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Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies
Miriam Iannicelli1, Francesco Brancati, Soumaya Mougou-Zerelli
1Casa 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.
Insights
Mutations in the TMEM67 gene are strongly linked to Joubert syndrome with liver issues (COACH phenotype) and Meckel syndrome. Specific mutation types in TMEM67 exons 8-15 correlate with Meckel syndrome severity.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Human ciliopathies are genetic disorders stemming from primary cilium protein defects.
- Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), and nephronophthisis (NPH) share clinical and genetic characteristics.
- The TMEM67 gene, encoding the transmembrane protein meckelin, is implicated in several ciliopathies.
Purpose of the Study:
- To investigate TMEM67 mutations in Joubert syndrome and Meckel syndrome.
- To identify genotype-phenotype correlations for TMEM67 mutations.
- To confirm the association between TMEM67 and liver involvement in JSRD.
Main Methods:
- Mutation analysis of the TMEM67 gene in 341 probands (265 JSRD, 76 MKS).
- Identification and characterization of TMEM67 mutations.
- Literature review of published TMEM67 mutation cases.
- Comparative analysis of mutation types and locations in relation to phenotype.
Main Results:
- 33 distinct TMEM67 mutations identified, 20 novel.
- Mutations found in 80% of JSRD with liver involvement (COACH phenotype) and 16% of MKS fetuses.
- No TMEM67 mutations detected in other JSRD subtypes, highlighting its role in liver-specific ciliopathies.
- Missense mutations in TMEM67 exons 8-15, particularly with truncating mutations, are enriched in lethal MKS phenotypes.
Conclusions:
- TMEM67 mutations are a significant cause of JSRD with COACH phenotype and MKS.
- Specific TMEM67 mutation patterns correlate with disease severity and lethality in MKS.
- Further research into the function of meckelin's extracellular domain (encoded by exons 8-15) is warranted.
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