Autosomal-dominant adult neuronal ceroid lipofuscinosis caused by duplication in DNAJC5 initially missed by Sanger and whole-exome sequencing

Jedličková, Ivana; Cadieux-Dion, Maxime; Přistoupilová, Anna; Stránecký, Viktor; Hartmannová, Hana; Hodaňová, Kateřina; Barešová, Veronika; Hůlková, Helena; Sikora, Jakub; Nosková, Lenka; Musalkova, Dita; Vyleťal, Petr; Sovová, Jana; Cossette, Patrick; Andermann, Eva; Andermann, Frédérick; Kmoch, Stanislav

doi:10.1038/s41431-019-0567-2

Cited by 11 publications

(14 citation statements)

References 24 publications

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“…Three heterozygous CSPα mutations (L115R, L116del and C124‐C133dup) associated with AD‐ANCL have been identified, which all lie within the cysteine‐string domain. All variants affect membrane affinity and/or impair palmitoylation, thus resulting in mislocalisation of the protein to the plasma membrane (Benitez et al., 2011; Jedlickova et al., 2020; Noskova et al., 2011). Interestingly, L115R and L116del mutations also increase the propensity of CSPα to oligomerise with WT CSPα, which reduces Hsc70 ATPase‐stimulating activity (Zhang & Chandra, 2014).…”

Section: Snare Chaperones: Cspα and α‐Synucleinmentioning

confidence: 99%

Disorders of synaptic vesicle fusion machinery

Melland

Carr

Gordon

2020

Journal of Neurochemistry

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Neuronal communication relies on the tightly controlled fusion of synaptic vesicles at nerve terminals, which results in the release of neurotransmitters with strict temporal and quantal precision. At rest, synaptic vesicle fusion is inhibited (Brunger et al., 2018). Action potential-mediated opening of voltage-gated Ca 2+ channels results in Ca 2+ influx into the nerve terminal, creating a Ca 2+ nanodomain that triggers the fusion of vesicles that are docked and primed at the plasma membrane, thereby evoking fast synchronous neurotransmitter release (Chanaday & Kavalali, 2018;Sudhof, 2013).Vesicles can additionally fuse asynchronously following evoked synchronous release and some spontaneous fusion of vesicles also occurs, though this is clamped (Chanaday & Kavalali, 2018).These processes are under exquisite regulatory control, preventing excessive neurotransmitter release and ensuring high-fidelity neuronal communication (Brunger et al., 2019;Rizo, 2018;; perturbation of this regulation can lead to a breakdown in neurotransmission.A range of presynaptic proteins are required to orchestrate these precision events. The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex, composed of the vesicular SNARE protein (v-SNARE) synaptobrevin and the target membrane SNARE proteins (t-SNAREs) syntaxin-1 and SNAP-25 (synaptosomal-associated protein-25), is the core fusion machinery that provides the energy required for fusion of synaptic vesicles with the plasma membrane (Weber et al., 1998). Several other key components regulate synaptic vesicle exocytosis in physiological environments (Brunger et al., 2019;Sudhof, 2014). SNARE complex assembly is orchestrated by Munc13 and Munc18, and further

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Section: Snare Chaperones: Cspα and α‐Synucleinmentioning

confidence: 99%

Disorders of synaptic vesicle fusion machinery

Melland

Carr

Gordon

2020

Journal of Neurochemistry

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“…Other patients positive for such mutations were later identified by others and us. A recent report discussed above identified a 30 bp duplication in gene DNAJC5A resulting in the same phenotype of ADNCL 17 (Figure 1). Testing for DNAJC5A mutations is now an accepted standard of care for the diagnosis of ADNCL.…”

Section: Etiology and Molecular Pathwaysmentioning

confidence: 64%

“…Several sporadic cases of adult onset NCL were also found to harbor such mutations. A recent report identified a 30‐bp duplication in gene DNAJC5A , NM_025219.3 ( DNAJC5) c.370_399dup (pCys124_Cys133dup), resulting in the same phenotype of ADNCL 17 (Figure 1). To our knowledge, no other pathogenic or likely pathogenic sequence variants in DNAJC5 without involvement of other genes were reported in the ClinVar or other mutation databases.…”

Section: Prevalence and Molecular Basismentioning

confidence: 99%

“…This patient died at 54. In contrast, a male patient (see also [13][14][15][16][17][18] Table 1 lists patients with personal or family identified mutation in DNAJC5, for whom clinical information is available. Age of onset, first presentation and age of death when known are listed for these patients.…”

Section: Prevalence and Molecular Basismentioning

confidence: 99%

“…To our knowledge, to date there are over 60 known ADNCL patients with identified DNAJC5 mutations or with family relatives positive for such mutations. At least 60 of them were reported, 13‐18 Table 1 lists patients with personal or family identified mutation in DNAJC5 , for whom clinical information is available. Age of onset, first presentation and age of death when known are listed for these patients.…”

Section: Clinical Descriptionmentioning

confidence: 99%

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Autosomal dominant neuronal ceroid lipofuscinosis: Clinical features and molecular basis

2020

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The neuronal ceroid lipofuscinoses (NCLs) are at least 13 distinct progressive neurodegenerative disorders unified by the accumulation of lysosomal auto-fluorescent material called lipofuscin. The only form that occurs via autosomal-dominant inheritance exhibits adult onset and is sometimes referred to as Parry type NCL. The manifestations may include behavioral symptoms followed by seizures, ataxia, dementia, and early death. Mutations in the gene DNAJC5 that codes for the presynaptic cochaperone cysteine string protein-α (CSPα) were recently reported in sporadic adultonset cases and in families with dominant inheritance. The mutant CSPα protein may lead to disease progression by both loss and gain of function mechanisms. Iron chelation therapy may be considered as a possible pharmaceutical intervention based on our recent mechanism-based proposal of CSPα oligomerization via ectopic Fe-S cluster-binding, summarized in this review.

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Extracellular chaperone networks and the export of J-domain proteins

Braun

2023

Journal of Biological Chemistry

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Autosomal-dominant adult neuronal ceroid lipofuscinosis caused by duplication in DNAJC5 initially missed by Sanger and whole-exome sequencing

Cited by 11 publications

References 24 publications

Disorders of synaptic vesicle fusion machinery

Disorders of synaptic vesicle fusion machinery

Autosomal dominant neuronal ceroid lipofuscinosis: Clinical features and molecular basis

Extracellular chaperone networks and the export of J-domain proteins

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