Inherited and de novo variants extend the etiology of TAOK1-associated neurodevelopmental disorder

Hunter, Jesse M.; Massingham, Lauren J.; Manickam, Kandamurugu; Williamson, Rachel K; Schwab, Jennifer; Marhabaie, Mohammad; Siemon, Amy; Reyes, Emily de los; Cottrell, Catherine E.; Wilson, Richard K.; Koboldt, Daniel C.

doi:10.1101/mcs.a006180

Cited by 9 publications

(10 citation statements)

References 33 publications

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“…To the best of our knowledge, only six studies have reported variants of TAOK1 in 40 patients with NDDs ( Xie et al, 2016 ; Dulovic-Mahlow et al, 2019 ; Satterstrom et al, 2020 ; Basel-Salmon et al, 2021 ; van Woerden et al, 2021 ; Hunter et al, 2022 ). The phenotypes of the affected individuals are summarized in Table 1 .…”

Section: Discussionmentioning

confidence: 99%

“…Variants in five (12.5%) affected individuals, P8, P9, P23, P37, and P38, were considered to be inherited from an affected mother or father ( Table 1 ), which are classified as pathogenic herein. The very mild cognitive phenotypes of some affected parents might be explained by incomplete penetrance and variable expressivity ( Hunter et al, 2022 ). Furthermore, no recurrent variants were reported in the region of 17q11.2 (chr17: 27064286-28761847), indicating that TAOK1 is not prone to hotspot variant, which was also mentioned by van Woerden et al (2021) .…”

Section: Discussionmentioning

confidence: 99%

“…TAOK1 is highly expressed in the human brain and plays a role in the establishment of neuronal polarity, neuronal differentiation, and early brain development ( Biernat et al, 2002 ; Timm et al, 2006 ; Draviam et al, 2007 ; Breuss and Keays, 2014 ; Poon et al, 2016 ). Many studies have provided evidence that TAOK1 dysfunction can result in neurodevelopmental disorders (NDDs) ( Cooper et al, 2011 ; Xie et al, 2016 ; Deciphering Developmental Disorders Study, 2017 ; Dulovic-Mahlow et al, 2019 ; Satterstrom et al, 2020 ; van Woerden et al, 2021 ; Hunter et al, 2022 ). However, dysfunction of this kinase in prenatal cases has not been reported.…”

Section: Introductionmentioning

confidence: 99%

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Paternal De Novo Variant of TAOK1 in a Fetus With Structural Brain Abnormalities

Yang

Shang

et al. 2022

Front. Genet.

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A dilated lateral ventricle is a relatively common finding on prenatal ultrasound, and the causes are complex. We aimed to explore the etiology of a fetus with a dilated lateral ventricle. Trio whole-exome sequencing was performed to detect causative variants. A de novo variant of TAOK1 (NM_020791.2: c.227A>G) was detected in the proband and evaluated for potential functional impacts using a variety of prediction tools. Droplet digital polymerase chain reaction was used to exclude the parental mosaicism and to verify the phasing of the de novo variant. Based on peripheral blood analysis, the parents did not exhibit mosaicism at this site, and the de novo variant was paternally derived. Here, we describe a fetus with a de novo likely pathogenic variant of TAOK1 who had a dilated lateral ventricle and a series of particular phenotypes. This case expands the clinical spectrum of TAOK1-associated disorders. We propose a method for solving genetic disorders in which the responsible genes have not yet gone through ClinGen curation, particularly for prenatal cases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Paternal De Novo Variant of TAOK1 in a Fetus With Structural Brain Abnormalities

Yang

Shang

et al. 2022

Front. Genet.

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“…Thousand and one amino acid kinase 1 (TAOK1) is an evolutionarily conserved serine-threonine kinase (Moore et al, 2000; Zihni et al, 2006). Recently, several missense and truncation mutations in TAOK1 have been recently identified in patients with severe neurodevelopmental delay (NDD) (Dulovic-Mahlow et al, 2019; Hunter et al, 2022; Satterstrom et al, 2020; Woerden et al, 2021). The core clinical features of patients with TAOK1-associated NDD syndrome include varying degrees of intellectual disability and developmental delay, neonatal feeding difficulties, overlapping dysmorphic facial features, behavior problems, hypotonia, and joint hypermobility (Dulovic-Mahlow et al, 2019; Hunter et al, 2022; Woerden et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, several missense and truncation mutations in TAOK1 have been recently identified in patients with severe neurodevelopmental delay (NDD) (Dulovic-Mahlow et al, 2019; Hunter et al, 2022; Satterstrom et al, 2020; Woerden et al, 2021). The core clinical features of patients with TAOK1-associated NDD syndrome include varying degrees of intellectual disability and developmental delay, neonatal feeding difficulties, overlapping dysmorphic facial features, behavior problems, hypotonia, and joint hypermobility (Dulovic-Mahlow et al, 2019; Hunter et al, 2022; Woerden et al, 2021). While evidence for the disease association of TAOK1 is compelling, little is known about the molecular and cellular function of TAOK1 in neuronal development.…”

Section: Introductionmentioning

confidence: 99%

Neurodevelopmental disorder associated mutations in TAOK1 reveal its function as a plasma membrane remodeling kinase

Beeman

Sapre

Ong

et al. 2022

Preprint

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Mutations in TAOK1, a serine-threonine kinase encoding gene are strongly associated with both autism spectrum disorder (ASD) and neurodevelopmental delay (NDD). However, molecular function of this evolutionarily conserved kinase and the mechanisms through which TAOK1 mutations lead to neuropathology are unknown. Here, we showed that TAOK1 is highly expressed in neurons within the brain, and has a functional role in remodeling the plasma membrane through direct association with phosphoinositides. We characterized four NDD-associated TAOK1 mutations, and demonstrated that these mutations render TAOK1 catalytically dead. Kinase dead TAOK1 mutants were aberrantly trapped in membrane-bound state, which induced exuberant membrane protrusions. Expression of TAOK1 disease mutants in hippocampal neurons led to abnormal growth of the dendritic arbor. The coiled-coil region C-terminal to the kinase domain are predicted to fold into a triple helix. We showed that this triple helix directly bound phospholipids, and was required for both TAOK1 membrane association and induction of aberrant protrusions. Further, TAOK1 mutants were rescued from their membrane-trapped state by exogenous expression of the isolated kinase domain. Utilizing mass-spectrometry, we identified critical residues in the triple helix phosphorylated by TAOK1 that autoregulated its plasma membrane association. These findings define a previously unknown function of TAOK1 as a unique plasma membrane remodeling kinase, and reveal the underlying mechanisms through which TAOK1 dysfunction leads to neurodevelopmental disorders.

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Corylifol A ameliorates muscle atrophy by inhibiting TAOK1/p38‐MAPK/FoxO3 pathway in cancer cachexia

Zhang

Shen

Wang

et al. 2023

J cachexia sarcopenia muscle

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BackgroundCorylifol A (CYA) is one of the main active components of Psoralea corylifolia L. CYA had been reported to have ameliorating effects on dexamethasone‐induced atrophy of C2C12 mouse skeletal myotubes, but its effects on cancer cachexia were unclear. Here, we checked the influence of CYA on muscle atrophy in cancer cachexia mice and tried to clarify its mechanisms.MethodsC26 tumour‐bearing mice were applied as the animal model to examine the effects of CYA in attenuating cachexia symptoms. The in vitro cell models of TNF‐α‐induced C2C12 myotubes or ad‐mRFP‐GFP‐LC3B‐transfected C2C12 myotubes were used to check the influence of CYA on myotube atrophy based on both ubiquitin proteasome system (UPS) and autophagy‐lysosome system. The possible direct targets of CYA were searched using the biotin‐streptavidin pull‐down assay and then confirmed using the Microscale thermophoresis binding assay. The levels of related signal proteins in both in vitro and in vivo experiments were examined using western blotting and immunocytochemical assay.ResultsThe administration of CYA prevented body weight loss and muscle wasting in C26 tumour‐bearing mice without affecting tumour growth. At the end of the experiment, the body weight of mice treated with 30 mg/kg of CYA (23.59 ± 0.94 g) was significantly higher than that of the C26 model group (21.66 ± 0.56 g) with P < 0.05. The values of gastrocnemius muscle weight/body weight of mice treated with 15 or 30 mg/kg CYA (0.53 ± 0.02% and 0.54 ± 0.01%, respectively) were both significantly higher than that of the C26 model group (0.45 ± 0.01%) with P < 0.01. CYA decreased both UPS‐mediated protein degradation and autophagy in muscle tissues of C26 tumour‐bearing mice as well as in C2C12 myotubes treated with TNF‐α. The thousand‐and‐one amino acid kinase 1 (TAOK1) was found to be the direct binding target of CYA. CYA inhibited the activation of TAOK1 and its downstream p38‐MAPK pathway thus decreased the level and nuclear location of FoxO3. siRNA knockdown of TAOK1 or regulation of the p38‐MAPK pathway using activator or inhibitor could affect the ameliorating effects of CYA on myotube atrophy.ConclusionsCYA ameliorates cancer cachexia muscle atrophy by decreasing both UPS degradation and autophagy. The ameliorating effects of CYA on muscle atrophy might be based on its binding with TAOK1 and inhibiting the TAOK1/p38‐MAPK/FoxO3 pathway.

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Inherited and de novo variants extend the etiology of TAOK1-associated neurodevelopmental disorder

Cited by 9 publications

References 33 publications

Paternal De Novo Variant of TAOK1 in a Fetus With Structural Brain Abnormalities

Paternal De Novo Variant of TAOK1 in a Fetus With Structural Brain Abnormalities

Neurodevelopmental disorder associated mutations in TAOK1 reveal its function as a plasma membrane remodeling kinase

Corylifol A ameliorates muscle atrophy by inhibiting TAOK1/p38‐MAPK/FoxO3 pathway in cancer cachexia

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