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

Abstract

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 (CSPα). The mutations are located in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of CSPα. We performed a comprehensive in silico analysis of the functional and structural impact of both mutations on CSPα. We found that these mutations dramatically decrease the affinity of CSPα for the membrane. We did not identify any significant effect on palmitoylation status of CSPα. However, a reduction of CSPα membrane affinity may change its palmitoylation and affect proper intracellular sorting. We confirm that CSPα 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 the identification of DNAJC5 as the disease-causing gene for autosomal dominant ANCL. The identification of the novel gene in ANCL will allow us to gain a better understanding of the pathological mechanism of ANCLs and constitutes a great advance toward the development of new molecular diagnostic tests and may lead to the development of potential therapies.

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

“…2011; Benitez et al. 2011)), and levels of CSP‐ α were also significantly modified in synapses from affected regions of CLN5 sheep brain. Similar links have been established for many of the other proteins we examined in our study, where previous data from a combined mouse/ Drosophila study identified them as potential regulators of synaptic and axonal degeneration (Wishart et al.…”

Mutations in palmitoyl-protein thioesterase 1 alter exocytosis and endocytosis at synapses in Drosophila larvae

“…Considering the recent implication of cysteine string protein (CSP) mutations (DNAJC5) in adult-onset NCL, [46][47][48] and the known palmitoylation of this presynaptic protein, 2,48 CSP is another candidate that likely has an altered function and localization in Ppt1-mutant Drosophila as well as INCL patients. In adult-onset NCL patients (also known as Kufs Disease), identified mutations in CSPα gene are found in the cysteinestring domain and are known to affect palmitoylation and its intracellular localization.…”

Neurological disorders, genetic correlations, and the role of exome sequencing

“…A United States incidence of 1 in 12,500 live births makes neuronal ceroid lipofuscinoses the most common group of inherited neurological degenerative disorders [6]. Whether examining the mitochondrial defect implicated in prenatal ventriculomegaly [7], the often early-stage atypical presentation of neurocanthocytosis [8], or the fatal amyotrophic lateral sclerosis [9], scientists recognize that exome sequencing "potentially widens the clinical spectrum associated with Amyotrophic Lateral Sclerosis (ALS) to include bone dysfunction and myopathy, and provides further insight into the importance of cellular protein degradation pathways…."…”

“…The method has yet to overcome the challenges that presented, such as phenotypic and biological manifestations which do not correlate well to molecular mutations due to the exceedingly complex nature of the brain. Exome sequencing has, however, shed additional light on causal mutations for sensory motor neuropathy with ataxia [3], which presents with cerebellar dysfunction, Spinocerebellar Ataxia with Psychomotor Retardation [4], and Spastic Ataxia-Neuropathy syndrome that manifested with remarkable variety between two brothers [5] due to different mutations in the same protease subunits.A United States incidence of 1 in 12,500 live births makes neuronal ceroid lipofuscinoses the most common group of inherited neurological degenerative disorders [6]. Whether examining the mitochondrial defect implicated in prenatal ventriculomegaly [7], the often early-stage atypical presentation of neurocanthocytosis [8], or the fatal amyotrophic lateral sclerosis [9], scientists recognize that exome sequencing "potentially widens the clinical spectrum associated with Amyotrophic Lateral Sclerosis (ALS) to include bone dysfunction and myopathy, and provides further insight into the importance of cellular protein degradation pathways…."…”