Adams–Oliver Syndrome Type 2 in Association with Compound Heterozygous <i><scp>DOCK</scp>6</i> Mutations

Jones, Krystal M.; Silfvast‐Kaiser, Annika; Leake, David R.; Diaz, Lucia Z.; Levy, Moise L.

doi:10.1111/pde.13239

Cited by 9 publications

(5 citation statements)

References 17 publications

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“…DOCK6, a member of the DOCK-C subfamily that displays GEF activity for both Rac1 and CDC42 through its Dock Homology Region-2 (DHR-2) domain, was also shared by hypothyroidism and sarcoidosis, as validated by two distinct datasets (GTEx and eQTLgene) [56]. Recent research indicates that DOCK6 is linked to various diseases, including cancers like gastric cancer and acute myeloid leukemia, and functions as an oncogene [57][58][59][60].…”

Section: Discussionmentioning

confidence: 99%

Shared genetic etiology between hypothyroidism and complex diseases: a large-scale genome-wide cross-trait analysis

Li,

Gong

2024

Preprint

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Hypothyroidism is a common condition of thyroid hormone insufficiency, and there is growing evidence of its link with additional diseases. It remains unclear whether these associations share a common genetic architecture. To address this gap, by leveraging summary-level genetic data from the UK Biobank of hypothyroidism and the FinnGen study of three complex diseases (sarcoidosis, chronic sinusitis, and interstitial lung disease (ILD) endpoints), we evaluated their shared genetic etiology. A significant genetic correlation was found between hypothyroidism and the three diseases. Cross-trait analyses utilizing the MTAG and CPASSOC models revealed 12, 2, and 12 shared loci between hypothyroidism and chronic sinusitis, ILD endpoints, and sarcoidosis, respectively. The SNP heritability enrichment analysis across 37 tissues and 136 cell types at the single-cell level identified candidate tissues and cell types that were shared by the diseases. Interestingly, we found a positive genetic relationship between these four diseases and central memory CD4+ T cells in the blood, supported by strong colocalization evidence (posterior probability >0.9). Mendelian randomization and colocalization analysis showed a link between hypothyroidism and sarcoidosis with two genes (DOCK6 and CD226) in the blood. Furthermore, among the hypothyroidism-driven plasma proteins, RIPK2 was identified as a potentially actionable mediator of hypothyroidism's effect on ILD endpoints. Overall, our findings contribute to improving our understanding of the molecular basis of these diseases' intricate relationships, as well as providing insights toward disease prevention and comorbidity management.

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Section: Discussionmentioning

confidence: 99%

Shared genetic etiology between hypothyroidism and complex diseases: a large-scale genome-wide cross-trait analysis

Li,

Gong

2024

Preprint

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“…To date, ~ 20 independent DOCK6 mutations have been described, accounting for 7 % of all reported AOS cases [88]. Predicted lossof-function variants cover all mutation types including missense and nonsense, and are located across the length of the gene [10,86,[89][90][91].…”

Section: Dock6mentioning

confidence: 99%

“…Ectasia and tortuosity of large veins, irregular medial thickness due to uneven mural cell deposition, and abnormal retinal vascularisation have all been observed [92]. Whilst the molecular causes of AOS in these patients remains unresolved, these characteristics may explain the observed clinical features in DOCK6-related AOS and suggest a role for the causal gene in the recruitment and migration of pericytes during angiogenesis [10,86,89,90]. However, the functional impact of AOS-specific mutations in vascular cell types remains to be examined, thus providing much scope for future investigations.…”

Section: Dock6mentioning

confidence: 99%

The DOCK protein family in vascular development and disease

Benson

Southgate

2021

Angiogenesis

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The vascular network is established and maintained through the processes of vasculogenesis and angiogenesis, which are tightly regulated during embryonic and postnatal life. The formation of a functional vasculature requires critical cellular mechanisms, such as cell migration, proliferation and adhesion, which are dependent on the activity of small Rho GTPases, controlled in part by the dedicator of cytokinesis (DOCK) protein family. Whilst the majority of DOCK proteins are associated with neuronal development, a growing body of evidence has indicated that members of the DOCK family may have key functions in the control of vasculogenic and angiogenic processes. This is supported by the involvement of several angiogenic signalling pathways, including chemokine receptor type 4 (CXCR4), vascular endothelial growth factor (VEGF) and phosphatidylinositol 3-kinase (PI3K), in the regulation of specific DOCK proteins. This review summarises recent progress in understanding the respective roles of DOCK family proteins during vascular development. We focus on existing in vivo and in vitro models and known human disease phenotypes and highlight potential mechanisms of DOCK protein dysfunction in the pathogenesis of vascular disease.

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“…Approximately 40–50% of cases suffering from AOS have no identifiable mutation; however, 17% of cases are attributed to mutations in DOCK6 . Notably, the individuals with DOCK6 mutations have the broadest range of anomalies (Jones et al , 2017). Abnormal cytoskeleton remodeling, impairing angiogenesis, limb bud ectodermal growth, malformations of the brain, intellectual disabilities, eye malformations and epilepsy (ranging from febrile to recurrent and severe seizures) are strongly affiliated with mutated DOCK6 (Cerikan and Schiebel, 2017; Jones et al , 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Notably, the individuals with DOCK6 mutations have the broadest range of anomalies (Jones et al , 2017). Abnormal cytoskeleton remodeling, impairing angiogenesis, limb bud ectodermal growth, malformations of the brain, intellectual disabilities, eye malformations and epilepsy (ranging from febrile to recurrent and severe seizures) are strongly affiliated with mutated DOCK6 (Cerikan and Schiebel, 2017; Jones et al , 2017). According to the VarSome database, almost 17 pathogenic mutations have been identified on the DOCK6 gene until now.…”

Section: Introductionmentioning

confidence: 99%

Homozygosity for a novel DOCK6 variant in an individual without aplasia cutis congenita of the scalp and terminal transverse limb defects

Zaersabet

Koochakkhani

Sarmast

et al. 2023

Clinical Dysmorphology

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Adams–Oliver Syndrome Type 2 in Association with Compound Heterozygous DOCK6 Mutations

Cited by 9 publications

References 17 publications

Shared genetic etiology between hypothyroidism and complex diseases: a large-scale genome-wide cross-trait analysis

Shared genetic etiology between hypothyroidism and complex diseases: a large-scale genome-wide cross-trait analysis

The DOCK protein family in vascular development and disease

Homozygosity for a novel DOCK6 variant in an individual without aplasia cutis congenita of the scalp and terminal transverse limb defects

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