Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish

Siekierska, Aleksandra; Stamberger, Hannah; Deconinck, Tine; Oprescu, Stephanie N.; Partoens, Michèle; Zhang, Yifan; Sourbron, Jo; Adriaenssens, Elias; Mullen, Patrick; Wiencek, Patrick; Hardies, Katia; Lee, Jeong Soo; Giong, Hoi Khoanh; Distelmaier, Felix; Elpeleg, Orly; Helbig, Katherine L.; Hersh, Joseph H.; Işıkay, Sedat; Jordan, Elizabeth; Karaca, Ender; Kecskés, Angela; Lupski, James R.; Kovács-Nagy, Réka; May, Patrick; Narayanan, Vinodh; Pendziwiat, Manuela; Ramsey, Keri; Rangasamy, Sampathkumar; Shinde, Deepali N.; Spiegel, Ronen; Timmerman, Vincent; Spiczak, Sarah von; Helbig, Ingo; Weckhuysen, Sarah; Francklyn, Christopher S.; Antonellis, Anthony; Witte, Peter de; Jonghe, Peter De

doi:10.1038/s41467-018-07953-w

Cited by 42 publications

(58 citation statements)

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“…A minoacyl-tRNA synthetases (ARSs) are a ubiquitously expressed group of highly specialized enzymes mediating the charging of amino acids onto cognate transfer RNAs (tRNAs) in both cytoplasm and mitochondria, essential for protein translation 1,2 . Among the ARS proteins encoded by 37 ARS genes, responsible for the 20 typical amino acids, 17 function in the cytoplasm, 17 function in mitochondria, and 3 function in both cellular compartments [3][4][5][6] . Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure.…”

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“…Both heterozygous and homozygous disease-causing variants in several ARS genes have been reported 11 . Biallelic damaging variants in ARS2 genes, encoding mitochondriallocalized enzymes, tend to cause mitochondrial encephalopathies, whereas biallelic damaging variants in ARS1 genes, encoding cytoplasm-localized enzymes, tend to cause epileptic encephalopathies or other systemic conditions 3,4,[12][13][14][15] . Interestingly, certain variants in ARS genes show peripheral neuropathy (i.e., Charcot-Marie-Tooth syndrome) with dominant inheritance, at least partially explained by toxic gain-of-function effects of mutant proteins binding to neuropilin-2 [16][17][18][19][20][21][22] .…”

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confidence: 99%

“…Mutations in genes involved in centriolar biogenesis/assembly (MCPH), microtubule regulation (TUB genes), DNA damage (PNKP), signaling pathways (ALFY/ASPM), transcription and metabolism are linked to microcephaly [29][30][31][32][33][34][35] . Recently, QARS, KARS, VARS, and CARS ARS family genes were implicated in microcephaly, but mammalian model systems and mechanisms remain unexplored 3,4,11,36,37 .…”

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Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly

Wang

Sievert

et al. 2020

Nat Commun

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Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Here, we identify biallelic missense and frameshift mutations in NARS1 in seven patients from three unrelated families with microcephaly and neurodevelopmental delay. Patient cells show reduced NARS1 protein, impaired NARS1 activity and impaired global protein synthesis. Cortical brain organoid modeling shows reduced proliferation of radial glial cells (RGCs), leading to smaller organoids characteristic of microcephaly. Single-cell analysis reveals altered constituents of both astrocytic and RGC lineages, suggesting a requirement for NARS1 in RGC proliferation. Our findings demonstrate that NARS1 is required to meet protein synthetic needs and to support RGC proliferation in human brain development.

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Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly

Wang

Sievert

et al. 2020

Nat Commun

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“…While the seven previously characterized HARS CMT variants display a loss‐of‐function effect in yeast and/or cell‐free enzymatic assays, the aminoacylation function of these ARS‐CMT variants has not been directly assessed in patient cells. Using a previously described method, we examined aminoacylation activity directly in cell lysates collected from V133F patient fibroblasts. We observed that the rate of tRNA His aminoacylation was significantly reduced (~25%) in patient cell lysates, relative to extracts obtained from control fibroblasts (Fig.…”

Section: Patient and Methodsmentioning

confidence: 99%

Peripheral neuropathy and cognitive impairment associated with a novel monoallelic HARS variant

Royer‐Bertrand

Tsouni

Mullen

et al. 2019

Ann Clin Transl Neurol

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Background A 49‐year‐old male presented with late‐onset demyelinating peripheral neuropathy, cerebellar atrophy, and cognitive deficit. Nerve biopsy revealed intra‐axonal inclusions suggestive of polyglucosan bodies, raising the suspicion of adult polyglucosan bodies disease (OMIM 263570). Methods and Results While known genes associated with polyglucosan bodies storage were negative, whole‐exome sequencing identified an unreported monoallelic variant, c.397G>T (p.Val133Phe), in the histidyl‐tRNA synthetase (HARS) gene. While we did not identify mutations in genes known to be associated with polygucosan body disease, whole‐exome sequencing revealed an unreported monoallelic variant, c.397G>T in the histidyl‐tRNA synthetase (HARS) gene, encoding a substitution (Val133Phe) in the catalytic domain. Expression of this variant in patient cells resulted in reduced aminoacylation activity in extracts obtained from dermal fibroblasts, without compromising overall protein synthesis. Interpretation Genetic variants in the genes coding for the different aminoacyl‐tRNA synthases are associated with various clinical conditions. To date, a number of HARS variant have been associated with peripheral neuropathy, but not cognitive deficits. Further studies are needed to explore why HARS mutations confer a neuronal‐specific phenotype.

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“…At 23 dpf, i.e., after 8 DOT (days of treatment), surviving fish (in case of AB larvae, only the ones exposed to 0.5 µM) were examined for major dysmorphologies using a stereo microscope (Leica MZ10 F, Wetzlar, Germany) equipped with a digital color camera (Leica DFC310 FX with Leica Application Suite V3.6 software, (V3.6, Leica, Wetzlar, Germany, 2010). Body length was measured from the anterior tip of the snout to the base of the posterior caudal fin using ImageJ software (1.52p, NIH, Bethesda, MD, USA, 2019), as performed before [48]. The data were normalized to the body length of VHC-treated AB larvae.…”

Section: Morphological Phenotyping and Lethalitymentioning

confidence: 99%

Nephrotoxic Effects in Zebrafish after Prolonged Exposure to Aristolochic Acid

Wang

Giusti

et al. 2020

Toxins

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With the aim to explore the possibility to generate a zebrafish model of renal fibrosis, in this study the fibrogenic renal effect of aristolochic acid I (AAI) after immersion was assessed. This compound is highly nephrotoxic able to elicit renal fibrosis after exposure of rats and humans. Our results reveal that larval zebrafish at 15 days dpf (days post-fertilization) exposed for 8 days to 0.5 µM AAI showed clear signs of AKI (acute kidney injury). The damage resulted in the relative loss of the functional glomerular filtration barrier. Conversely, we did not observe any deposition of collagen, nor could we immunodetect α-SMA, a hallmark of myofibroblasts, in the tubules. In addition, no increase in gene expression of fibrogenesis biomarkers after whole animal RNA extraction was found. As zebrafish have a high capability for tissue regeneration possibly impeding fibrogenic processes, we also used a tert−/− zebrafish line exhibiting telomerase deficiency and impaired tissue homeostasis. AAI-treated tert−/− larvae displayed an increased sensitivity towards 0.5 µM AAI. Importantly, after AAI treatment a mild collagen deposition could be found in the tubules. The outcome implies that sustained AKI induced by nephrotoxic compounds combined with defective tert−/− stem cells can produce a fibrotic response.

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Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish

Cited by 42 publications

References 46 publications

Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly

Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly

Peripheral neuropathy and cognitive impairment associated with a novel monoallelic HARS variant

Nephrotoxic Effects in Zebrafish after Prolonged Exposure to Aristolochic Acid

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