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

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.