Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies

Miriam Iannicelli, Francesco Brancati, Soumaya Mougou-Zerelli, Annalisa Mazzotta, Sophie Thomas, Nadia Elkhartoufi, Lorena Travaglini, Céline Gomes, Gian Luigi Ardissino, Enrico Bertini, Eugen Boltshauser, Pierangela Castorina, Stefano D'Arrigo, Rita Fischetto, Brigitte Leroy, Philippe Loget, Maryse Bonnière, Lena Starck, Julia Tantau, Barbara GentilinSilvia Majore, Dominika Swistun, Elizabeth Flori, Faustina Lalatta, Chiara Pantaleoni, Johannes Penzien, Paola Grammatico, Bruno Dallapiccola, Joseph G. Gleeson, Tania Attie-Bitach, Enza Maria Valente, L. Ali Pacha, M. Tazir, A. Zankl, R. Leventer, P. Grattan-Smith, A. Janecke, M. D'Hooghe, Y. Sznajer, R. Van Coster, L. Demerleir, K. Dias, C. Moco, A. Moreira, C. Ae Kim, G. Maegawa, D. Loncarevic, V. Mejaski-Bosnjak, D. Petkovic, G. M.H. Abdel-Salam, A. Abdel-Aleem, M. S. Zaki, I. Marti, S. Quijano-Roy, S. Sigaudy, P. De Lonlay, S. Romano, A. Verloes, R. Touraine, M. Koenig, C. Lagier-Tourenne, J. Messer, P. Collignon, N. Wolf, H. Philippi, J. Lemke, C. Dacou-Voutetakis, S. Kitsiou Tzeli, R. Pons, L. Sztriha, S. Halldorsson, J. Johannsdottir, P. Ludvigsson, S. R. Phadke, V. Udani, B. Stuart, A. Magee, D. Lev, M. Michelson, B. Ben-Zeev, M. Di Giacomo, M. Gentile, G. Guanti, O. D'Addato, F. Papadia, M. Spano, F. Bernardi, M. Seri, F. Benedicenti, F. Stanzial, R. Borgatti, P. Accorsi, S. Battaglia, E. Fazzi, L. Giordano, C. Izzi, L. Pinelli, L. Boccone, P. Guanciali, R. Romoli, S. Bigoni, A. Ferlini, E. Andreucci, M. A. Donati, M. Genuardi, G. Caridi, M. T. Divizia, F. Faravelli, G. Ghiggeri, A. Pessagno, M. Amorini, M. Briguglio, S. Briuglia, L. Rigoli, C. Salpietro, G. Tortorella, A. Adami, G. Marra, D. Riva, B. Scelsa, L. Spaccini, G. Uziel, G. Coppola, E. Del Giudice, G. Vitiello, A. M. Laverda, K. Ludwig, A. Permunian, A. Suppiej, C. Macaluso, S. Signorini, C. Uggetti, R. Battini, M. Di Giacomo, M. Priolo, M. R. Cilio, A. D'Amico, M. L. Di Sabato, F. Emma, V. Leuzzi, P. Parisi, G. Stringini, G. Zanni, M. Pollazzon, A. Renieri, M. Vascotto, M. Silengo, R. De Vescovi, D. Greco, C. Romano, M. Cazzagon, A. Simonati, A. A. Al-Tawari, L. Bastaki, A. Mégarbané, A. Matuleviciene, V. Sabolic Avramovska, E. Said, M. M. De Jong, T. Prescott, P. Stromme, C. Von Der Lippe, R. Koul, A. Rajab, M. Azam, C. Barbot, B. Jocic-Jakubi, B. Gener Querol, L. Martorell Sampol, B. Rodriguez, I. Pascual-Castroviejo, S. Strozzi, J. Fluss, S. Teber M, Topcu, B. Anlar, S. Comu, E. Karaca, H. Kayserili, A. Yüksel, M. Akgul, M. Akcakus, L. Al Gazali, D. Nicholl, C. G. Woods, C. Bennett, J. Hurst, E. Sheridan, A. Barnicoat, L. Carr, R. Hennekam, M. Lees, F. McKay, L. Yates, E. Blair, S. Bernes, H. Sanchez, A. E. Clark, E. DeMarco, C. Donahue, E. Sherr, J. Hahn, T. D. Sanger, T. E. Gallager, W. B. Dobyns, C. Daugherty, K. S. Krishnamoorthy, D. Sarco, C. A. Walsh, T. McKanna, J. Milisa, W. K. Chung, D. C. De Vivo, H. Raynes, R. Schubert, A. Seward, D. G. Brooks, A. Goldstein, J. Caldwell, E. Finsecke, B. L. Maria, K. Holden, R. P. Cruse, K. J. Swoboda, D. Viskochil

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Abstract

Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.

Original languageEnglish
Pages (from-to)E1319-E1331
JournalHuman mutation
Volume31
Issue number5
DOIs
Publication statusPublished - May 1 2010

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Keywords

  • COACH syndrome
  • Congenital hepatic fibrosis
  • Joubert syndrome
  • MKS3
  • Meckel syndrome
  • TMEM67

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Iannicelli, M., Brancati, F., Mougou-Zerelli, S., Mazzotta, A., Thomas, S., Elkhartoufi, N., Travaglini, L., Gomes, C., Ardissino, G. L., Bertini, E., Boltshauser, E., Castorina, P., D'Arrigo, S., Fischetto, R., Leroy, B., Loget, P., Bonnière, M., Starck, L., Tantau, J., ... Viskochil, D. (2010). Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies. Human mutation, 31(5), E1319-E1331. https://doi.org/10.1002/humu.21239