique for mapping biotin transporter activity in the murine placenta. Visualization of transporter activity can employ MRI's unique T2*-dependent signal 'off-switch', which is triggered by transporter mediated aggregation of biotinylated contrast agent (b-BSA-Gd-DTPA). MRI data were collected from pregnant mice after administration of b-BSA-Gd-DTPA and analyzed using a new sub-voxel biophysical signal model. Validation experiments included competition with native biotin, comparative tests using PET, histology, and ICPMS. MRI signal was governed by binding, aggregation, and clearance of biotin (confirmed by histology). Signal dynamics reflected the placenta's perfusion pattern modulated by biotin transporter activity and trophoblast mediated retention, and were in congruence with a three-compartment sub-voxel model. Pre-saturation of the transporters with free biotin suppressed b-BSA-Gd-DTPA uptake. The results were confirmed by PET, histology and ICPMS. The presented MRI-based platform allows to track activity of essential molecular transporters in the placenta, reflecting a transporter-mediated uptake, followed by retention and aggregation, and recycling associated with the large b-BSA-Gd-DTPA conjugate. The presented DCE-MRI technique can furthermore be used to map and characterize microstructural compartmentation and transporter activity without exposing the fetus to contrast media. [ABSTRACT FROM AUTHOR]

Published
2020
Full Text
View/download PDF

41. 13q Deletion and central nervous system anomalies: further insights from karyotype-phenotype analyses of 14 patients

Author

Ballarati, L., Rossi, E., Bonati, M. T., Gimelli, S., Maraschio, P., Finelli, P., Giglio, S., Lapi, E., Bedeschi, M. F., Guerneri, S., Arrigo, G., Patricelli, M. G., Mattina, T., Guzzardi, O., Vanna Pecile, Police, A., Scarano, G., Larizza, L., Zuffardi, O., and Giardino, D.

Subjects
Adult, Male, Monosomy, Adolescent, Chromosome Disorders, Biology, Electronic Letter, ZIC2, Dandy–Walker syndrome, Genetics, medicine, Humans, Abnormalities, Multiple, Child, In Situ Hybridization, Fluorescence, Genetics (clinical), Chromosomes, Human, Pair 13, 13q deletion syndrome, Infant, Newborn, Neural tube, Infant, Nuclear Proteins, Nucleic Acid Hybridization, Chromosome, Karyotype, medicine.disease, Phenotype, DNA-Binding Proteins, medicine.anatomical_structure, Child, Preschool, Karyotyping, Female, Chromosome Deletion, Carrier Proteins, Dandy-Walker Syndrome, Transcription Factors
Abstract

Background: Chromosome 13q deletion is associated with varying phenotypes, which seem to depend on the location of the deleted segment. Although various attempts have been made to link the 13q deletion intervals to distinct phenotypes, there is still no acknowledged consensus correlation between the monosomy of distinct 13q regions and specific clinical features. Methods: 14 Italian patients carrying partial de novo 13q deletions were studied. Molecular–cytogenetic characterisation was carried out by means of array-comparative genomic hybridisation (array-CGH) or fluorescent in situ hybridisation (FISH). Results: Our 14 patients showed mental retardation ranging from profound–severe to moderate–mild: eight had central nervous system (CNS) anomalies, including neural tube defects (NTDs), six had eye abnormalities, nine had facial dysmorphisms and 10 had hand or feet anomalies. The size of the deleted regions varied from 4.2 to 75.7 Mb. Conclusion: This study is the first systematic molecular characterisation of de novo 13q deletions, and offers a karyotype–phenotype correlation based on detailed clinical studies and molecular determinations of the deleted regions. Analyses confirm that patients lacking the 13q32 band are the most seriously affected, and critical intervals have been preliminarily assigned for CNS malformations. Dose-sensitive genes proximal to q33.2 may be involved in NTDs. The minimal deletion interval associated with the Dandy–Walker malformation (DWM) was narrowed to the 13q32.2–33.2 region, in which the ZIC2 and ZIC5 genes proposed as underlying various CNS malformations are mapped.

43. Mosaic Segmental and Whole-Chromosome Upd(11)mat in Silver-Russell Syndrome

Author

Elena Andreucci, Orazio Palumbo, Massimo Carella, Angela Sparago, Elisabetta Lapi, Flavia Cerrato, Laura Pignata, Andrea Riccio, Romano Tenconi, Pignata, L., Sparago, A., Palumbo, O., Andreucci, E., Lapi, E., Tenconi, R., Carella, M., Riccio, A., and Cerrato, F.

Subjects
0301 basic medicine, Male, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Beckwith–Wiedemann syndrome, QH426-470, 030105 genetics & heredity, Biology, Article, Imprinting disorder, 03 medical and health sciences, Silver–Russell syndrome, Genomic Imprinting, Young Adult, Gene duplication, Genetics, medicine, imprinting disorders, Humans, Imprinting (psychology), Genetics (clinical), Loss function, Mosaicism, Chromosomes, Human, Pair 11, Chromosome, Uniparental Disomy, medicine.disease, Uniparental disomy, Pedigree, Silver-Russell Syndrome, 030104 developmental biology, Maternal Inheritance, Genomic imprinting, Human
Abstract

Molecular defects altering the expression of the imprinted genes of the 11p15.5 cluster are responsible for the etiology of two congenital disorders characterized by opposite growth disturbances, Silver–Russell syndrome (SRS), associated with growth restriction, and Beckwith–Wiedemann syndrome (BWS), associated with overgrowth. At the molecular level, SRS and BWS are characterized by defects of opposite sign, including loss (LoM) or gain (GoM) of methylation at the H19/IGF2:intergenic differentially methylated region (H19/IGF2:IG-DMR), maternal or paternal duplication (dup) of 11p15.5, maternal (mat) or paternal (pat) uniparental disomy (upd), and gain or loss of function mutations of CDKN1C. However, while upd(11)pat is found in 20% of BWS cases and in the majority of them it is segmental, upd(11)mat is extremely rare, being reported in only two SRS cases to date, and in both of them is extended to the whole chromosome. Here, we report on two novel cases of mosaic upd(11)mat with SRS phenotype. The upd is mosaic and isodisomic in both cases but covers the entire chromosome in one case and is restricted to 11p14.1-pter in the other case. The segmental upd(11)mat adds further to the list of molecular defects of opposite sign in SRS and BWS, making these two imprinting disorders even more specular than previously described.

Published
2021

44. The Transcriptional Coactivator Yes-Associated Protein Drives p73 Gene-Target Specificity in Response to DNA Damage

Author

Natalia Pediconi, Giovanni Blandino, Gennaro Citro, Massimo Levrero, Giannino Del Sal, Olimpia Monti, Alexander Damalas, Ada Sacchi, Sabrina Strano, Fiamma Mantovani, Alessia Baccarini, Giulia Fontemaggi, Eleonora Lapi, Strano, S, Monti, O, Pediconi, N, Baccarini, A, Fontemaggi, G, Lapi, E, Mantovani, Fiamma, Damalas, A, Citro, G, Sacchi, A, DEL SAL, Giannino, Levrero, M, and Blandino, G.

Subjects
Transcription, Genetic, Cell, Cell Cycle Proteins, Promyelocytic Leukemia Protein, Genes, Reporter, Antibiotics, Acetylation, Antibiotics, Antineoplastic, Apoptosis Regulatory Proteins, Cisplatin, DNA Damage, DNA-Binding Proteins, Doxorubicin, Genes, Tumor Suppressor, Humans, Neoplasm Proteins, Nuclear Proteins, Proteins, Trans-Activators, Transcription Factors, Tumor Suppressor Proteins, Tumor Protein p73, skin and connective tissue diseases, apoptosis, Gene targeting, Antineoplastic, Histone, medicine.anatomical_structure, Transcriptional Coactivator, p73 tumor suppressor, Transcription, Tumor Suppressor, DNA damage, Biology, Promyelocytic leukemia protein, Genetic, Coactivator, medicine, Gene silencing, neoplasms, Gene, Reporter, Molecular Biology, PML, Promoter, Cell Biology, Genes, Nuclear receptor coactivator 3, biology.protein, Nuclear receptor coactivator 2, Cancer research
Abstract

The transcriptional coactivator Yes-associated protein (YAP) has been shown to interact with and to enhance p73-dependent apoptosis in response to DNA damage. Here, we show that YAP requires the promyelocytic leukemia gene (PML) and nuclear body localization to coactivate p73. YAP imparts selectivity to p73 by promoting the activation of a subset of p53 and/or p73 target promoters. Endogenous p73, YAP, and p300 proteins are concomitantly recruited onto the regulatory regions of the apoptotic target gene p53AIP1 only when cells are exposed to apoptotic conditions. Silencing of YAP by specific siRNA impairs p300 recruitment and reduces histone acetylation on the p53AIP1 target gene, resulting in delayed or reduced apoptosis mediated by p73. We also found that YAP contributes to the DNA damage-induced accumulation of p73 and potentiates the p300-mediated acetylation of p73. Altogether, our findings identify YAP as a key determinant of p73 gene targeting in response to DNA damage.

Published
2005
Full Text
View/download PDF

45. The KCNQ1OT1 Imprinting Control Region and non-coding RNA: new properties derived from the study of Beckwith-Wiedemann syndrome and Silver-Russell syndrome cases

Author

Alessandro Mussa, Silvia Russo, Giovanni Battista Ferrero, Agostina De Crescenzo, Margherita Silengo, Massimo Carella, Nicoletta Chiesa, Maria Vittoria Cubellis, Andrea Riccio, Lucia Perone, Angela Sparago, Elisabetta Lapi, Flavia Cerrato, Kankadeb Mishra, Chandrasekhar Kanduri, Orazio Palumbo, Chiesa, N, De Crescenzo, A, Mishra, K, Perone, L, Carella, M, Palumbo, O, Mussa, A, Sparago, A, Cerrato, Flavia, Russo, S, Lapi, E, Cubellis, Mv, Kanduri, C, Silengo, Mc, Riccio, Andrea, Ferrero, Gb, Cerrato, F, Cubellis, MARIA VITTORIA, Cirillo Silengo, M, Riccio, A, and Ferrero, G. B.

Subjects
Adult, Male, Beckwith-Wiedemann Syndrome, RNA, Untranslated, MECHANISMS, Russell-Silver Syndrome, Biology, Genomic Imprinting, Gene Duplication, Gene duplication, Genetics, Humans, Gene Silencing, Epigenetics, Imprinting (psychology), Molecular Biology, Genetics (clinical), KCNQ1OT1, Chromosomes, Human, Pair 11, CDKN1C P57(KIP2), Infant, Articles, GROWTH-FACTOR-II, General Medicine, DNA Methylation, Molecular biology, Chromatin, Pedigree, Silver-Russell Syndrome, Potassium Channels, Voltage-Gated, Child, Preschool, DNA methylation, Female, MS-MLPA, Genomic imprinting, Protein Binding
Abstract

A cluster of imprinted genes at chromosome 11p15.5 is associated with the growth disorders, Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS). The cluster is divided into two domains with independent imprinting control regions (ICRs). We describe two maternal 11p15.5 microduplications with contrasting phenotypes. The first is an inverted and in cis duplication of the entire 11p15.5 cluster associated with the maintenance of genomic imprinting and with the SRS phenotype. The second is a 160 kb duplication also inverted and in cis, but resulting in the imprinting alteration of the centromeric domain. It includes the centromeric ICR (ICR2) and the most 5' 20 kb of the non-coding KCNQ1OT1 gene. Its maternal transmission is associated with ICR2 hypomethylation and the BWS phenotype. By excluding epigenetic mosaicism, cell clones analysis indicated that the two closely located ICR2 sequences resulting from the 160 kb duplication carried discordant DNA methylation on the maternal chromosome and supported the hypothesis that the ICR2 sequence is not sufficient for establishing imprinted methylation and some other property, possibly orientation-dependent, is needed. Furthermore, the 1.2 Mb duplication demonstrated that all features are present for correct imprinting at ICR2 when this is duplicated and inverted within the entire cluster. In the individuals maternally inheriting the 160 kb duplication, ICR2 hypomethylation led to the expression of a truncated KCNQ1OT1 transcript and to down-regulation of CDKN1C. We demonstrated by chromatin RNA immunopurification that the KCNQ1OT1 RNA interacts with chromatin through its most 5' 20 kb sequence, providing a mechanism likely mediating the silencing activity of this long non-coding RNA. © The Author 2011. Published by Oxford University Press.

Published
2012
Full Text
View/download PDF

46. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

Author

Stephen W. Scherer, Mònica Gratacòs, Kari Stefansson, Muriel Holder, Unnur Thorsteinsdottir, Lukas Forer, Katharina M. Roetzer, Josette Lucas, Claudia Schurmann, Satu Kaksonen, Armand Valsesia, Carina Wallgren-Pettersson, Barbara Leube, Alexandra I. F. Blakemore, Alexandre Moerman, Marco Belfiore, Anne Faudet, Dominique Gaillard, Roberto Ravazzolo, Dominique Bonneau, Marjo-Riitta Järvelin, Yongguo Yu, Louis Vallée, Bénédicte Demeer, Sophie Visvikis-Siest, Frédérique Béna, Brigitte H. W. Faas, Benoit Arveiler, Georg Homuth, Charles Coutton, Bénédicte de Fréminville, Giorgio Gimelli, Xavier Estivill, Richard I. Fisher, Stefania Gimelli, Wendy Roberts, Jacques S. Beckmann, Emilie Landais, Orah S. Platt, Robin G. Walters, Gudmar Thorleifsson, Alexandre Reymond, Anna-Liisa Hartikainen, Solenn Legallic, James F. Gusella, Peter Vollenweider, Gian Paolo Ramelli, Tõnu Esko, Boris Keren, Nine V A M Knoers, Fanny Morice-Picard, Dominique Campion, Odile Boute, Evica Rajcan-Separovic, Rolph Pfundt, Nathalie Bednarek, Martine Doco-Fenzy, Suzanne M E Lewis, Gérard Didelot, Mylène Beri, Engilbert Sigurdsson, Véronique Satre, Audrey Labalme, Carola Tengstrom, Florian Kronenberg, Florence Petit, Simon Zwolinksi, Philippe Froguel, Paul Elliott, Dorothée Cailley, Christian R. Marshall, Bruno Leheup, Klaus Dieterich, Janina S. Ried, Sylvie Jaillard, Armand Bottani, Stylianos E. Antonarakis, Elisabetta Lapi, Jean-Christophe Cuvellier, Robert M. Witwicki, Gérard Waeber, Christèle Dubourg, Marion Gérard, Lachlan J. M. Coin, Magalie Barth, Anita Kloss-Brandstätter, Vincent Mooser, Cristóbal Richart, Giuseppe Merla, Bénédicte Duban-Bedu, Yiping Shen, Ants Kurg, Audrey Guilmatre, Juliane Hoyer, Susana Jiménez-Murcia, Mafalda Mucciolo, Bai-Lin Wu, Alessandra Ferrarini, Séverine Drunat, Yves Alembik, Páll Magnússon, Han G. Brunner, Maria Antonietta Mencarelli, Dominique Descamps, R. Frank Kooy, Azzedine Aboura, Valérie Layet, Sven Bergmann, Thomas Meitinger, Peter M. Kroisel, Nathalie Van der Aa, Olivier Guillin, Michèle Mathieu-Dramard, Zoltán Kutalik, Elisabeth Flori, Laurent Pasquier, André Reis, Noam D. Beckmann, Bertrand Isidor, Delphine Héron, Philippe Jonveaux, Sergi Villatoro Gomez, Ann Nordgren, José Manuel Fernández-Real, Florence Fellmann, Fernando Fernández-Aranda, Laurence Faivre, Dimitri J. Stavropoulos, Katrin Männik, Christian Gieger, Evald Saemundsen, Agnès Guichet, Jean-Marie Cuisset, R. Touraine, Laura Bernardini, Marie-Ange Delrue, Alessandra Renieri, Omar Gustafsson, Flore Zufferey, David A. Koolen, Massimiliano Rossi, Jacqueline Chrast, Ghislaine Plessis, Faida Walha, Joris Andrieux, Ellen van Binsbergen, Albert David, Catherine Vincent-Delorme, Cédric Le Caignec, Jean Chiesa, Ndeye Coumba Ndiaye, Geraldine Joly Helas, Damien Sanlaville, Anita Rauch, Louise Harewood, Mark I. McCarthy, Bridget A. Fernandez, Sébastien Jacquemont, Hreinn Stefansson, Anneke T. Vulto-van Silfhout, Zdenek Jaros, Matthias Nauck, Hans J. Grabe, Sonia Bouquillon, Mieke M. van Haelst, Andres Metspalu, Loyse Hippolyte, Patrick Callier, Bert B.A. de Vries, Francisco J. Tinahones, Nicole de Leeuw, Julia S. El-Sayed Moustafa, Claudine Rieubland, Kay D. MacDermot, Vittoria Disciglio, Henry Völzke, Caroline Rooryck, Bettina Blaumeiser, Danielle Martinet, Marie-Claude Addor, Bruno Delobel, Jacquemont, S, Reymond, A, Zufferey, F, Harewood, L, Walters, Rg, Kutalik, Z, Martinet, D, Shen, Y, Valsesia, A, Beckmann, Nd, Thorleifsson, G, Belfiore, M, Bouquillon, S, Campion, D, de Leeuw, N, de Vries, Bb, Esko, T, Fernandez, Ba, Fernández-Aranda, F, Fernández-Real, Jm, Gratacòs, M, Guilmatre, A, Hoyer, J, Jarvelin, Mr, Kooy, Rf, Kurg, A, Le Caignec, C, Männik, K, Platt, O, Sanlaville, D, Van Haelst, Mm, Villatoro Gomez, S, Walha, F, Wu, Bl, Yu, Y, Aboura, A, Addor, Mc, Alembik, Y, Antonarakis, Se, Arveiler, B, Barth, M, Bednarek, N, Béna, F, Bergmann, S, Beri, M, Bernardini, L, Blaumeiser, B, Bonneau, D, Bottani, A, Boute, O, Brunner, Hg, Cailley, D, Callier, P, Chiesa, J, Chrast, J, Coin, L, Coutton, C, Cuisset, Jm, Cuvellier, Jc, David, A, de Freminville, B, Delobel, B, Delrue, Ma, Demeer, B, Descamps, D, Didelot, G, Dieterich, K, Disciglio, V, Doco-Fenzy, M, Drunat, S, Duban-Bedu, B, Dubourg, C, El-Sayed Moustafa, J, Elliott, P, Faas, Bh, Faivre, L, Faudet, A, Fellmann, F, Ferrarini, A, Fisher, R, Flori, E, Forer, L, Gaillard, D, Gerard, M, Gieger, C, Gimelli, S, Gimelli, G, Grabe, Hj, Guichet, A, Guillin, O, Hartikainen, Al, Heron, D, Hippolyte, L, Holder, M, Homuth, G, Isidor, B, Jaillard, S, Jaros, Z, Jiménez-Murcia, S, Helas, Gj, Jonveaux, P, Kaksonen, S, Keren, B, Kloss-Brandstätter, A, Knoers, Nv, Koolen, Da, Kroisel, Pm, Kronenberg, F, Labalme, A, Landais, E, Lapi, E, Layet, V, Legallic, S, Leheup, B, Leube, B, Lewis, S, Lucas, J, Macdermot, Kd, Magnusson, P, Marshall, C, Mathieu-Dramard, M, Mccarthy, Mi, Meitinger, T, Mencarelli, Ma, Merla, G, Moerman, A, Mooser, V, Morice-Picard, F, Mucciolo, M, Nauck, M, Ndiaye, Nc, Nordgren, A, Pasquier, L, Petit, F, Pfundt, R, Plessis, G, Rajcan-Separovic, E, Ramelli, Gp, Rauch, A, Ravazzolo, R, Reis, A, Renieri, A, Richart, C, Ried, J, Rieubland, C, Roberts, W, Roetzer, Km, Rooryck, C, Rossi, M, Saemundsen, E, Satre, V, Schurmann, C, Sigurdsson, E, Stavropoulos, Dj, Stefansson, H, Tengström, C, Thorsteinsdóttir, U, Tinahones, Fj, Touraine, R, Vallée, L, van Binsbergen, E, Van der Aa, N, Vincent-Delorme, C, Visvikis-Siest, S, Vollenweider, P, Völzke, H, Vulto-van Silfhout, At, Waeber, G, Wallgren-Pettersson, C, Witwicki, Rm, Zwolinksi, S, Andrieux, J, Estivill, X, Gusella, Jf, Gustafsson, O, Metspalu, A, Scherer, Sw, Stefansson, K, Blakemore, Ai, Beckmann, J, Froguel, P, Faculteit Medische Wetenschappen/UMCG, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Department of Genomics of Common Disease, Imperial College London, Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Laboratory Medicine, Boston Children's Hospital, Center for Human Genetic Research, Massachusetts General Hospital [Boston], Ludwig Institute for Cancer Research, deCODE Genetics, deCODE genetics [Reykjavik], Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Estonian Genome and Medicine, University of Tartu, Department of human genetics, Radboud University Medical Center [Nijmegen]-Nijmegen Centre for Molecular Life Sciences-Institute for Genetic and Metabolic Disorders, Institute of Molecular and Cell Biology, Disciplines of Genetics and Medicine, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Department of Psychiatry (IDIBELL), CIBERobn Fisiopatología de la Obesidad y Nutrición-University Hospital of Bellvitge, Section of Diabetes, Endocrinology and Nutrition, University Hospital of Girona-Biomedical Research Institute 'Dr Josep Trueta'-CIBERobn Fisiopatología de la Obesidad y Nutrición, Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Department of child and adolescent health, University of Oulu-Institute of Health Sciences and Biocenter Oulu-National Institute for Health and Welfare [Helsinki], Antwerp University Hospital [Edegem] (UZA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, University Medical Center [Utrecht], Institutes of Biomedical Science, Fudan University [Shanghai]-Children's Hospital, Shanghai Children's Medical Center, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de cytogénétique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Génétique médicale, Hôpitaux Universitaires de Genève (HUG), Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université de Reims Champagne-Ardenne (URCA), Department of Molecular Genetics, Weizmann Institute of Science [Rehovot, Israël], Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Service de Génétique clinique, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Cytogénétique, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-faculté de médecine-pharmacie, AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Service de Neuropédiatrie, Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), CHU Amiens-Picardie, Centre Hospitalier de Béthune (CH Béthune), GHT de l'Artois, Service de Génétique Clinique, Department of Biotechnology, Università degli Studi di Siena = University of Siena (UNISI)-Medical Genetics, Service de Génétique, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Department of Epidemiology and Public Health, Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Department of Experimental Cardiology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Heart Failure Research Center (HFRC), CHU Pitié-Salpêtrière [AP-HP], Institute of human genetics, International Centre for Life, Division of genetic epidemiology, HMNC Brain Health-Molecular and Clinical Pharmacology-Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Department of Obstetrics and Gynecology, University of Oulu-Institute of Clinical Medicine, Laboratorio di citogenetica, G. Gaslini Institute, Department of Psychiatry and Psychotherapy, Universität Greifswald - University of Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Abteilung für Kinder und Jugendheilkunde, Landesklinikum Waldviertel Zwettl, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), The Habilitation Unit of Folkhalsan, Medical University Graz, Medical Genetics Unit, Children's Hospital Anna Meyer, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Institute of Human Genetics and Anthropology, Heinrich-Heine University Hospital Duesseldorf, Child and Family Research Institute-University of British Columbia (UBC), North West Thames Regional Genetics Service, Northwick Park & St Marks Hospital, Child and Adolescent Psychiatry, Landspitali University Hospital, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, The Wellcome Trust Centre for Human Genetics [Oxford], Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Genetics, GlaxoSmithKline R&D, GlaxoSmithKline, Institute of Clinical Chemistry and Laboratory Medicine, Génétique cardiovasculaire (GC), Université Henri Poincaré - Nancy 1 (UHP), Molecular Medicine and Surgery department, Karolinska Institutet [Stockholm], Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Pathology, Division of pediatrics, Ospedale San Giovanni, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Department of pediatrics and CEBR, Università degli studi di Genova = University of Genoa (UniGe)-G. Gaslini Institute, Department of Internal Medicine, Universitat Rovira i Virgili-University Hospital Juan XXIII-Instituto Salud Carlos III-Ciber Fisiopatologia Obesidad y Nutricion (CIBEROBN), Division of Human Genetics, Department of Paediatrics, Inselspital-University of Bern, Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, State Diagnostic, Counseling Center, University of Iceland [Reykjavik], Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Genetic Services, Rinnekoti Research Foundation, Department of Endocrinology and Nutrition, Instituto Salud Carlos III-Clinic Hospital of Virgen de la Victoria-Ciber Fisiopatologia y Nutricion (CIBEROBN), Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, Institute for Community Medicine, Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Leenaards Foundation Prize (SJ, DM and AR), the Jérôme Lejeune Foundation (AR), the Telethon Action Suisse Foundation (AR), the Swiss National Science Foundation (AR, JSB, SB and SEA), a SNSF Sinergia grant (SJ, DM, SB, JSB and AR), the European Commission anEUploidy Integrated Project grant 037627 (AR, SB, XE, HGB and SEA), the Ludwig Institute for Cancer Research (AV), the Swiss Institute of Bioinformatics (SB, ZK), an Imperial College Dept of Medicine PhD studentship (JSe-SM), the Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust, and the National Institute for Health Research (PE), the Wellcome Trust and the Medical Research Council (AIFB and PF), the Instituto de Salud Carlos III (ISCIII)-FIS, the German Mental Retardation Network funded through a grant of the German Federal Ministry of Education and Research (NGFNplus 01GS08160) to A Reis and European Union-FEDER (PI081714, PS09/01778), SAF2008-02278 (XE, MG, FFA), the Belgian National Fund for Scientific Research - Flanders (NVA, RFK), the Dutch Organisation for Health Research and Development (ZONMW grant 917-86-319) and Hersenstichting Nederland (BBAdV), grant 81000346 from the Chinese National Natural Science Foundation (YGY), the Simons Foundation Autism Research Initiative, Autism Speaks and NIH grant GM061354 (JFG), and the OENB grant 13059 (AK-B). YS holds a Young Investigator Award from the Children's Tumor Foundation and Catalyst Award from Harvard Medical School, and BLW, a Fudan Scholar Research Award from Fudan University, a grant from Chinese National '973' project on Population and Health (2010CB529601) and a grant from Science and Technology Council of Shanghai (09JC1402400). ERS and SL, recipients of the Michael Smith Foundation for Health Research Scholar award, acknowledge the CIHR MOP 74502 operational grant. EGCUT received support from the EU Centre of Excellence in Genomics and FP7 grants #201413 and #245536, from Estonian Government SF0180142s08, SF0180026s09 and SF0180027s10 (AM, KM, AK). The Helmholtz Zentrum Munich and the State of Bavaria financed KORA, also supported by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823), the German Federal Ministry of Education and Research (BMBF), and the Munich Center of Health Sciences (MC Health, LMUinnovativ). CIBEROBN and CIBERESP are initiatives of ISCIII (Spain). SWS holds the GlaxoSmithKline-Canadian Institutes of Health (CIHR) Chair in Genetics, Genomics at the University of Toronto and the Hospital for Sick Children and is supported by Genome Canada and the McLaughlin Centre. deCODE was funded in part by NIH grant MH071425 (KS), EU grant HEALTH-2007-2.2.1-10-223423 (Project PsychCNV) and EU grant IMI-JU-NewMeds., Centre de génomique intégrative, Université de Lausanne (UNIL), Swiss Institute of Bioinformatics (SIB), Swiss Institute of Bioinformatics, Memorial University of Newfoundland [St. John's], Friedrich Alexander University [Erlangen-Nürnberg], Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Weizmann Institute of Science, IRCCS Casa Sollievo della Sofferenza Hospital, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Saint-Etienne-Hôpital nord, Hôpital Saint Vincent de Paul-GHICL, Centre hospitalier de Béthune, Università degli Studi di Siena (UNISI)-Medical Genetics, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Innsbruck Medical University [Austria] (IMU)-HMNC Brain Health-Molecular and Clinical Pharmacology, Czech Academy of Sciences [Prague] (ASCR), University of Oxford [Oxford], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, University of Zürich [Zürich] (UZH), Universita degli studi di Genova -G. Gaslini Institute, University of Toronto-The Hospital for Sick Children, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), De Villemeur, Hervé, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland., Other departments, Reymond, Alexandre, Antonarakis, Stylianos, Sloan Bena, Frédérique, Bottani, Armand, Callier, Patrick, Gimelli, Stefania, Merla, Giuseppe, Vollenweider, Peter, Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Université de Lille-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Aging, Transcription, Genetic, Adolescent, Adult, Aged, Body Height, Body Mass Index, Case-Control Studies, Child, Child, Preschool, Chromosomes, Human, Pair 16, Cohort Studies, Comparative Genomic Hybridization, Developmental Disabilities, Energy Metabolism, Europe, Female, Gene Dosage, Gene Duplication, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Head, Heterozygote, Humans, Infant, Infant, Newborn, Mental Disorders, Middle Aged, Mutation, North America, Obesity, Phenotype, RNA, Messenger, Sequence Deletion, Thinness, Young Adult, Physiology, RNA, Messenger/analysis/genetics, Genome-wide association study, HIDDEN-MARKOV MODEL, 0302 clinical medicine, Sequence Deletion/genetics, ddc:576.5, 0303 health sciences, education.field_of_study, Body Height/genetics, Genetic Predisposition to Disease/genetics, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, population characteristics, Chromosomes, Human, Pair 16/genetics, Human, Locus (genetics), Gene Duplication/genetics, Article, 03 medical and health sciences, Genetic, education, SNP GENOTYPING DATA, Thinness/genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Pair 16, Case-control study, nutritional and metabolic diseases, social sciences, medicine.disease, DEPENDENT PROBE AMPLIFICATION, Human medicine, Body mass index, 030217 neurology & neurosurgery, Messenger, Obesity/genetics, FAILURE-TO-THRIVE, [SDV.GEN] Life Sciences [q-bio]/Genetics, Head/anatomy & histology, METABOLIC SYNDROME, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, Genetics, Multidisciplinary, TIME QUANTITATIVE PCR, Failure to thrive, medicine.symptom, Underweight, Transcription, geographic locations, Mutation/genetics, Population, Biology, Chromosomes, 150 000 MR Techniques in Brain Function, medicine, Preschool, 030304 developmental biology, COPY NUMBER VARIATION, Mental Disorders/genetics, Energy Metabolism/genetics, RELATIVE QUANTIFICATION, Gene Dosage/genetics, Newborn, BODY-MASS INDEX, CIRCULAR BINARY SEGMENTATION, RNA, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], human activities, Developmental Disabilities/genetics
Abstract

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance. Leenaards Foundation Jerome Lejeune Foundation Telethon Action Suisse Foundation Swiss National Science Foundation European Commission 037627 QLG1-CT-2000-01643 Ludwig Institute for Cancer Research Swiss Institute of Bioinformatics Imperial College Department of Medicine Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust National Institute for Health Research Wellcome Trust Medical Research Council Instituto de Salud Carlos III (ISCIII)-FIS German Mental Retardation Network German Federal Ministry of Education and Research NGFNplus 01GS08160 European Union PI081714 PS09/01778 201413 245536 info:eu-repo/grantAgreement/EC/FP7/223423 Belgian National Fund for Scientific Research, Flanders Dutch Organisation for Health Research and Development (ZON-MW) 917-86-319 Hersenstichting Nederland (B.B.A.d.V.) Chinese National Natural Science Foundation 81000346 Simons Foundation Autism Research Initiative Autism Speaks NIH GM061354 MH071425 Oesterreichische Nationalbank (OENB) 13059 Children's Tumor Foundation Harvard Medical School Fudan University Chinese National '973' project on Population and Health 2010CB529601 Science and Technology Council of Shanghai 09JC1402400 Michael Smith Foundation for Health CIHR MOP 74502 Estonian Government SF0180142s08 SF0180026s09 SF0180027s10 Helmholtz Zentrum Munich State of Bavaria German National Genome Research Network 01GS0823 German Federal Ministry of Education and Research (BMBF) Munich Center of Health Sciences (MC Health, LMUinnovativ) Genome Canada McLaughlin Centre Academy of Finland 104781 120315 129269 1114194 University Hospital Oulu Biocenter University of Oulu, Finland 75617 NHLBI 5R01HL087679-02 1RL1MH083268-01 NIH/NIMH 5R01MH63706:02 ENGAGE project Medical Research Council, UK G0500539 G0600705 Academy of Finland Biocentrum Helsinki SAF2008-02278 HEALTH-F4-2007-201413

Published
2011
Full Text
View/download PDF

47. The urothelial gene regulatory network: understanding biology to improve bladder cancer management.

Author

Ramal M, Corral S, Kalisz M, Lapi E, and Real FX

Subjects
Humans, Gene Regulatory Networks, Urothelium pathology, Transcription Factors genetics, Genomics, Biomarkers, Tumor genetics, Urinary Bladder Neoplasms pathology, Carcinoma, Transitional Cell pathology
Abstract

The urothelium is a stratified epithelium composed of basal cells, one or more layers of intermediate cells, and an upper layer of differentiated umbrella cells. Most bladder cancers (BLCA) are urothelial carcinomas. Loss of urothelial lineage fidelity results in altered differentiation, highlighted by the taxonomic classification into basal and luminal tumors. There is a need to better understand the urothelial transcriptional networks. To systematically identify transcription factors (TFs) relevant for urothelial identity, we defined highly expressed TFs in normal human bladder using RNA-Seq data and inferred their genomic binding using ATAC-Seq data. To focus on epithelial TFs, we analyzed RNA-Seq data from patient-derived organoids recapitulating features of basal/luminal tumors. We classified TFs as "luminal-enriched", "basal-enriched" or "common" according to expression in organoids. We validated our classification by differential gene expression analysis in Luminal Papillary vs. Basal/Squamous tumors. Genomic analyses revealed well-known TFs associated with luminal (e.g., PPARG, GATA3, FOXA1) and basal (e.g., TP63, TFAP2) phenotypes and novel candidates to play a role in urothelial differentiation or BLCA (e.g., MECOM, TBX3). We also identified TF families (e.g., KLFs, AP1, circadian clock, sex hormone receptors) for which there is suggestive evidence of their involvement in urothelial differentiation and/or BLCA. Genomic alterations in these TFs are associated with BLCA. We uncover a TF network involved in urothelial cell identity and BLCA. We identify novel candidate TFs involved in differentiation and cancer that provide opportunities for a better understanding of the underlying biology and therapeutic intervention., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2024
Full Text
View/download PDF

48. STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cells.

Author

Richart L, Lapi E, Pancaldi V, Cuenca-Ardura M, Pau EC, Madrid-Mencía M, Neyret-Kahn H, Radvanyi F, Rodríguez JA, Cuartero Y, Serra F, Le Dily F, Valencia A, Marti-Renom MA, and Real FX

Subjects
Base Sequence, Cell Cycle Proteins antagonists & inhibitors, Cell Cycle Proteins metabolism, Cell Line, Tumor, Chromatin metabolism, Chromosomal Proteins, Non-Histone genetics, Chromosomal Proteins, Non-Histone metabolism, DNA, Neoplasm genetics, DNA, Neoplasm metabolism, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Ontology, HEK293 Cells, Histones genetics, Histones metabolism, Humans, Molecular Sequence Annotation, Nuclear Proteins metabolism, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Signal Transduction, Urinary Bladder Neoplasms metabolism, Urinary Bladder Neoplasms pathology, Cell Cycle Proteins genetics, Chromatin chemistry, Loss of Function Mutation, Nuclear Proteins genetics, Transcription, Genetic, Urinary Bladder Neoplasms genetics
Abstract

Cohesin exists in two variants containing STAG1 or STAG2. STAG2 is one of the most mutated genes in cancer and a major bladder tumor suppressor. Little is known about how its inactivation contributes to tumorigenesis. Here, we analyze the genomic distribution of STAG1 and STAG2 and perform STAG2 loss-of-function experiments using RT112 bladder cancer cells; we then analyze the genomic effects by integrating gene expression and chromatin interaction data. Functional compartmentalization exists between the cohesin complexes: cohesin-STAG2 displays a distinctive genomic distribution and mediates short and mid-ranged interactions that engage genes at higher frequency than those established by cohesin-STAG1. STAG2 knockdown results in down-regulation of the luminal urothelial signature and up-regulation of the basal transcriptional program, mirroring differences between STAG2-high and STAG2-low human bladder tumors. This is accompanied by rewiring of DNA contacts within topological domains, while compartments and domain boundaries remain refractive. Contacts lost upon depletion of STAG2 are assortative, preferentially occur within silent chromatin domains, and are associated with de-repression of lineage-specifying genes. Our findings indicate that STAG2 participates in the DNA looping that keeps the basal transcriptional program silent and thus sustains the luminal program. This mechanism may contribute to the tumor suppressor function of STAG2 in the urothelium., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Published
2021
Full Text
View/download PDF

49. Mosaic Segmental and Whole-Chromosome Upd(11)mat in Silver-Russell Syndrome.

Author

Pignata L, Sparago A, Palumbo O, Andreucci E, Lapi E, Tenconi R, Carella M, Riccio A, and Cerrato F

Subjects
Adolescent, Chromosomes, Human, Pair 11 genetics, Humans, Male, Mosaicism, Pedigree, Silver-Russell Syndrome diagnosis, Young Adult, Genomic Imprinting, Maternal Inheritance, Silver-Russell Syndrome genetics, Uniparental Disomy genetics
Abstract

Molecular defects altering the expression of the imprinted genes of the 11p15.5 cluster are responsible for the etiology of two congenital disorders characterized by opposite growth disturbances, Silver-Russell syndrome (SRS), associated with growth restriction, and Beckwith-Wiedemann syndrome (BWS), associated with overgrowth. At the molecular level, SRS and BWS are characterized by defects of opposite sign, including loss (LoM) or gain (GoM) of methylation at the H19/IGF2 :intergenic differentially methylated region ( H19/IGF2 :IG-DMR), maternal or paternal duplication (dup) of 11p15.5, maternal (mat) or paternal (pat) uniparental disomy (upd), and gain or loss of function mutations of CDKN1C . However, while upd(11)pat is found in 20% of BWS cases and in the majority of them it is segmental, upd(11)mat is extremely rare, being reported in only two SRS cases to date, and in both of them is extended to the whole chromosome. Here, we report on two novel cases of mosaic upd(11)mat with SRS phenotype. The upd is mosaic and isodisomic in both cases but covers the entire chromosome in one case and is restricted to 11p14.1-pter in the other case. The segmental upd(11)mat adds further to the list of molecular defects of opposite sign in SRS and BWS, making these two imprinting disorders even more specular than previously described.

Published
2021
Full Text
View/download PDF

50. Essential Roles of Cohesin STAG2 in Mouse Embryonic Development and Adult Tissue Homeostasis.

Author

De Koninck M, Lapi E, Badía-Careaga C, Cossío I, Giménez-Llorente D, Rodríguez-Corsino M, Andrada E, Hidalgo A, Manzanares M, Real FX, and Losada A

Subjects
Animals, Homeostasis, Mice, Mice, Knockout, Cohesins, Cell Cycle Proteins metabolism, Chromosomal Proteins, Non-Histone metabolism, Embryonic Development physiology
Abstract

Cohesin mediates sister chromatid cohesion and 3D genome folding. Two versions of the complex carrying STAG1 or STAG2 coexist in somatic vertebrate cells. STAG2 is commonly mutated in cancer, and germline mutations have been identified in cohesinopathy patients. To better understand the underlying pathogenic mechanisms, we report the consequences of Stag2 ablation in mice. STAG2 is largely dispensable in adults, and its tissue-wide inactivation does not lead to tumors but reduces fitness and affects both hematopoiesis and intestinal homeostasis. STAG2 is also dispensable for murine embryonic fibroblasts in vitro. In contrast, Stag2-null embryos die by mid-gestation and show global developmental delay and defective heart morphogenesis, most prominently in structures derived from secondary heart field progenitors. Both decreased proliferation and altered transcription of tissue-specific genes contribute to these defects. Our results provide compelling evidence on cell- and tissue-specific roles of different cohesin complexes and how their dysfunction contributes to disease., Competing Interests: Declaration of Interests The authors declare no competing interests, (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2020
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results