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Hum Mutat. 2010 May;31(5):E1319-31. doi: 10.1002/humu.21239.

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

Collaborators (194)

Ali Pacha L, Tazir M, Zankl A, Leventer R, Grattan-Smith P, Janecke A, D'Hooghe M, Sznajer Y, Van Coster R, Demerleir L, Dias K, Moco C, Moreira A, Ae Kim C, Maegawa G, Loncarevic D, Mejaski-Bosnjak V, Petkovic D, Abdel-Salam GM, Abdel-Aleem A, Zaki MS, Marti I, Quijano-Roy S, Sigaudy S, de Lonlay P, Romano S, Verloes A, Touraine R, Koenig M, Lagier-Tourenne C, Messer J, Collignon P, Wolf N, Philippi H, Lemke J, Dacou-Voutetakis C, Kitsiou Tzeli S, Pons R, Sztriha L, Halldorsson S, Johannsdottir J, Ludvigsson P, Phadke SR, Udani V, Stuart B, Magee A, Lev D, Michelson M, Ben-Zeev B, Di Giacomo M, Gentile M, Guanti G, D'Addato O, Papadia F, Spano M, Bernardi F, Seri M, Benedicenti F, Stanzial F, Borgatti R, Accorsi P, Battaglia S, Fazzi E, Giordano L, Izzi C, Pinelli L, Boccone L, Guanciali P, Romoli R, Bigoni S, Ferlini A, Andreucci E, Donati MA, Genuardi M, Caridi G, Divizia MT, Faravelli F, Ghiggeri G, Pessagno, Amorini M, Briguglio M, Briuglia S, Rigoli L, Salpietro C, Tortorella G, Adami A, Marra G, Riva D, Scelsa B, Spaccini L, Uziel G, Coppola G, Del Giudice E, Vitiello G, Laverda AM, Ludwig K, Permunian A, Suppiej A, Macaluso C, Signorini S, Uggetti C, Battini R, Di Giacomo M, Priolo M, Cilio MR, D'Amico A, Di Sabato ML, Emma F, Leuzzi V, Parisi P, Stringini G, Zanni G, Pollazzon M, Renieri A, Vascotto M, Silengo M, De Vescovi R, Greco D, Romano C, Cazzagon M, Simonati A, Al-Tawari AA, Bastaki L, Mégarbané A, Matuleviciene A, Sabolic Avramovska V, Said E, de Jong MM, Prescott T, Stromme P, von der Lippe C, Koul R, Rajab A, Azam M, Barbot C, Jocic-Jakubi B, Gener Querol B, Martorell Sampol L, Rodriguez B, Pascual-Castroviejo I, Strozzi S, Fluss J, Teber S, Topcu M, Anlar B, Comu S, Karaca E, Kayserili H, Yüksel A, Akgul M, Akcakus M, Al Gazali L, Nicholl D, Woods CG, Bennett C, Hurst J, Sheridan E, Barnicoat A, Carr L, Hennekam R, Lees M, McKay F, Yates L, Blair E, Bernes S, Sanchez H, Clark AE, DeMarco E, Donahue C, Sherr E, Hahn J, Sanger TD, Gallager TE, Dobyns WB, Daugherty C, Krishnamoorthy KS, Sarco D, Walsh CA, McKanna T, Milisa J, Cjung WK, De Vivo DC, Raynes H, Schubert R, Seward A, Brooks DG, Goldstein A, Caldwell J, Finsecke E, Maria BL, Holden K, Cruse RP, Swoboda KJ, Viskochil D.

Author information

1
Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo and CSS-Mendel Institute, viale Regina Margherita 261, Rome, Italy.

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.

PMID:
20232449
PMCID:
PMC2918781
DOI:
10.1002/humu.21239
[Indexed for MEDLINE]
Free PMC Article
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