Exome-Sequencing Confirms DNAJC5 Mutations as Cause of Adult Neuronal Ceroid-Lipofuscinosis

We performed whole-exome sequencing in two autopsy-confirmed cases and an elderly unaffected control from a multigenerational family with autosomal dominant neuronal ceroid lipofuscinosis (ANCL). A novel single-nucleotide variation (c.344T.G) in the DNAJC5 gene was identified. Mutational screening in an independent family with autosomal dominant ANCL found an in-frame single codon deletion (c.346_348 delCTC) resulting in a deletion of p.Leu116del. These variants fulfill all genetic criteria for disease-causing mutations: they are found in unrelated families with the same disease, exhibit complete segregation between the mutation and the disease, and are absent in healthy controls. In addition, the associated amino acid substitutions are located in evolutionarily highly conserved residues and are predicted to functionally affect the encoded protein (CSPa). The mutations are located in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of CSPa. We performed a comprehensive in silico analysis of the functional and structural impact of both mutations on CSPa. We found that these mutations dramatically decrease the affinity of CSPa for the membrane. We did not identify any significant effect on palmitoylation status of CSPa. However, a reduction of CSPa membrane affinity may change its palmitoylation and affect proper intracellular sorting. We confirm that CSPa has a strong intrinsic aggregation propensity; however, it is not modified by the mutations. A complementary disease-network analysis suggests a potential interaction with other NCLs genes/pathways. This is the first replication study of th