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Expanding CEP290 mutational spectrum in ciliopathies

Authors

  • Lorena Travaglini,

    1. CSS-Mendel Institute, Casa Sollievo della Sofferenza Hospital, Rome, Italy
    2. Department of Experimental Medicine, Sapienza University, Rome, Italy
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  • Francesco Brancati,

    1. CSS-Mendel Institute, Casa Sollievo della Sofferenza Hospital, Rome, Italy
    2. Department of Biomedical Sciences, CeSI, Aging Research Centre, G. d'Annunzio University Foundation, Chieti, Italy
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  • Tania Attie-Bitach,

    1. Department of Genetics, Necker-Enfants Malades Hospital, University Paris Descartes, Paris, France
    2. INSERM U781, Necker-Enfants Malades Hospital, Paris, France
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  • Sophie Audollent,

    1. Department of Genetics, Necker-Enfants Malades Hospital, University Paris Descartes, Paris, France
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  • Enrico Bertini,

    1. Department of Laboratory Medicine, IRCCS Bambino Gesù Hospital, Rome, Italy
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  • Josseline Kaplan,

    1. INSERM U781, Necker-Enfants Malades Hospital, Paris, France
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  • Isabelle Perrault,

    1. INSERM U781, Necker-Enfants Malades Hospital, Paris, France
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  • Miriam Iannicelli,

    1. CSS-Mendel Institute, Casa Sollievo della Sofferenza Hospital, Rome, Italy
    2. Department of Experimental Medicine, Sapienza University, Rome, Italy
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  • Brunella Mancuso,

    1. CSS-Mendel Institute, Casa Sollievo della Sofferenza Hospital, Rome, Italy
    2. Department of Experimental Medicine, Sapienza University, Rome, Italy
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  • Luciana Rigoli,

    1. Department of Medical and Surgical Paediatric Sciences, University of Messina, Messina, Italy
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  • Jean-Michel Rozet,

    1. INSERM U781, Necker-Enfants Malades Hospital, Paris, France
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  • Dominika Swistun,

    1. Neurogenetics Laboratory, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California
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  • Jerlyn Tolentino,

    1. Neurogenetics Laboratory, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California
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  • The International JSRD Study Group,

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    • Members of the International JSRD Study Group are: A. Zankl (Brisbane, Australia); R. Leventer (Parkville, Australia); P. Grattan-Smith (Sydney, Australia); A. Janecke (Innsbruck, Austria); M. D'Hooghe (Brugge, Belgium); Y. Sznajer (Bruxelles, Belgium); R. Van Coster (Ghent, Belgium); L. Demerleir (Brussels, Belgium); K. Dias, C. Moco, A. Moreira (Porto Alegre, Brazil); C. Ae Kim (Sao Paulo, Brazil); G. Maegawa (Toronto, Canada); D. Petkovic (Zagreb, Croatia); G.M.H. Abdel-Salam, A. Abdel-Aleem, M.S. Zaki (Cairo, Egypt); I. Marti, S. Quijano-Roy (Garches, France); S. Sigaudy (Marseille, France); P. de Lonlay, S. Romano (Paris, France); R. Touraine (St. Etienne, France); M. Koenig, C. Lagier-Tourenne, J. Messer (Strasbourg, France); P. Collignon (Toulon, France); N. Wolf (Heidelberg, Germany); H. Philippi (Mainz, Germany); S. Kitsiou Tzeli (Athens, Greece); S. Halldorsson, J. Johannsdottir, P. Ludvigsson (Reykjavik, Iceland); S.R. Phadke (Lucknow, India); V. Udani (Mumbay, India); B. Stuart (Dublin, Ireland); A. Magee (Belfast, Northern Ireland); D. Lev, M. Michelson (Holon, Israel); B. Ben-Zeev (Ramat-Gan, Israel); R. Fischetto (Bari, Italy); F. Benedicenti, F. Stanzial (Bolzano, Italy); R. Borgatti (Bosisio Parini, Italy); P. Accorsi, S. Battaglia, E. Fazzi, L. Giordano, L. Pinelli (Brescia, Italy); L. Boccone (Cagliari, Italy); S. Bigoni, A. Ferlini (Ferrara, Italy); M.A. Donati (Florence, Italy); G. Caridi, M.T. Divizia, F. Faravelli, G. Ghiggeri, A. Pessagno (Genoa, Italy); M. Briguglio, S. Briuglia, C.D. Salpietro, G. Tortorella (Messina, Italy); A. Adami, P. Castorina, F. Lalatta, G. Marra, D. Riva, B. Scelsa, L. Spaccini, G. Uziel (Milan, Italy); E. Del Giudice (Napoli, Italy); A.M. Laverda, K. Ludwig, A. Permunian, A. Suppiej (Padova, Italy); S. Signorini, C. Uggetti (Pavia, Italy); R. Battini (Pisa, Italy); M. Di Giacomo (Potenza, Italy); M.R. Cilio, M.L. Di Sabato, V. Leuzzi, P. Parisi (Rome, Italy); M. Pollazzon (Siena, Italy); M. Silengo (Torino, Italy); R. De Vescovi (Trieste, Italy); D. Greco, C. Romano (Troina, Italy); M. Cazzagon (Udine, Italy); A. Simonati (Verona, Italy); A.A. Al-Tawari, L. Bastaki, (Kuwait City, Kuwait); A. Mégarbané (Beirut, Lebanon); V. Sabolic Avramovska (Skopje, Macedonia); M.M. de Jong (Groningen, the Netherlands); P. Stromme (Oslo, Norway); R. Koul, A. Rajab (Muscat, Oman); M. Azam (Islamabad, Pakistan); C. Barbot (Oporto, Portugal); L. Martorell Sampol (Barcelona, Spain); B. Rodriguez (La Coruna, Spain); I. Pascual-Castroviejo (Madrid, Spain); S. Teber (Ankara, Turkey); B. Anlar, S. Comu, E. Karaca, H. Kayserili, A. Yüksel (Istanbul, Turkey); M. Akcakus (Kayseri, Turkey); L. Al Gazali, L. Sztriha (Al Ain, UAE); D. Nicholl (Birmingham, UK); C.G. Woods (Cambridge, UK); C. Bennett, J. Hurst, E. Sheridan (Leeds, UK); A. Barnicoat, R. Hennekam, M. Lees (London, UK); E. Blair (Oxford, UK); S. Bernes (Mesa, AZ, USA); H. Sanchez (Fremont, CA, USA); A.E. Clark (Laguna Niguel, CA, USA); E. DeMarco, C. Donahue, E. Sherr (San Francisco, CA, USA); J. Hahn, T.D. Sanger (Stanford, CA, USA); T.E. Gallager (Manoa, HI, USA); W.B. Dobyns (Chicago, IL, USA); C. Daugherty (Bangor, ME, USA); K.S. Krishnamoorthy, D. Sarco, C.A. Walsh (Boston, MA, USA); T. McKanna (Grand Rapids, MI, USA); J. Milisa (Albuquerque, NM, USA); W.K. Chung, D.C. De Vivo, H. Raynes, R. Schubert (New York, NY, USA); A. Seward (Columbus, OH, USA); D.G. Brooks (Philadephia, PA, USA); A. Goldstein (Pittsburg, PA, USA); J. Caldwell, E. Finsecke (Tulsa, OK, USA); B.L. Maria (Charleston, SC, USA), K. Holden (Mt. Pleasant, SC, USA); R.P. Cruse (Houston, TX, USA); K.J. Swoboda, D. Viskochil (Salt Lake City, UT, USA).

  • Bruno Dallapiccola,

    1. CSS-Mendel Institute, Casa Sollievo della Sofferenza Hospital, Rome, Italy
    2. Department of Experimental Medicine, Sapienza University, Rome, Italy
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  • Joseph G. Gleeson,

    1. Neurogenetics Laboratory, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California
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  • Enza Maria Valente

    Corresponding author
    1. CSS-Mendel Institute, Casa Sollievo della Sofferenza Hospital, Rome, Italy
    2. Department of Medical and Surgical Paediatric Sciences, University of Messina, Messina, Italy
    • Neurogenetics Unit, CSS-Mendel Institute, Casa Sollievo della Sofferenza Hospital, Viale Regina Margherita 261, 00198 Rome, Italy.
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  • How to cite this article: Travaglini L, Brancati F, Attie-Bitach T, Audollent S, Bertini E, Kaplan J, Perrault I, Iannicelli M, Mancuso B, Rigoli L, Rozet J, Swistun D, Tolentino J, The International JSRD Study Group, Dallapiccola B, Gleeson JG, Valente EM. 2009. Expanding CEP290 mutational spectrum in ciliopathies. Am J Med Genet Part A 149A:2173–2180.

Abstract

Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified. © 2009 Wiley-Liss, Inc.

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