Biallelic Mutations of VAC14 in Pediatric-Onset Neurological Disease

Lenk, Guy M.; Sztefko, Krystyna; Dębska–Vielhaber, Grażyna; Rydzanicz, Małgorzata; Walczak, Anna; Bekiesińska‐Figatowska, Monika; Vielhaber, Stefan; Hallmann, Kerstin; Stawiński, Piotr; Buehring, Sonja; Hsu, David; Kunz, Wolfram S.; Meisler, Miriam H.; Płoski, Rafał

doi:10.1016/j.ajhg.2016.05.008

Cited by 46 publications

(58 citation statements)

References 32 publications

(46 reference statements)

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“…SNPs in FGD4 , a Mendelian gene for congenital peripheral neuropathy (Charcot–Marie–Tooth disease), associated with paclitaxel-induced peripheral neuropathy (45). SNPs in VAC14 associated with docetaxel-induced peripheral neuropathy (46), and the gene was recently shown to be mutated in pediatric-onset neurological disease (47). Beyond chemotherapy studies, genetic variants that associate with the euphoric effects of d -amphetamine significantly overlap with variants that decrease risk for schizophrenia and attention deficit hyperactivity disorder (48).…”

Section: Discussionmentioning

confidence: 99%

Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity

Wheeler

Gamazon

Frisina

et al. 2017

Clinical Cancer Research

120

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Purpose Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO). Experimental Design We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4–12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding. Results One SNP, rs62283056, in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for WFS1 met genome-wide significance for association with CAO (P=1.4×10−8). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele (P=0.035). The association between decreased WFS1 expression and hearing loss was replicated in an independent BioVU cohort (n=18,620 patients, Bonferroni adjusted P<0.05). Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low P-values in the GWAS (P=0.048). Conclusions We show for the first time the role of WFS1 in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pre-therapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses.

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Section: Discussionmentioning

confidence: 99%

Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity

Wheeler

Gamazon

Frisina

et al. 2017

Clinical Cancer Research

120

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“…Autosomal dominant mutations in FIG4 are also a rare cause of amyotrophic lateral sclerosis and primary lateral sclerosis [113]. Biallelic mutations in the VAC14 gene are responsible for neurological disease [114]. …”

Section: Ptdins(35)p2 a Regulator Of Endosome-lysosome Traffickingmentioning

confidence: 99%

Phosphoinositides, Major Actors in Membrane Trafficking and Lipid Signaling Pathways

Craene

Bertazzi

Bär

et al. 2017

IJMS

162

147

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Abstract:Phosphoinositides are lipids involved in the vesicular transport of proteins and lipids between the different compartments of eukaryotic cells. They act by recruiting and/or activating effector proteins and thus are involved in regulating various cellular functions, such as vesicular budding, membrane fusion and cytoskeleton dynamics. Although detected in small concentrations in membranes, their role is essential to cell function, since imbalance in their concentrations is a hallmark of many cancers. Their synthesis involves phosphorylating/dephosphorylating positions D3, D4 and/or D5 of their inositol ring by specific lipid kinases and phosphatases. This process is tightly regulated and specific to the different intracellular membranes. Most enzymes involved in phosphoinositide synthesis are conserved between yeast and human, and their loss of function leads to severe diseases (cancer, myopathy, neuropathy and ciliopathy).Keywords: lipids; membrane trafficking; vesicles; phosphoinositides; phosphatase; kinase Phosphoinositides in Cellular Membranes Lipids, Major Membrane ComponentsThe dynamic modulation of the physicochemical properties of membranes is required for eukaryotic cells function. Indeed, cells live in an environment characterized by temperature, relative humidity, pH, sun exposure, osmotic pressure and nutrient variations. Living organisms have to adapt to variations of these different factors in order to keep their intracellular balance. Eukaryotic cells have achieved this by adopting a compartmentalized organization, which minimizes the intracellular variations resulting from extracellular fluctuations. The plasma membrane is the first barrier separating the cytoplasm from the extracellular medium. Its composition ensures a mechanical protection, but also allows exchanges with the medium through transporters and receptors, as a form of very selective permeability.Membranes are composed of two phospholipid leaflets organized as a bilayer in which sterols, glycolipids and proteins are inserted. The phospholipids of this bilayer are amphiphilic with a hydrophilic group (head) linked to a hydrophobic group (tail) ( Figure 1A). In the bilayer, the hydrophobic groups face each other, thus creating a hydrophobic space in between them, which ensures its role as a barrier. This property is very important for the anchoring of hydrophobic molecules, such as sterols or ceramides, transmembrane domains or the lipid anchor of proteins. The lipid composition of membranes varies according to the organism (eukaryotes or prokaryotes), the cell type (among the different tissues of a multicellular organism), the membrane type (plasma Int.

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“…The corresponding yeast mutation, Fig4 I59T, results in reduced cellular PI(3,5)P 2 levels (Chow et al , 2007). In addition, mutations in Vac14 have been associated with a progressive neurological disorder (Lenk et al , 2016). The PIKfyve-Vac14-Fig4 complex is therefore linked to human neurological disorders.…”

Section: Phosphatidylinositol 35-bisphosphate (Pi(35)p2)mentioning

confidence: 99%

PI5P and PI(3,5)P<sub>2</sub>: Minor, but Essential Phosphoinositides

Hasegawa

Strunk

Weisman

2017

Cell Struct. Funct.

118

111

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In most eukaryotes, phosphoinositides (PIs) have crucial roles in multiple cellular functions. Although the cellular levels of phosphatidylinositol 5-phosphate (PI5P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) are extremely low relative to some other PIs, emerging evidence demonstrates that both lipids are crucial for the endocytic pathway, intracellular signaling, and adaptation to stress. Mutations that causes defects in the biosynthesis of PI5P and PI(3,5)P2 are linked to human diseases including neurodegenerative disorders. Here, we review recent findings on cellular roles of PI5P and PI(3,5)P2, as well as the pathophysiological importance of these lipids.

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Biallelic Mutations of VAC14 in Pediatric-Onset Neurological Disease

Cited by 46 publications

References 32 publications

Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity

Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity

Phosphoinositides, Major Actors in Membrane Trafficking and Lipid Signaling Pathways

PI5P and PI(3,5)P<sub>2</sub>: Minor, but Essential Phosphoinositides

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