Trio exome sequencing identified a novel de novo WASF1 missense variant leading to recurrent site substitution in a Chinese patient with developmental delay, microcephaly, and early-onset seizures: A mutational hotspot p.Trp161 and literature review

Zhao, Arman; Zhou, Rui; Gu, Qin; Liu, Min; Zhang, Bingbing; Huang, Jing; Yang, Bin; Yao, Rutao; Wang, Jian; Lv, Haitao; Wang, Jian; Shen, Yiping; Wang, Hongying; Chen, Xuqin

doi:10.1016/j.cca.2021.08.030

Cited by 8 publications

(4 citation statements)

References 29 publications

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“…Disruption of WRC function can profoundly affect the nervous system in animals, resulting in altered spine morphology and density, intellectual disability, and embryonic death ( Dahl et al, 2003 ; Soderling et al, 2003 ). Mutations in WAVE and other WRC subunits have been linked to various neurodevelopmental disorders in humans, including neurodevelopmental disorder with absent language and variable seizures, developmental and epileptic encephalopathy-65, and Alzheimer’s disease ( Begemann et al, 2021 ; Conway et al, 2018 ; Ito et al, 2018 ; Kirkpatrick et al, 2017 ; Kramer et al, 2022 ; Kumar et al, 2013 ; Olive et al, 2020 ; Rottner et al, 2021 ; Shimojima Yamamoto et al, 2021 ; Sims et al, 2017 ; Srivastava et al, 2021 ; Zhao et al, 2021 ; Zweier et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

The intrinsically disordered cytoplasmic tail of a dendrite branching receptor uses two distinct mechanisms to regulate the actin cytoskeleton

Kramer

Narvaez-Ortiz

Patel

et al. 2023

eLife

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Dendrite morphogenesis is essential for neural circuit formation, yet the molecular mechanisms underlying complex dendrite branching remain elusive. Previous studies on the highly branched Caenorhabditis elegans PVD sensory neuron identified a membrane co-receptor complex that links extracellular signals to intracellular actin remodeling machinery, promoting high-order dendrite branching. In this complex, the claudin-like transmembrane protein HPO-30 recruits the WAVE regulatory complex (WRC) to dendrite branching sites, stimulating the Arp2/3 complex to polymerize actin. We report here our biochemical and structural analysis of this interaction, revealing that the intracellular domain (ICD) of HPO-30 is intrinsically disordered and employs two distinct mechanisms to regulate the actin cytoskeleton. First, HPO-30 ICD binding to the WRC requires dimerization and involves the entire ICD sequence, rather than a short linear peptide motif. This interaction enhances WRC activation by the GTPase Rac1. Second, HPO-30 ICD directly binds to the sides and barbed end of actin filaments. Binding to the barbed end requires ICD dimerization and inhibits both actin polymerization and depolymerization, resembling the actin capping protein CapZ. These dual functions provide an intriguing model of how membrane proteins can integrate distinct mechanisms to fine-tune local actin dynamics.

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Section: Introductionmentioning

confidence: 99%

The intrinsically disordered cytoplasmic tail of a dendrite branching receptor uses two distinct mechanisms to regulate the actin cytoskeleton

Kramer

Narvaez-Ortiz

Patel

et al. 2023

eLife

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“…Neurodevelopmental disorder with absent language and variable seizures (NEDALVS, # 618707) is an autosomal dominant disorder of neurodevelopment, which has clinical heterogeneity [ 1 ]. The phenotype of NEDALVS involves multiple organs and body parts [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

The recurrent WASF1 nonsense variant identified in two unaffected Chinese families with neurodevelopmental disorder: case report and review of the literatures

Tang,

Liu,

Lin

et al. 2023

BMC Med Genomics

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Background Neurodevelopmental disorder with absent language and variable seizures (NEDALVS, # 618707) are characterized by delayed speech and motor development, ocular abnormalities, and seizures. NEDAVLS is an autosomal dominant disorder caused by de novo mutations in the wasp protein family member 1 (WASF1) gene. Case presentation We identified a de novo nonsense variant c.1516 C > T (p.Arg506*) of WASF1 gene (NM_003931.3) in two pediatric female patients with delayed motor and language development. Conclusion This case demonstrates the effective role of WES in the diagnosis of NEDALVS. To the best of our knowledge, this variant has not been reported in the Chinese population. This contributes to our further understanding of the disease and to research related to the genetic and clinical heterogeneity, the treatment and prognosis of the disease.

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“…Disrupting the WRC in animals profoundly impacts the nervous system, leading to altered spine morphology and density, intellectual disability, as well as embryonic death (Dahl et al, 2003; Soderling et al, 2003). Mutations in WAVE and other subunits of the WRC lead to a variety of neurodevelopmental disorders in human patients, including neurodevelopmental disorder with absent language and variable seizures (NEDALVS), developmental and epileptic encephalopathy-65 (DEE-65), and Alzheimer’s disease (Begemann et al, 2021; Conway et al, 2018; Ito et al, 2018; Kirkpatrick et al, 2017; Kramer et al, 2022; Kumar et al, 2013; Olive et al, 2020; Rottner et al, 2021; Shimojima Yamamoto et al, 2021; Sims et al, 2017; Srivastava et al, 2021; Zhao et al, 2021; Zweier et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

The intrinsically disordered cytoplasmic tail of a dendrite branching receptor uses two distinct mechanisms to regulate the actin cytoskeleton

Kramer

Narvaez-Ortiz

Patel³

et al. 2022

Preprint

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Dendrite morphogenesis is essential to neural circuit formation, but the molecular mechanisms that control the growth of complicated dendrite branches are not well understood. Prior studies using the C. elegans PVD sensory neuron identified a multi-protein signaling complex that bridges extracellular cues with intracellular actin remodeling to promote high-order dendrite branching. In this complex, the transmembrane protein HPO-30 recruits the WAVE Regulatory Complex (WRC) to dendrite branching sites, where WRC stimulates the Arp2/3 complex to polymerize actin. Here we report biochemical and structural characterization of this interaction, revealing that the intracellular domain (ICD) of HPO-30 uses two novel mechanisms to regulate the actin cytoskeleton. First, the unstructured HPO-30 ICD undergoes dimerization and folding into a three-dimensional structure in order to bind the WRC. Second, the HPO-30 ICD directly binds to actin filaments, which stabilizes actin structures by preventing both actin polymerization and depolymerization. The novel dual functions of this dendrite receptor provide an intriguing example of how membrane proteins can use different mechanisms to locally fine-tune actin dynamics.

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Trio exome sequencing identified a novel de novo WASF1 missense variant leading to recurrent site substitution in a Chinese patient with developmental delay, microcephaly, and early-onset seizures: A mutational hotspot p.Trp161 and literature review

Cited by 8 publications

References 29 publications

The intrinsically disordered cytoplasmic tail of a dendrite branching receptor uses two distinct mechanisms to regulate the actin cytoskeleton

The intrinsically disordered cytoplasmic tail of a dendrite branching receptor uses two distinct mechanisms to regulate the actin cytoskeleton

The recurrent WASF1 nonsense variant identified in two unaffected Chinese families with neurodevelopmental disorder: case report and review of the literatures

The intrinsically disordered cytoplasmic tail of a dendrite branching receptor uses two distinct mechanisms to regulate the actin cytoskeleton

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