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

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

Miriam Iannicelli  1 , 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 Gentilin, Silvia Majore, Dominika Swistun, Elizabeth Flori, Faustina Lalatta, Chiara Pantaleoni, Johannes Penzien, Paola Grammatico; International JSRD Study Group; Bruno Dallapiccola, Joseph G Gleeson, Tania Attie-Bitach, Enza Maria Valente
Collaborators, Affiliations

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

Miriam Iannicelli et al. Hum Mutat. 2010 May.

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.

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Figures

Figure 1
Figure 1
Conservation across species of novel TMEM67 missense mutations. *indicates affected residues
Figure 2
Figure 2
Distribution across the TMEM67 gene of truncating, splice site and missense mutations so far reported.
Figure 3
Figure 3
Distribution across the TMEM67 gene of missense mutations so far identified in patients with lethal (MKS) and non-lethal (JSRD, NPH and ARPDK-like) phenotypes. Correspondence between TMEM67 exons and predicted meckelin domains is depicted at the bottom. SP: signal peptide; CR: cystein rich domain; TM1-2-3: transmembrane segments; CC: coiled coil domain; the dashed box indicates the extracellular region of meckelin encoded by exons 8 to 15.
Figure 4
Figure 4
Combination of mutation types so far reported in patients with lethal and non-lethal phenotypes. Statistical comparison has been performed only for the three groups on the left (two truncating mutations, truncating + missense, two missense mutations). Trunc: truncating (frameshift and nonsense mutations); miss: missense; splice: splice-site affecting mutation. *p<0.05
See this image and copyright information in PMC

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