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Autosomal-dominant adult neuronal ceroid lipofuscinosis caused by duplication in DNAJC5 initially missed by Sanger and whole-exome sequencing
I. Jedličková, M. Cadieux-Dion, A. Přistoupilová, V. Stránecký, H. Hartmannová, K. Hodaňová, V. Barešová, H. Hůlková, J. Sikora, L. Nosková, D. Mušálková, P. Vyleťal, J. Sovová, P. Cossette, E. Andermann, F. Andermann, S. Kmoch, Adult NCL Gene...
Language English Country Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
NLK
Free Medical Journals
from 2009
PubMed Central
from 2009 to 1 year ago
Europe PubMed Central
from 2009 to 1 year ago
ProQuest Central
from 2000-01-01 to 1 year ago
Open Access Digital Library
from 1998-01-01
Health & Medicine (ProQuest)
from 2000-01-01 to 1 year ago
- MeSH
- Cell Line MeSH
- Adult MeSH
- Gene Duplication * MeSH
- False Negative Reactions MeSH
- Genetic Testing standards MeSH
- Middle Aged MeSH
- Humans MeSH
- Membrane Proteins genetics metabolism MeSH
- Mice MeSH
- Neuronal Ceroid-Lipofuscinoses genetics pathology MeSH
- Neurons metabolism MeSH
- Protein Processing, Post-Translational MeSH
- HSP40 Heat-Shock Proteins genetics metabolism MeSH
- Whole Genome Sequencing standards MeSH
- Protein Transport MeSH
- Animals MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Adult-onset neuronal ceroid lipofuscinoses (ANCL, Kufs disease) are rare hereditary neuropsychiatric disorders characterized by intralysosomal accumulation of ceroid in tissues. The ceroid accumulation primarily affects the brain, leading to neuronal loss and progressive neurodegeneration. Although several causative genes have been identified (DNAJC5, CLN6, CTSF, GRN, CLN1, CLN5, ATP13A2), the genetic underpinnings of ANCL in some families remain unknown. Here we report one family with autosomal dominant (AD) Kufs disease caused by a 30 bp in-frame duplication in DNAJC5, encoding the cysteine-string protein alpha (CSPα). This variant leads to a duplication of the central core motif of the cysteine-string domain of CSPα and affects palmitoylation-dependent CSPα sorting in cultured neuronal cells similarly to two previously described CSPα variants, p.(Leu115Arg) and p.(Leu116del). Interestingly, the duplication was not detected initially by standard Sanger sequencing due to a preferential PCR amplification of the shorter wild-type allele and allelic dropout of the mutated DNAJC5 allele. It was also missed by subsequent whole-exome sequencing (WES). Its identification was facilitated by reanalysis of original WES data and modification of the PCR and Sanger sequencing protocols. Independently occurring variants in the genomic sequence of DNAJC5 encoding the cysteine-string domain of CSPα suggest that this region may be more prone to DNA replication errors and that insertions or duplications within this domain should be considered in unsolved ANCL cases.
Center for Pediatric Genomic Medicine Children's Mercy Hospital Kansas City MO USA
Centre Hospitalier de L´Universite de Montréal Montréal QC Canada
Montreal Neurological Hospital and Institute McGill University Montreal QC Canada
References provided by Crossref.org
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