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Chanarin Dorfman Syndrome is a rare autosomal recessive disorder, characterized by triacylglycerol (TG) accumulation in lipid droplets (LDs) within different tissues including skin, liver, skeletal muscle, bone marrow, eyes, ears, and central nervous system. Here, we describe a novel ABHD5 frameshift mutation, associated with a severe manifestation of CDS. We report a severe multisystemic involvement in two patients, and an unusual neurological manifestation in one of them. In CDS, as well as in other genetic disorders, the genotype–phenotype correlation cannot completely explain clinical variability.

Joubert syndrome (JBTS) is characterized by a specific brain malformation with various additional pathologies. It results from mutations in any one of at least 10 different genes, including NPHP1, which encodes nephrocystin-1. JBTS has been linked to dysfunction of primary cilia, since the gene products known to be associated with the disorder localize to this evolutionarily ancient organelle. Here we report the identification of a disease locus, JBTS12, with mutations in the KIF7 gene, an ortholog of the Drosophila kinesin Costal2, in a consanguineous JBTS family and subsequently in other JBTS patients. Interestingly, KIF7 is a known regulator of Hedgehog signaling and a putative ciliary motor protein. We found that KIF7 co-precipitated with nephrocystin-1. Further, knockdown of KIF7 expression in cell lines caused defects in cilia formation and induced abnormal centrosomal duplication and fragmentation of the Golgi network. These cellular phenotypes likely resulted from abnormal tubulin acetylation and microtubular dynamics. Thus, we suggest that modified microtubule stability and growth direction caused by loss of KIF7 function may be an underlying disease mechanism contributing to JBTS.