Variants in DOCK3 cause developmental delay and hypotonia
Open accessAbstract
The DOCK3 gene encodes the Dedicator of cytokinesis 3 (DOCK3) protein, which belongs to the family of guanine nucleotide exchange factors and is expressed almost exclusively in the brain and spinal cord. We used whole exome sequencing (WES) to investigate the molecular cause of developmental delay and hypotonia in three unrelated probands. WES identified truncating and splice site variants in Patient 1 and compound heterozygous and homozygous missense variants in Patients 2 and 3, respectively. We studied the effect of the three missense variants in vitro by using site-directed mutagenesis and pull-down assay and show that the induction of Rac1 activation was significantly lower in DOCK3 mutant cells compared with wild type human DOCK3 (P < 0.05). We generated a protein model to further examine the effect of the two missense variants within or adjacent to the DHR-2 domain in DOCK3 and this model supports pathogenicity. Our results support a loss of function mechanism but the data on the patients with missense variants should be cautiously interpreted because of the variability of the phenotypes and limited number of cases. Prior studies have described DOCK3 bi-allelic loss of function variants in two families with ataxia, hypotonia, and developmental delay. Here, we report on three patients with DOCK3-related developmental delay, wide-based or uncoordinated gait, and hypotonia, further supporting DOCK3's role in a neurodevelopmental syndrome and expanding the spectrum of phenotypic and genotypic variability.
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DOCK3 gene variants leading to potentially nonfunctional protein cause developmental and motor issues in patients.
“DOCK3 gene variants leading to potentially nonfunctional protein were identified to cause developmental and motor issues in patients confirmed by a RAC1 pull-down assay and protein modeling (70).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [70]
The Abstract reports developmental delay, hypotonia and gait problems in patients with DOCK3 variants. It says the Rac1 pull-down assay and protein model support a loss-of-function mechanism and pathogenicity, but cautions that the missense-variant findings should be interpreted carefully. Those tests support the proposed link; they do not confirm that the variants caused the patients’ clinical problems. (LLM, conf=0.85)
Experimental — accuracy not yet measuredWiltrout et al. reported three individuals with developmental delay, hypotonia, coordination or gait abnormalities and bi-allelic variants in DOCK3.
“Furthermore, Wiltrout et al. reported three individuals with DD, hypotonia, coordination or gait abnormalities and bi-allelic variants in DOCK3 (MIM: #618,292) (Wiltrout et al. 2019).”
From Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly (2024) · cites this paper as Wiltrout et al. 2019
DOCK3 is a GEF for RAC1 and acts as a regulator of actin reorganization in neuronal tissue.
“DOCK3, a GEF for RAC1, acts as regulator of actin reorganization in neuronal tissue (69, 70, 71, 72).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [70]
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- Authors
- Wiltrout, K., Ferrer, A., van de Laar, I., Namekata, K., Harada, T., Klee, E. W., Zimmerman, M. T., Cousin, M. A., Kempainen, J. L., Babovic-Vuksanovic, D., van Slegtenhorst, M. A., Aarts-Tesselaar, C. D., Schnur, R. E., Andrews, M., & Shinawi, M.
- Affiliations
- Washington University in St. Louis (US)
- Mayo Clinic (US)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Medical College of Wisconsin (US)
- Amphia Ziekenhuis (NL)
- Corresponding author
- Shinawi, Marwan
- ORCID
- Venue
- European Journal of Human Genetics
- Published
- 2019-04-11
- Volume
- 27
- Issue
- 8
- Pages
- 1225-1234
- ISSN
- 1018-4813 (ISSN-L)
- 1476-5438
- PMC
- PMC6777627
- OpenAlex
- W2936667766
- Cited by
- 17
- References
- 24
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 2
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- MEXT | Japan Society for the Promotion of Science (JP16K08635, JP15H04999)
- Takeda Science Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- developmental delay, hypotonia, guanine nucleotide exchange factor, Rac1 activation, missense mutations, compound heterozygosity, truncating mutations, loss of function, neurodevelopmental syndrome, ataxia, variant pathogenicity
- MeSH terms
- Exome Sequencing, Loss of Function Mutation, Child, Developmental Disabilities, Child, Preschool, Female, Genotype, Humans, Infant, Male, Intellectual Disability, Muscle Hypotonia, Nerve Tissue Proteins, Phenotype, Genetic Predisposition to Disease, Guanine Nucleotide Exchange Factors
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