title: 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.
authors.affiliation: Department of Psychiatry, Washington University, St Louis, Missouri, United States of America.
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Benitez
authors.forename: David
authors.initials: D
authors.lastname: Alvarado
authors.forename: Yefei
authors.initials: Y
authors.lastname: Cai
authors.forename: Kevin
authors.initials: K
authors.lastname: Mayo
authors.forename: Sumitra
authors.initials: S
authors.lastname: Chakraverty
authors.forename: Joanne
authors.initials: J
authors.lastname: Norton
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sands
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D050956:HSP40 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics*; D010375:Pedigree; D017386:Sequence Homology, Amino Acid
chemical_list: D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; C088460:cysteine string protein
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