Keylock, Annette Ai Lin; (2018) Novel Genetic Causes of Cerebral and Systemic Vasculopathies. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Vasculopathies are a varied group of disorders that affect the vascular tree resulting in arterial stenosis or dilatation causing multi-organ ischaemia and significant cardiac and cerebral circulation complications. Commonly, vasculopathies present in infancy and segregate within families so a genetic cause is often suspected but not always identified by the current routinely available genetic tests in the UK National Health Service (NHS). Due to the overlapping phenotypes of these disorders genetic sequencing is required for accurate diagnosis and appropriate clinical intervention. In this thesis, a cohort of children with cerebral and systemic vasculopathies was subject to next-generation genetic sequencing. Several discoveries were made and various families are discussed herein. Firstly, a novel heterozygous mutation in MYH11, a gene affecting smooth muscle myosin heavy chain, was identified in a child with a moyamoya-like cerebrovascular disease and renal artery stenosis. This expanded the vasculopathic phenotype associated with MYH11, which previously was associated with familial aortopathy. Secondly, multiple members of three families diagnosed with a moyamoya arteriopathy were studied and were all found to have heterozygous mutations in c-CBL, an E3 ubiquitin ligase that down regulates various receptor tyrosine kinases. Detailed in vitro functional expression studies were undertaken in the patients with mutations in c-CBL showing impaired CBL-mediated degradation of cell-surface receptors in a dominant negative fashion. These results were compatible with dysregulated intracellular signaling through RAS. Lastly, three families with systemic vasculopathies associated with heterozygous mutations in RNF213 were also studied. This protein possesses both ubiquitin ligase and ATPase activity and adversely affects endothelial cell function. For the first time I showed that heterozygous mutations in RNF213 cause a vasculopathy that is not confined to the cerebral circulation.

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