Identification of a Large<i>DNAJB2</i>Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism

Sánchez, Elena; Darvish, Hossein; Mesias, Roxana; Taghavi, Shaghyegh; Firouzabadi, Saghar Ghasemi; Walker, Ruth H.; Tafakhori, Abbas; Paisán-Ruı́z, Coro

doi:10.1002/humu.23055

Cited by 40 publications

(41 citation statements)

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“…A,B), which also revealed a 7‐bp insertion (GCACTTC); see Figure A. Three VPS13C exons (exons 19, 35, 61) expanding the deletion breakpoints were also subject to copy number variation (CNV) quantification by performing droplet digital PCR (ddPCR; QX100 system; Bio‐rad), as previously described . Only the affected member showed no copies of the implicated e xons, further confirming this large VPS13C deletion as the causal genetic defect in our reported patient (Fig.…”

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confidence: 99%

Identification of a large homozygous VPS13C deletion in a patient with early‐onset Parkinsonism

et al. 2018

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confidence: 99%

Identification of a large homozygous VPS13C deletion in a patient with early‐onset Parkinsonism

et al. 2018

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“…Human mutations in CSPα (DnaJC5) and DnaJB6 lead to adult neuronal ceroid lipofuscinosis (ANCL) 3,54,70 , and limb-girdle muscular dystrophy 33,57,62,63,67 respectively. Mutations in DnaJB2, depending on their location, cause Charcot Marie Tooth disease type 2 25 , distal hereditary motor neuropathy 4 , spinal muscular atrophy or juvenile Parkinsonism 61 . The association of DnaJB2 with neurofibrillary tangles in Alzheimer's disease patients 10 , the presence of DnaJB6 in lewy bodies in Parkinson's disease patients 17 and the intralysosomal accumulation of lipofuscin caused by CSPα mutations 3,54,70 link these J proteins to neural quality control mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Cargo-Loading of Misfolded Proteins into Extracellular Vesicles: The CSPα-EV Export Pathway

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Donnelier

Lewis

et al. 2018

Preprint

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Extracellular vesicles (EVs) are a collection of secreted vesicles of diverse size and cargo that are implicated in the physiological removal of nonfunctional proteins as well as the cell-tocell transmission of disease-causing-proteins in several neurodegenerative diseases. We have shown that the molecular chaperone, cysteine string protein (CSPα; DnaJC5), is responsible for the export of disease-causing-misfolded proteins from neurons via EVs. We show here that CSPα-EVs efficiently deliver GFP-tagged 72Q huntingtin exon1 to naive neurons. When we analyzed the heterogeneous EV pool, we found that the misfolded GFP-tagged 72Q huntingtin exon1 cargo was primarily found in EVs between 180-240nm. We further determined that cargo-loading of GFP-tagged 72Q huntingtin exon1 into EVs was impaired by resveratrol. Importantly, in addition to CSPα, we identified two other J protein co-chaperones, DnaJB2 and DnaJB6, that facilitate EV export of GFP-tagged 72Q huntingtin exon1 . While human mutations in CSPα cause the neurodegenerative disorder, adult neuronal ceroid lipofuscinosis, mutations in DnaJB6 cause limb-girdle muscular dystrophy and mutations in DnaJB2 are linked to the neurodegenerative disorders, Charcot Marie Tooth disease, distal hereditary motor neuropathy, spinal muscular atrophy and juvenile Parkinsonism. Our data provides new insights into the parallels between proteostasis and EV export, as three J proteins linked to disease in humans are the same as those that mediate EV genesis and export of misfolded proteins.CSPα (DnaJC5) 1-198 DnaJB2 1-324-long DnaJB6 1-365-long J J CCC J CAAX box UIM UIM NLS

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“…DNA samples from all participants were isolated from whole blood, using standard procedures. WGS was performed as previously described (Sanchez, et al, 2016). Specifically, deletions were called by using GenomeSTRiP (v2.0) (Handsaker, Korn, Nemesh, & McCarroll, 2011) and were jointly called by using 17 HapMap individuals (CEPH Platinum Genomes pedigree).…”

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Molecular characterization of PRKN structural variations identified through whole‐genome sequencing

Bravo

Darvish

Tafakhori

et al. 2018

Molec Gen & Gen Med

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BackgroundEarly‐onset Parkinson's disease (PD) is the most common inherited form of parkinsonism, with the PRKN gene being the most frequently identified mutated. Exon rearrangements, identified in about 43.2% of the reported PD patients and with higher frequency in specific ethnicities, are the most prevalent PRKN mutations reported to date in PD patients.MethodsIn this study, three consanguineous families with early‐onset PD were subjected to whole‐genome sequencing (WGS) analyses that were followed by Sanger sequencing and droplet digital PCR to validate and confirm the disease segregation of the identified genomic variations and to determine their parental origin.ResultsFive different PRKN structural variations (SVs) were identified. Because the genomic sequences surrounding the break points of the identified SVs might hold important information about their genesis, these were also characterized for the presence of homology and repeated sequences.ConclusionWe concluded that all identified PRKN SVs might originate through retrotransposition events.

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Identification of a LargeDNAJB2Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism

Cited by 40 publications

References 42 publications

Identification of a large homozygous VPS13C deletion in a patient with early‐onset Parkinsonism

Identification of a large homozygous VPS13C deletion in a patient with early‐onset Parkinsonism

Cargo-Loading of Misfolded Proteins into Extracellular Vesicles: The CSPα-EV Export Pathway

Molecular characterization of PRKN structural variations identified through whole‐genome sequencing

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