Biallelic variants in
            <i>WARS1</i>
            cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function

Lin, Sheng‐Jia; Vona, Barbara; Porter, Hillary M.; Izadi, Mahmoud; Huang, Kevin; Lacassie, Yves; Rosenfeld, Jill A.; Khan, Sher Alam; Petree, Cassidy; Ali, Taqdir; Muhammad, Nazif; Khan, Sher Alam; Muhammad, Noor; Liu, Pengfei; Haymon, Marie Louise; Rüschendorf, Franz; Kong, Il‐Keun; Schnapp, Linda; Shur, Natasha; Chorich, Lynn P.; Layman, Lawrence C.; Haaf, Thomas; Pourkarimi, Ehsan; Kim, Hyung‐Goo; Varshney, Gaurav K.

doi:10.1002/humu.24435

Cited by 9 publications

(14 citation statements)

References 62 publications

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“…Our previous observation aligns with a human WARS1 loss-of-function mutation associated with the microcephaly (21). wars-1 KD results in sterility and a dramatic reduction of germ cells in various regions, especially in the mitotic zone of the C. elegans germline (21). Germline exhibits distal-proximal polarity, with the mitotically dividing cells at the distal end and the meiotic cells at the proximal region.…”

Section: Introductionsupporting

confidence: 87%

Section: Introductionsupporting

confidence: 82%

“…Previously, we reported an association between WARS-1 depletion and defects in germ cell development and mitotic cell cycle progression in the Caenorhabditis elegans (C. elegans) germline (21). Our previous observation aligns with a human WARS1 loss-of-function mutation associated with the microcephaly (21). wars-1 KD results in sterility and a dramatic reduction of germ cells in various regions, especially in the mitotic zone of the C. elegans germline (21).…”

Section: Introductionsupporting

confidence: 80%

“…To knock down wars-1 throughout C. elegans development, we generated an RNAi construct complementary to the coding region of wars-1 that effectively downregulated its expression (Sup. Figure 1, p < 0.0001) (21). To further characterize the defect in the mitotic cell cycle, we compared the mitotic index of the wars-1 RNAi germline with that of the wild type.…”

Section: Resultsmentioning

confidence: 98%

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Tryptophanyl-tRNA synthetase-1 (WARS1) depletion and high tryptophan concentration lead to genomic instability in Caenorhabditis elegans

Izadi,

Ali,

Shurrab

et al. 2023

Preprint

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The fidelity of translation is ensured by a family of proteins named aminoacyl-tRNA synthetases, making them crucial for development and survival. More recently, mutations in the tryptophanyl-tRNA synthetase (WARS1) have been linked to various human diseases, from intellectual disability to various types of cancer. To understand the function of WARS1, we investigated the effect of WARS-1 depletion during the mitotic and meiotic cell cycle in the developing germline of C. elegans and demonstrated the role of WARS-1 in genome integrity. wars-1 knockdown results in cell cycle arrest of the mitotically active germ cells. Such mitotic arrest is also associated with canonical DNA damage-induced checkpoint signaling in mitotic and meiotic germ cells. Significantly, such DNA checkpoint activation is associated with the morphological anomalies in chromatin structures that are the hallmarks of genome instability, such as the formation of chromatin bridges, micronuclei, and chromatin buds. We believe that WARS-1 depletion increases the intracellular concentration of tryptophan and an elevated level of its catabolites, leading to genomic instability. Our result demonstrates that exposing C. elegans to a high tryptophan dosage leads to DNA damage checkpoint activation. All in all, we have strong evidence that knocking down wars-1 results in defects in genomic integrity.

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Section: Introductionsupporting

confidence: 87%

Section: Introductionsupporting

confidence: 82%

Section: Introductionsupporting

confidence: 80%

Section: Resultsmentioning

confidence: 98%

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Tryptophanyl-tRNA synthetase-1 (WARS1) depletion and high tryptophan concentration lead to genomic instability in Caenorhabditis elegans

Izadi,

Ali,

Shurrab

et al. 2023

Preprint

Self Cite

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“…Acoustically evoked behavioral response tests were carried out using Zebrabox behavior chambers (Viewpoint Life Sciences) as previously described 12 involving the percentage of responses for 12 stimuli per larva. The visual startle response test was performed using the DanioVision system running EthoVision XT software (Noldus Information Technology, Leesburg), as previously reported 12,13 based on the number of responses for five stimuli per larva. For locomotor behavior recording during light/dark transitions, 4 dpf larvae were transferred to a 96-well plate, with one larva per well in 150 µL of embryo water.…”

Section: Methodsmentioning

confidence: 99%

Loss of symmetric cell division of apical neural progenitors drivesDENND5A-related developmental and epileptic encephalopathy

Banks

Kharfallah

Fonov

et al. 2022

Preprint

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Epileptic encephalopathies comprise a clinically and genetically heterogenous group of disorders characterized by global developmental delay and ongoing seizure activity. It is generally considered that seizure activity is the primary pathology and leads to altered cognitive function. However, epileptic encephalopathy can also result from primary defects in neurodevelopment that lead to seizures. Here we examine the symptomology of individuals with epileptic encephalopathy resulting from biallelic pathogenic variants in DENND5A, encoding a protein involved in intracellular membrane trafficking. We established a cohort of 15 individuals from 14 families with 21 unique variants in DENND5A and analyzed phenotypic surveys answered by their treating clinicians. We obtained cells derived from several cohort members and examined DENND5A expression and stability, and we examined the role of DENND5A in symmetric cell division capability. Finally, we generated a mouse line expressing a homozygous mutation found in the cohort and analyzed brain morphology in vivo using a 7 Tesla magnetic resonance imaging system. Our cohort study reveals that global developmental delay, gross abnormalities in brain development including ventriculomegaly and corpus callosum dysgenesis, seizures, microcephaly and hypotonia are found in the majority of the cohort. Patient-derived neural precursor cells from induced pluripotent stem cells, as well as patient-derived lymphoblasts, display loss of DENND5A protein and exhibit problems with symmetric cell division, an essential process in early neural development. The introduction of a homozygous human point mutation into the conserved sequence in mouse leads to an animal with reduced brain volume and widespread regional brain dysgenesis and ventriculomegaly, phenotypes shared with the human cohort. Taken together, our multi-dimensional study establishes DENND5A as a critical gene during neurodevelopment and that biallelic loss of function variants, including missense and truncating variants as well as intronic splice site variants, result in a developmental epileptic encephalopathy.

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Hereditary Motor Neuropathy

De Winter,

Baets

2024

Reference Module in Neuroscience and Biobehavioral Psychology

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Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function

Cited by 9 publications

References 62 publications

Tryptophanyl-tRNA synthetase-1 (WARS1) depletion and high tryptophan concentration lead to genomic instability in Caenorhabditis elegans

Tryptophanyl-tRNA synthetase-1 (WARS1) depletion and high tryptophan concentration lead to genomic instability in Caenorhabditis elegans

Loss of symmetric cell division of apical neural progenitors drivesDENND5A-related developmental and epileptic encephalopathy

Hereditary Motor Neuropathy

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