A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.

no / Retinal dystrophies are an overlapping group of genetically heterogeneous conditions resulting from mutations in more than 250 genes. Here we describe five families affected by an adult-onset retinal dystrophy with early macular involvement and associated central visual loss in the third or fourth decade of life. Affected individuals were found to harbor disease-causing variants in DRAM2 (DNA-damage regulated autophagy modulator protein 2). Homozygosity mapping and exome sequencing in a large, consanguineous British family of Pakistani origin revealed a homozygous frameshift variant (c.140delG [p.Gly47Valfs∗3]) in nine affected family members. Sanger sequencing of DRAM2 in 322 unrelated probands with retinal dystrophy revealed one European subject with compound heterozygous DRAM2 changes (c.494G>A [p.Trp165∗] and c.131G>A [p.Ser44Asn]). Inspection of previously generated exome sequencing data in unsolved retinal dystrophy cases identified a homozygous variant in an individual of Indian origin (c.64_66del [p.Ala22del]). Independently, a gene-based case-control association study was conducted via an exome sequencing dataset of 18 phenotypically similar case subjects and 1,917 control subjects. Using a recessive model and a binomial test for rare, presumed biallelic, variants, we found DRAM2 to be the most statistically enriched gene; one subject was a homozygote (c.362A>T [p.His121Leu]) and another a compound heterozygote (c.79T>C [p.Tyr27His] and c.217_225del [p.Val73_Tyr75del]). DRAM2 encodes a transmembrane lysosomal protein thought to play a role in the initiation of autophagy. Immunohistochemical analysis showed DRAM2 localization to photoreceptor inner segments and to the apical surface of retinal pigment epithelial cells where it might be involved in the process of photoreceptor renewal and recycling to preserve visual function.

This PhD Thesis has been immersed in investigating the holistic experience of way-finding in buildings by people who have a range of visual ability. Previous research studies, spanning across a broad spectrum of disciplines, have focused on various characteristics of human way-finding (Arthur and Passini, 1992;Lynch, 1960;Downs and Stea, 1973). It is specifically recognised that the built environment is failing people with visual loss (Barker et al., 1995) and the strategic task and skill of way-finding within a building is a particular problem (Arthur and Passini, 1992). Under the social model of disability (Oliver, 1990) this is recognised as a form of architectural disablement (Goldsmith, 1997). There are few evidence-based studies of way-finding in a building. Furthermore, there are no studies of real-life experiences of way-finding undertaken by real-life participants who have a range of visual ability within the context of a real-life building. This leads to a research question: What are the design issues revealed by participants who have a range of visual ability as they way-find in a large public building? This doctoral research, based within the discipline of architecture, focuses on the holistic experiential components of a Journey (Myerson, 2001;Harper and Green, 2000). It coins and defines the term Way-finding Hot-spot as it explores the events [positive and negative] which are experienced and therefore impact on a Way-finding Journey around a building. To fill an important gap in the current knowledge a research enquiry, based on a user-centred design approach, was implemented. Exploratory in nature, the methodology was inductive and it evolved throughout the study. A series of Research Principles, borrowed from the established methodologies of Grounded Theory (Glaser, 1968) and Case Study (Yin, 2003a;Yin, 2003b), guided this study. Ten participants [with varying degrees of visual ability, different ages and other forms of disability] undertook a Way-finding Scenario designed to evaluate both existing memories of way-finding and present way-finding experience. This was composed of a Purposeful Conversation (Burgess, 1982) and a context specific Way-finding Task. The study has produced a large amount of data based on user experience in a real-world way-finding context – this has not been done before. Participant data contributed to a new Theory of Way-finding – The Experiential Charting of a Way-finding Journey – which derived from experiential data, was found to be composed of three elements: Journey Stages, Tasks Components and Communication Requirements. This thesis presents detailed findings which generate dialogue in the design of way-finding systems suitable for a diverse range of way-finders. It provides a research-based foundation to open the problem area and provide an insight into the issues people with different visual abilities encounter as they undertake a Way-finding Journey around a building. It generates a greater understanding of the problems and joys of way-finding in a building which will be of use in professional practice across disciplines of architecture and design as well as in areas of rehabilitation, policy-making and academia. This research is a start, but it is not the end. Future research questions have been revealed and these, combined with further reviews of literature and creative use of method, will further explore the phenomenon of way-finding within the context of buildings.