Identification of a large homozygous <i>VPS13C</i> deletion in a patient with early‐onset Parkinsonism

Darvish, Hossein; Bravo, Paloma; Tafakhori, Abbas; Azcona, Luís; Ranji-Burachaloo, Sakineh; Johari, Amir Hossein; Paisán-Ruı́z, Coro

doi:10.1002/mds.27516

Cited by 44 publications

(34 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since there was also extensive AD pathology in patient P3, there is a small likelihood that the pathological ndings are associated with a DLB clinical syndrome. Nevertheless, both our clinical and neuropathological data of VPS13C mutation carriers supports the phenotype of most VPS13C patient carriers reported to date, including an early-onset age, severe disease progression and the co-occurrence of parkinsonism and dementia ( Table 1, Table S1, ) [18][19][20].…”

Section: Discussionsupporting

confidence: 83%

“…Shortly after, a large homozygous deletion comprising 50 exons of VPS13C was identi ed by WGS data of an sporadic patient with sensorimotor polyneuropathy and early-onset parkinsonism (Fig. 1b) [20]. This patient presented with normal cognitive functioning and a milder disease severity.…”

Section: Discussionmentioning

confidence: 97%

“…Moreover, GBA is the most common genetic risk factor of PD with 7-12% of PD patients carrying mono-or bi-allelic mutations in GBA and an estimated odds ratio of 5.4 [18,24,74,75]. More recently, new data showed that rare variants in VPS13C and ATP10B, implicated in sporadic earlyonset PD patient are mimicking recessive inheritance [17][18][19][20]. PD patient carriers of pathogenic mutations in SNCA or GBA have a higher risk of developing cognitive impairment and presenting a clinical phenotype of DLB [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Homozygous and compound heterozygous rare variants in VPS13C contribute to Lewy body diseases

Smolders

Philtjens

Crosiers

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are clinically, pathologically and etiologically overlapping disorders. They are included in the Lewy body disease (LBD) continuum characterized by α-synuclein-positive Lewy body pathology in neurons. Homozygous PTC mutations in Vacuolar Protein Sorting 13 homolog C gene (VPS13C) are associated with early-onset PD. Methods Whole genome sequencing of two affected siblings and healthy parents of family A with onset age below 50 years and DLB pathology confirmed at autopsy. Targeted resequencing of the VPS13C coding region in 844 LBD patients and 664 control individuals. Phasing cis-trans location of the compound heterozygous VPS13C variants. Analysis of VPS13C protein expression in lymphoblast cells and brain lysates. Immunohistochemistry and live cell labeling in HeLa and SH-SY5Y cells overexpressing wild type or mutant VPS13C. Results In the two affected siblings of family A, we identified compound heterozygous rare variants located in trans in VPS13C Rare VPS13C variants (MAF ≤ 1%), are significantly associated (p = 0.0233) in the LBD patient cohort using optimized sequence kernel association test (SKAT-O). We identified 11 carriers of compound heterozygous variants and 1 carrier of homozygous variants in VPS13C. Trans location of the variants in compound heterozygous carriers was confirmed in 4 and cis location in 3 patients. The frequency of patient carriers with bi-allelic variants mimicking recessive inheritance is 1.07% (9/844). In post-mortem brain tissue of two unrelated DLB carriers of compound trans heterozygous variants, we observed a reduction of VPS13C protein expression. Overexpressing of wild type or mutant VPS13C, in HeLa and SH-SY5Y cells, demonstrated that the mutations abolish the endosomal/lysosomal localization of VPS13C. Conclusions Our data indicate that rare alleles are associated with LBD, and when present bi-allelic in patients, these combinations have variable effects on expression and functioning of VPS13C. Apart from the recessive PTC mutations, some combinations of rare missense mutations might mimic recessive inheritance and explain part of the sporadic LBD patients. We propose that homozygous or compound heterozygous rare missense variants in VPS13C reducing VPS13C protein expression can contribute to risk of LBD.

show abstract

Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Homozygous and compound heterozygous rare variants in VPS13C contribute to Lewy body diseases

Smolders

Philtjens

Crosiers

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Notably, homozygosity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity, identified VPS13C as a candidate gene for autosomal recessive PD [61]. The use of a validation cohort [61], and an independent replication cohort confirmed a role for VPS13C in autosomal recessive PD [24,97]. Another whole exome sequencing study in 50 earlyonset patients with PD has nominated interesting variants in SPG7 [106].…”

Section: Discussionmentioning

confidence: 85%

Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export

et al. 2020

View full text Add to dashboard Cite

Parkinson's disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of α-synucleinpositive Lewy bodies in surviving neurons. Here, we performed whole exome sequencing in 52 early-onset PD patients and identified 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identified 4 additional compound heterozygous mutation carriers (6/617 PD patients, 0.97%; 1/226 DLB patients, 0.44%). We established that ATP10B encodes a late endo-lysosomal lipid flippase that translocates the lipids glucosylceramide (GluCer) and phosphatidylcholine (PC) towards the cytosolic membrane leaflet. The PD associated ATP10B mutants are catalytically inactive and fail to provide cellular protection against the environmental PD risk factors rotenone and manganese. In isolated cortical neurons, loss of ATP10B leads to general lysosomal dysfunction and cell death. Impaired lysosomal functionality and integrity is well known to be implicated in PD pathology and linked to multiple causal PD genes and genetic risk factors. Our results indicate that recessive loss of function mutations in ATP10B increase risk for PD by disturbed lysosomal export of GluCer and PC. Both ATP10B and glucocerebrosidase 1, encoded by the PD risk gene GBA1, reduce lysosomal GluCer levels, emerging lysosomal GluCer accumulation as a potential PD driver.Keywords Parkinson's disease · Massive parallel sequencing · ATP10B P-type ATPase · Endo-lysosomal lipid flippase · Loss-of-function · Glucosylceramide Shaun Martin and Stefanie Smolders shared first authors and have contributed equally. Peter Vangheluwe and Christine Van Broeckhoven shared last and corresponding authors and have contributed equally.

show abstract

“…A follow-up study in 80 EOPD patients identified an additional patient with compound-heterozygous mutations with similar clinical features to the previously reported patients 9 . In another recent study, a homozygous deletion in VPS13C was reported to be the probable cause of an early onset parkinsonism in one patient 10 . Thus far, full sequencing studies of VPS13C have not been reported in late onset PD (LOPD).…”

Section: Introductionmentioning

confidence: 91%

Analysis of common and rare VPS13C variants in late onset Parkinson disease

Rudakou

Ruskey

Krohn

et al. 2019

Preprint

View full text Add to dashboard Cite

ObjectiveWe aimed to study the role of coding VPS13C variants in a large cohort of late-onset PD (LOPD) patients.MethodsVPS13C and its untranslated regions were sequenced using targeted next-generation sequencing in 1,567 PD patients and 1,667 controls from 3 cohorts. Association tests of rare potential homozygous and compound heterozygous variants and burden tests for rare heterozygous variants were performed. Common variants were analyzed using logistic regression adjusted for age and sex in each of the cohorts, followed by a meta-analysis.ResultsNo bi-allelic carriers of rare VPS13C variants were found among patients and two carriers of compound heterozygous variants were found in two controls. There was no statistically significant burden of rare (MAF<1%) or very rare (MAF<0.1%) coding VPS13C variants in PD. A VPS13C haplotype including the p.R153H-p.I398I-p.I1132V-p.Q2376Q variants was nominally associated with a reduced risk for PD (meta-analysis of the tagging SNP p.I1132V (OR=0.48, 95%CI=0.28-0.82, p=0.0052). This haplotype was not in linkage disequilibrium (LD) with the known genome-wide association study (GWAS) top hit.ConclusionsOur results do not support a role for rare heterozygous or bi-allelic VPS13C variants in LOPD. Additional genetic replication and functional studies are needed to examine the role of the haplotype identified here associated with reduced risk for PD.

show abstract

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

Cited by 44 publications

References 5 publications

Homozygous and compound heterozygous rare variants in VPS13C contribute to Lewy body diseases

Homozygous and compound heterozygous rare variants in VPS13C contribute to Lewy body diseases

Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export

Analysis of common and rare VPS13C variants in late onset Parkinson disease

Contact Info

Product

Resources

About