The DOCK protein family in vascular development and disease.

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.

Whole Exome Sequence Analysis Provides Novel Insights into the Genetic Framework of Childhood-Onset Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) describes a rare, progressive vascular disease caused by the obstruction of pulmonary arterioles, typically resulting in right heart failure. Whilst PAH most often manifests in adulthood, paediatric disease is considered to be a distinct entity with increased morbidity and often an unexplained resistance to current therapies. Recent genetic studies have substantially increased our understanding of PAH pathogenesis, providing opportunities for molecular diagnosis and presymptomatic genetic testing in families. However, the genetic architecture of childhood-onset PAH remains relatively poorly characterised. We sought to investigate a previously unsolved paediatric cohort (n = 18) using whole exome sequencing to improve the molecular diagnosis of childhood-onset PAH. Through a targeted investigation of 26 candidate genes, we applied a rigorous variant filtering methodology to enrich for rare, likely pathogenic variants. This analysis led to the detection of novel PAH risk alleles in five genes, including the first identification of a heterozygous ATP13A3 mutation in childhood-onset disease. In addition, we provide the first independent validation of BMP10 and PDGFD as genetic risk factors for PAH. These data provide a molecular diagnosis in 28% of paediatric cases, reflecting the increased genetic burden in childhood-onset disease and highlighting the importance of next-generation sequencing approaches to diagnostic surveillance.