A homozygous mutation of<i>VWA3B</i>causes cerebellar ataxia with intellectual disability

Kawarai, Toshitaka; Tajima, Atsushi; Kuroda, Yukiko; Saji, Naoki; Orlacchio, Antonio; Terasawa, Hideo; Shimizu, Hirotaka; Kita, Yasushi; Izumi, Yuishin; Mitsui, Takao; Imoto, Issei; Kaji, Ryuji

doi:10.1136/jnnp-2014-309828

Cited by 16 publications

(6 citation statements)

References 45 publications

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“…This site is located in the intron regions of VWA3B, which showed a tendency toward malignancy development. VWA3B encodes an intracellular protein thought to function in transcription, DNA repair, and membrane transport (Kawarai et al, 2016;Huttlin et al, 2017), playing a role similar to MACROD2, which was reported to influence DNA repair and sensitivity to DNA damage and result in chromosome instability (Sakthianandeswaren et al, 2018). In the patients of bladder urothelial carcinoma, evident copy number alterations were observed in the 2q12 regions in which the VWA3B was mapped (E. Pontes et al, 2013), in line with the suggestion that VWA3B plays a crucial role in bladder carcinogenesis.…”

Section: Rules For Homozygous Deletionsupporting

confidence: 65%

Copy Number Variation Pattern for Discriminating MACROD2 States of Colorectal Cancer Subtypes

Zhang

Pan

Zeng

et al. 2019

Front. Bioeng. Biotechnol.

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Copy number variation (CNV) is a common structural variation pattern of DNA, and it features a higher mutation rate than single-nucleotide polymorphisms (SNPs) and affects a larger fragment of genomes. CNV is related with the genesis of complex diseases and can thus be used as a strategy to identify novel cancer-predisposing markers or mechanisms. In particular, the frequent deletions of mono-ADP-ribosylhydrolase 2 (MACROD2) locus in human colorectal cancer (CRC) alters DNA repair and the sensitivity to DNA damage and results in chromosomal instability. The relationship between CNV and cancer has not been explained. In this study, on the basis of the genome variation profiling by the SNP array from 651 CRC primary tumors, we computationally analyzed the CNV data to select crucial SNP sites with the most relevance to three different states of MACROD2 (heterozygous deletion, homozygous deletion, and normal state), suggesting that these CNVs may play functional roles in CRC tumorigenesis. Our study can shed new insights into the genesis of cancer based on CNV, providing reference for clinical diagnosis, and treatment prognosis of CRC.

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Section: Rules For Homozygous Deletionsupporting

confidence: 65%

Copy Number Variation Pattern for Discriminating MACROD2 States of Colorectal Cancer Subtypes

Zhang

Pan

Zeng

et al. 2019

Front. Bioeng. Biotechnol.

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“…LPL , lipoprotein lipase, is increased in AD brains and associated with AD progression 33 . Mutations in VWA3B cause a recessive form of Spinocerebellar Ataxia 34 .…”

Section: Resultsmentioning

confidence: 99%

Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers

et al. 2023

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Genetic studies of Alzheimer disease (AD) have prioritized variants in genes related to the amyloid cascade, lipid metabolism, and neuroimmune modulation. However, the cell-specific effect of variants in these genes is not fully understood. Here, we perform single-nucleus RNA-sequencing (snRNA-seq) on nearly 300,000 nuclei from the parietal cortex of AD autosomal dominant (APP and PSEN1) and risk-modifying variant (APOE, TREM2 and MS4A) carriers. Within individual cell types, we capture genes commonly dysregulated across variant groups. However, specific transcriptional states are more prevalent within variant carriers. TREM2 oligodendrocytes show a dysregulated autophagy-lysosomal pathway, MS4A microglia have dysregulated complement cascade genes, and APOEε4 inhibitory neurons display signs of ferroptosis. All cell types have enriched states in autosomal dominant carriers. We leverage differential expression and single-nucleus ATAC-seq to map GWAS signals to effector cell types including the NCK2 signal to neurons in addition to the initially proposed microglia. Overall, our results provide insights into the transcriptional diversity resulting from AD genetic architecture and cellular heterogeneity. The data can be explored on the online browser (http://web.hararilab.org/SNARE/).

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“…29 Only one pathogenic mutation in a case study has been reported in a similar protein, VWA3B, which, as homozygous, causes cerebellar ataxia. 30 The 3A domain is involved specifically in collagen binding, and this domain plays a key role in platelet adhesion in damaged blood vessels. Binding to collagen (specifically types I and III) via the 3A domain, which comes from the connective tissue of the vessel wall, allows the platelet plug to start formation.…”

Section: Discussionmentioning

confidence: 99%

Association of a Variant in VWA3A with Response to Anti-Vascular Endothelial Growth Factor Treatment in Neovascular AMD

Grunin

Beykin

Rahmani

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Anti-vascular endothelial growth factor (VEGF) therapy for neovascular AMD (nvAMD) obtains a variable outcome. We performed a genome-wide association study for anti-VEGF treatment response in nvAMD to identify variants potentially underlying such a variable outcome. METHODS. Israeli patients with nvAMD who underwent anti-VEGF treatment (n = 187) were genotyped on a whole exome chip containing approximately 500,000 variants. Genotyping was correlated with delta visual acuity (deltaVA) between baseline and after three injections of anti-VEGF. Top principal components, age, and baseline VA were included in the analysis. Two lead associated variants were genotyped in an independent validation set of patients with nvAMD (n = 108). RESULTS. Linear regression analysis on 5,353,842 variants revealed five exonic variants with an association P value of less than 6 × 10 −5. The top variant in the gene VWA3A (P = 1.77 × 10 −6) was tested in the validation cohort. The minor allele of the VWA3A variant was associated with worse response to treatment (P = 0.02). The average deltaVA of discovery plus validation was-0.214 logMAR (≈ a gain of 10.7 Early Treatment Diabetic Retinopathy Study letters) for homozygote for the major allele, 0.172 logMAR for heterozygotes (≈ a loss of 8.6 Early Treatment Diabetic Retinopathy Study letters), and 0.21 logMAR for homozygote for the minor allele (≈ a loss of 10.5 Early Treatment Diabetic Retinopathy Study letters). Minor allele carriers had a higher frequency of macular hemorrhage at baseline. CONCLUSIONS. An VWA3A gene variant was associated with worse response to anti-VEGF treatment in Israeli patients with nvAMD. The VWA3A protein is a precursor of the multimeric von Willebrand factor which is involved in blood coagulation, a system previously associated with nvAMD.

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A homozygous mutation ofVWA3Bcauses cerebellar ataxia with intellectual disability

Abstract: Mutated VWA3B was found to be likely associated with cerebellar degeneration with intellectual disability. Although a rare cause of cerebellar degeneration, these findings indicate a critical role for VWA3B in the apoptosis pathway in neuronal tissues.

Cited by 16 publications

References 45 publications

Copy Number Variation Pattern for Discriminating MACROD2 States of Colorectal Cancer Subtypes

Copy Number Variation Pattern for Discriminating MACROD2 States of Colorectal Cancer Subtypes

Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers

Association of a Variant in VWA3A with Response to Anti-Vascular Endothelial Growth Factor Treatment in Neovascular AMD

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