Carla Cossu

AIRE acetylation and deacetylation: effect on protein stability and transactivation activity.

BackgroundThe AIRE protein plays a remarkable role as a regulator of central tolerance by controlling the promiscuous expression of tissue-specific antigens in thymic medullary epithelial cells. Defects in AIRE gene cause the autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy, a rare disease frequent in Iranian Jews, Finns, and Sardinian population.AIRE protein is primarily known as a transcriptional regulator and is capable of interacting with numerous proteins. The first characterized partner of AIRE is the ubiquitous transcription factor CREB-binding protein (CBP), which regulates DNA transcription through the acetylation and deacetylation of histones. More recently, the role of p300 in AIRE acetylation, which could influence the selection of AIRE activated genes, has been described.ResultsIn this study, we have precisely mapped, by mass spectrometry experiments, the sites of protein acetylation and, by mutagenesis assays, we have described a set of acetylated lysines as being crucial in influencing the subcellular localization of AIRE. Furthermore, we have also determined that the de-acetyltransferase enzymes HDAC1-2 are involved in the lysine de-acetylation of AIRE.ConclusionsOn the basis of our results and those reported in literature, we propose a model in which lysines acetylation increases the stability of AIRE in the nucleus. In addition, we observed that the interaction of AIRE with deacetylases complexes inhibits its transcriptional activity and is probably responsible for the instability of AIRE, which becomes more susceptible to degradation in the proteasome.

New mutations in DYNC2H1 and WDR60 genes revealed by whole-exome sequencing in two unrelated Sardinian families with Jeune asphyxiating thoracic dystrophy

Jeune asphyxiating thoracic dystrophy (JATD; Jeune syndrome, MIM 208500) is a rare autosomal recessive chondrodysplasia, phenotypically overlapping with short-rib polydactyly syndromes (SRPS). JATD typical hallmarks include skeletal abnormalities such as narrow chest, shortened ribs, limbs shortened bones, extra fingers and toes (polydactyly), as well as extraskeletal manifestations (renal, liver and retinal disease). To date, disease-causing mutations have been found in several genes, highlighting a marked genetic heterogeneity that prevents a molecular diagnosis of the disease in most families. Here, we report the results of whole-exome sequencing (WES) carried out in four JATD cases, belonging to three unrelated families of Sardinian origin. The exome analysis allowed to identify mutations not previously reported in the DYNC2H1 (MIM 603297) and WDR60 (MIM 615462) genes, both codifying for ciliary intraflagellar transport components whose mutations are known to cause Jeune syndrome.

Loss of CBL E3-ligase activity in B-lineage childhood acute lymphoblastic leukaemia

lated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycle of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage Hodgkin’s lymphoma: final analysis of the HD 12 trial of ther German Hodgkin Study Group. Journal of Clinical Oncology, 29, 4234–4242. Engert, A., Diehl, V., Franklin, J., Lohri, A., Dörken, B., Ludwig, W., Koch, P., Hänel, M., Pfreundschuh, M., Wilhelm, M., Trümper, L., Aulitzky, W., Bentz, M., Rummel, M., Sezer, O., Müller-Hermelink, H.K., Hasenclever, D. & Loffler, M. (2009) Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin’s lymphoma: 10 years of follow-up of the GHSG HD9 study. Journal of Clinical Oncology, 2009, 4548–4554. Engert, A., Haverkamp, H., Kobe, C., Markova, J., Renner, C., Ho, A., Zijlstra, J., Fuchs, M., Hallek, M., Kanz, L., Döhner, H., Dörken, B., Engel, N., Klutmann, S., Amthauer, H., Bockisch, A., Kulge, R., Kratochwil, C., Schober, O., Greil, R., Andreesen, R., Kneba, M., Pfreundschuh, M., Stein, H., Eich, H.T., Müller, R., Dietlein, M., Borchmann, P. & Diehl, V. (2012) Reduced-intensity chemotherapy and PETguided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomized, open-label, phase 3 non-inferiority trial. Lancet, 379, 1791–1799. Federico, M., Luminari, S., Iannitto, E., Polimeno, G., Marcheselli, L., Montanini, A., La Sala, A., Merli, F., Stelitano, C., Pozzi, S., Scalone, R., Di Renzo, N., Musto, P., Baldini, L., Cervetti, G., Angrilli, F., Mazza, P., Brugiatelli, M. & Gobbi, P.G. (2009) ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin’s lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi trial. Journal of Clinical Oncology, 27, 805–811. Hasenclever, D., Diehl, V., Armitage, J.O., Assouline, D., Bjorkholm, M., Brusamolino, E., Canellos, G., Carde, P., Crowther, D., Cunningham, D., Eghbali, H., Ferm, C., Fisher, R., Glick, J., Glimelius, B., Gobbi, P., Holte, H., Horning, S., Lister, A., Longo, D., Mandelli, F., Polliack, A., Proctor, S., Specht, L., Sweetenham, J. & Hudson, G. (1998) A prognostic score for advanced Hodgkin’s disease. New England Journal of Medicine, 339, 1506–1514. Johnson, P.W.M., Radford, J.A., Cullen, M.H., Sydes, M.R., Walewski, J., Jack, A.S., MacLenna, K.A., Stenning, S.P., Clawson, S., Smith, P., Ryder, D. & Hancock, B.W. (2005) Comparison of ABVD and alternating or hybrid multidrug regimens for the treatment of advanced Hodgkin’s Lymphoma: results of the United Kingdom Lymphoma Group LY09 Trial (ISRCTN97144519). Journal of Clinical Oncology, 23, 9208–9218. Lavoie, J.C., Connors, J.M., Phillips, G.L., Reece, D.E., Barnett, M.J., Forrest, D.L., Gascoyne, R. D., Hogge, D.E., Nantel, S.H., Shepherd, J.D., Smith, C.A., Song, K.W., Sutherland, H.J., Toze, C.L., Voss, N. & Nevill, T.J. (2005) High-dose chemotherapy and autologous stem cell transplantation for primary refractory or relapse Hogdkin lymphoma: long-term outcome in the first 100 patients treated in Vancouver. Blood, 106, 1473–1478. NCCN Clinical Practice Guidelines in Oncology (2012) Hodgkin lymphoma. Version 2.2012. http://www.nccn.org/professionals/physician_gls/ pdf/hodgkins.pdf Viviani, S., Zinzani, P.L., Rambaldi, A., Brusamolino, E., Levis, A., Bonfante, V., Vitolo, U., Pulsoni, A., Liberati, A.M., Specchia, G., Valagussa, P., Rossi, A., Zaja, F., Pogliani, E.M., Pregno, P., Gotti, M., Gallamini, A., Scalabrini, D.R., Bonadonna, G. & Gianni, M. (2011) ABVD versus BEACOPP for Hodgkin’s lymphoma when high-dose salvage is planned. New England Journal of Medicine, 365, 203–212.

β-defensin CNV is not associated with susceptibility to Candida albicans infections in Sardinian APS I patients.

OBJECTIVE The aim of this study was to investigate whether a variation in the genomic copy number (CNV) of the β-defensin cluster could be associated with the pre-disposition to chronic mucocutaneous candidiasis (CMC) in Sardinian APECED patients. SUBJECTS AND METHODS The β-defensin copy number variation was determined by MLPA analysis in 18 Sardinian APECED patients with CMC and in 21 Sardinian controls. Statistical analyses were performed with one-way ANOVA test. RESULTS No statistically significant results were observed between the patients and controls groups. CONCLUSIONS According to the results we have obtained, it appears that either β-defensin genomic CNV is not a modifier locus for CMC susceptibility in APECED patients, or any effect is too small for it to be detected using such sample size. An extensive study on APECED patients from different geographical areas might reveal the real implication of the β-defensin CNV in the susceptibility to Candida albicans infections.