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Ceroid lipofuscinosis, neuronal, 4 (Kufs type) is a hereditary neurodegenerative disorder characterized by adult-onset seizures, cognitive decline, and accumulation of lipofuscin in neurons. It can manifest as autosomal dominant adult neuronal ceroid lipofuscinosis (ADANCL) in a subset of patients. In 2011, exome sequencing in two autopsy-confirmed individuals from a multigenerational kindred revealed a heterozygous c.344T>G (p.Leu115Arg) variant in DNAJC5 that segregated with disease across seven generations (PMID:22073189). A subsequent PLoS One study of the Parry family and eight unrelated pedigrees identified an additional c.343_345delCTC (p.Leu116del) change in affected members and confirmed segregation in nine probands (PMID:22235333). Together, these studies establish DNAJC5 as an ADANCL gene with multiple independent variant findings. Pathogenic alleles cluster within the palmitoylated cysteine-string domain of the synaptic vesicle co-chaperone CSPα.
Genetic evidence includes nine probands harboring DNAJC5 variants in independent families, with complete segregation in extended pedigrees (PMID:22235333, PMID:22073189). A total of three distinct pathogenic alleles have been reported: two in-frame deletions (p.Leu116del) and a missense change (p.Leu115Arg), as well as a 30 bp in-frame duplication affecting the same cysteine-string region (PMID:31919451). Segregation across seven generations in the Parry family accounts for at least seven affected relatives. No loss-of-function truncating variants have been identified, consistent with a gain-of-function mechanism. Recurrence of alleles in unrelated individuals indicates a mutational hotspot in the cysteine-string domain. Carrier screening in controls failed to detect these variants, supporting their rarity and pathogenicity.
Variant spectrum is limited to in-frame and missense changes within the cysteine-string domain of CSPα, which is critical for palmitoylation-dependent vesicle targeting. The recurrent c.344T>G (p.Leu115Arg) missense variant has been observed in two independent kindreds, and the c.343_345delCTC (p.Leu116del) in three families including the Parry kindred (PMID:22073189, PMID:22235333). A 30 bp in-frame duplication (c.370_399dup (p.Cys124_Cys133dup)) was identified by reanalysis of exome data in an additional ADANCL pedigree (PMID:31919451). No deep-intronic or promoter variants have been implicated to date. Hypomorphic or structural variants outside the cysteine-string domain remain unreported. These findings delineate a narrow mutational spectrum focused on gain-of-function alterations.
Functional studies demonstrate that mutations in the J-domain and cysteine-string region of CSPα impair its co-chaperone activity. Mutation of the conserved HPD motif (H43Q, D45A) reduces Hsc70 ATPase stimulation and client binding in vitro (PMID:9395474). Deletion of Csp in Drosophila neuromuscular junctions impairs calcium secretion coupling of evoked exocytosis but spares vesicle recycling, supporting a role in neurotransmission (PMID:9437017). Hypomorphic Drosophila Hsc70-4 mutations phenocopy CSP loss-of-function and interact genetically, reinforcing the CSP-Hsc70 pathway (PMID:11395008). In mammalian cells, the L116del variant fails to attenuate α-synuclein aggregation and oxidative stress, abrogating the protective function of CSPα (PMID:37566176). These assays confirm that disease-associated variants disrupt CSPα’s chaperone functions, consistent with a pathogenic gain-of-function mechanism.
An in vivo mouse model overexpressing human CSPα variants recapitulates NCL pathology, including neuronal lipofuscin accumulation and granular osmiophilic deposits, whereas knockout of endogenous DnaJC5 does not produce similar storage pathology (PMID:40397740). Mutant L115R and L116Δ transgenic lines display motor deficits and microglial activation, mirroring human Kufs disease phenotypes. The absence of lipofuscinosis in CSPα-null mice indicates that pathogenic alleles confer a toxic gain of function rather than haploinsufficiency. These findings delineate the mechanistic basis for autosomal dominant inheritance. Concordance between animal and human phenotypes strengthens the causal linkage. Such in vivo evidence elevates the association to a definitive level.
Integration of genetic and experimental data supports a model in which specific cysteine-string domain variants in DNAJC5 confer neurotoxicity via disrupted chaperone and secretory functions, leading to lysosomal dysfunction and lipofuscin accumulation. The narrow variant spectrum and multi-generation segregation in nine families provide robust genetic validity. Functional assays and animal studies consistently demonstrate deleterious effects of pathogenic alleles on protein function and neuronal homeostasis. No conflicting reports have refuted this association, and identification of the same alleles in independent cohorts underscores their pathogenicity. Additional large-scale sequencing may uncover rare alleles but is unlikely to alter the definitive classification. Key take-home: DNAJC5 should be included in genetic testing panels for adult-onset neuronal ceroid lipofuscinosis to facilitate precise diagnosis and inform potential therapeutic strategies.
Gene–Disease AssociationDefinitive9 probands in independent pedigrees with complete segregation, multi-family replication, and in vivo disease models ([PMID:22073189], [PMID:22235333], [PMID:40397740]) Genetic EvidenceStrongIdentification of three variant alleles (p.Leu115Arg, p.Leu116del, p.Cys124_Cys133dup) in 9 probands with autosomal dominant segregation and absence in controls ([PMID:22073189], [PMID:22235333], [PMID:31919451]) Functional EvidenceModerateIn vitro assays and Drosophila studies show disrupted co-chaperone function of CSPα variants; mouse models demonstrate pathological gain-of-function ([PMID:9395474], [PMID:40397740]) |