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. 2011;6(11):e26741.
doi: 10.1371/journal.pone.0026741. Epub 2011 Nov 4.

Exome-sequencing confirms DNAJC5 mutations as cause of adult neuronal ceroid-lipofuscinosis

Bruno A Benitez  1 , David Alvarado, Yefei Cai, Kevin Mayo, Sumitra Chakraverty, Joanne Norton, John C Morris, Mark S Sands, Alison Goate, Carlos Cruchaga
Affiliations

Exome-sequencing confirms DNAJC5 mutations as cause of adult neuronal ceroid-lipofuscinosis

Bruno A Benitez et al. PLoS One. 2011.

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Pedigree of ANCL family, Sanger sequencing results and Multiple Alignment of CSPα.
(A) Pedigree of the ANCL family. Black symbols denote affected individuals; open symbols denote unaffected individuals. (B) Chromatograms of exon 4 of DNAJC5 gene, showing sequences of identified heterozygous mutations. (Upper panel) Sequence of an unaffected elderly control, (middle panel) sequence showing heterozygous mutation c.344T>G in the affected proband, (lower panel) sequence showing heterozygous mutation c.346_348delCTC in affected from a second family (Validation set). Arrow and black short line indicate the position of the missense and deletion mutation, respectively. (C) Multiple Sequence alignment of Cysteine-string domain of CSPα amino acid sequence among homologous genes in mammals. pL115 is highlighted in yellow and indicated by the arrow.
Figure 2
Figure 2. Palmitoylation, Hydrophobicity and membrane binding profile of CSPα.
(A). In silico predicted palmitoylation profile of cysteine-string domain in wild-type, p.L115R, p.L116del and positive control (C121-124S). (B) Intrinsic hydropathy plots of CSD amino acid sequences in wild-type, p.L115R and p.L116del(C) The posterior probability for transmembrane helix for the wild-type, p.L115R, p.L116del and positive control (C113-118-9S). (D) Transmembrane profile amino acid sequences of wild-type, p.L115R, p.L116del and positive control (C113-118-9S). Wild-type (Black Line), p.L115R (Red Line), p.L116del (Green Line) and positive controls (Blue line).
Figure 3
Figure 3. Aggregation profile of CSPα.
(A). Intrinsic aggregation (Zagg Score) and folding propensity (Zfold score) profile of amino acid sequence of CSPα Wild type. (B) Predicted protection factors (lnp score) of wild-type, p.L115R and p.L116del amino acid sequence. (lnp5 for protected residues, dashed straight line) (C) Toxicity profile (Ztox score) of cysteine-string domain of wild-type, p.L115R and p.L116del amino acid sequence. High toxic propensity (Zagg>1, dashed straight line). (D) Aggregation propensity (Zagg score) profile of cysteine-string domain of wild-type, p.L115R and p.L116del amino acid sequence region. High intrinsic aggregation propensity (Zagg>1, dashed straight line). Wild-type (Black Line), p.L115R (Red Line) and p.L116del (Green Line).
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