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610 and Genetics

Extremes of brain growth have frequently been associated with impaired neurodevelopment and cognition. A significant contribution to our understanding of the processes involved in brain development has been made by the study of single gene disorders which are rare in the general population, but occur with increased frequency in certain endogamous populations. This project stems from findings of a long-running clinical-genetic program, called ‘Windows of Hope’, based amongst the Amish. The project aims were to clinically characterise three new autosomal recessive disorders of brain growth and development, to define the genes and mutations responsible for each, and to investigate the function of the molecules identified. A final further objective of the project in keeping with the wider aims of the Windows of Hope study was to translate the findings of this research into direct clinical benefits to the families and community involved. A combination of clinical phenotyping, autozygosity and linkage mapping, and functional studies, were used to investigate each disorder, which enabled the identification of the novel disease genes in each case. Chapter three describes the identification of a hypomorphic mutation in PCNA responsible for a novel DNA repair disorder. Thus, although it was considered by many that mutations in PCNA would not be compatible with life due to its crucial role in genomic stability and cell division, this study disproves this notion and describes a molecular ‘missing piece’ in DNA repair spectrum disorders. While the relationship between pervasive developmental disorders and megalencephaly is well described, very few single gene disorders associated with this clinical relationship have been identified. Chapter four documents the discovery of two founder mutations in the KPTN gene associated with such a phenotype. The functional data shows that the encoded wild type molecule (kaptin) associates with dynamic actin cytoskeletal structures in cultured neurons and that the causative mutations result in loss of function perturbing this interaction, defining kaptin as a new molecule which is crucial for normal human brain development and function. Chapter five details the investigation of the eponymously named “Hershberger syndrome”, a disorder originally described by McKusick in the Ohio Amish in 1967. Clinical and genetic studies of affected individuals revealed that the syndrome was comprised of two distinct disorders; Aicardi Goutières syndrome due to mutation in SAMHD1, and a new condition characterised by profound neurological impairment, cerebellar involvement and nephrosis. This condition, renamed “nephrocerebellar syndrome” was found to be caused by homozygous mutations in two closely linked genes, WHAMM and WDR73. The genetic and functional data supported the involvement of both molecules in the disease, suggesting that this is a composite phenotype. The identification and functional characterisation of three new genes responsible for abnormalities in brain growth provides an invaluable insight into disease pathogenesis and also identifies molecular pathways important for normal brain development. This is turn enables clinicians to provide a much needed diagnosis for affected individuals and their families as well as the wider community.