Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis.

Abstract

Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is characterized by accumulation of autofluorescent storage material in neural tissues and neurodegeneration and has an age of onset in the third decade of life or later. The genetic and molecular basis of the disease has remained unknown for many years. We carried out linkage mapping, gene-expression analysis, exome sequencing, and candidate-gene sequencing in affected individuals from 20 families and/or individuals with simplex cases; we identified in five individuals one of two disease-causing mutations, c.346_348delCTC and c.344T>G, in DNAJC5 encoding cysteine-string protein alpha (CSPα). These mutations-causing a deletion, p.Leu116del, and an amino acid exchange, p.Leu115Arg, respectively-are located within the cysteine-string domain of the protein and affect both palmitoylation-dependent sorting and the amount of CSPα in neuronal cells. The resulting depletion of functional CSPα might cause in parallel the presynaptic dysfunction and the progressive neurodegeneration observed in affected individuals and lysosomal accumulation of misfolded and proteolysis-resistant proteins in the form of characteristic ceroid deposits in neurons. Our work represents an important step in the genetic dissection of a genetically heterogeneous group of ANCLs. It also confirms a neuroprotective role for CSPα in humans and demonstrates the need for detailed investigation of CSPα in the neuronal ceroid lipofuscinoses and other neurodegenerative diseases presenting with neuronal protein aggregation.

• Authors: Lenka Nosková, Viktor Stránecký, Hana Hartmannová, Anna Přistoupilová, Veronika Barešová, Robert Ivánek, Helena Hůlková, Helena Jahnová, Julie van der Zee, John F Staropoli, Katherine B Sims, Jaana Tyynelä, Christine Van Broeckhoven, Peter C G Nijssen, Sara E Mole, Milan Elleder, Stanislav Kmoch
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 89 Issue 2 Pg. 241-52 (Aug 12 2011) ISSN: 1537-6605 [Electronic] United States
• PMID: 21820099 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• HSP40 Heat-Shock Proteins
• Membrane Proteins
• cysteine string protein

Topics

• Adult
• Age of Onset
• Base Sequence
• Brain (metabolism, pathology, ultrastructure)
• Chromosome Segregation (genetics)
• Exons (genetics)
• Family
• Female
• Gene Dosage (genetics)
• Gene Expression Regulation
• Genes, Dominant (genetics)
• Genetic Linkage
• HSP40 Heat-Shock Proteins (genetics)
• Humans
• Lipoylation
• Lysosomes (metabolism, ultrastructure)
• Male
• Membrane Proteins (genetics)
• Molecular Sequence Data
• Mutation (genetics)
• Neuronal Ceroid-Lipofuscinoses (epidemiology, genetics, pathology)
• Neurons (metabolism, pathology, ultrastructure)
• Pedigree
• Protein Transport
• Sequence Analysis, DNA