Habilitationsschrift--Universität-Münster Westfalen. English summary.

Understanding the molecular basis of Mendelian disorders featuring joint dislocation can enhance the knowledge of genetic or cellular pathways required in joint development, and provide candidate genes for studying related complex disorders, such as developmental dysplasia of the hip. Two strategies were employed in this project to investigate Mendelian contributors to congenital joint dislocation. The first strategy was to investigate in-depth a gene known to be associated with joint dislocation. Missense mutations or small in-frame deletions in FLNB, encoding filamin B, have previously been associated with a spectrum of osteochondrodysplasias. Screening a larger cohort established FLNB as the sole underlying disease gene for atelosteogenesis type I and III and also boomerang dysplasia, which was previously thought clinically to be allelic to AOI. Mutations in FLNB cause a large proportion of Larsen syndrome cases with phenotypes reminiscent of the early case series reported. Atypical or "recessive" Larsen syndrome may therefore be due to a different underlying genetic aberration. The disease-associated amino acid substitutions or in-frame deletion/insertions cluster to two main regions of the filamin B protein: the calponin homology 2 domain of the actin-binding domain, and repeats 13-17 of the rod domain. To analyse the functions of these regions, yeast two-hybrid analyses were performed. No interactors were identified with the calponin homology 2 domain, which suggests the amino acid substitutions may disrupt actin binding or the regulation thereof. A candidate interactor, centromere protein J, was identified that binds to repeats 13-15, and could suggest a model for aberrant cell division seen in growth plates of bones of individuals with atelosteogenesis types I and III and boomerang dysplasia. The second strategy used in this project was to investigate the genetic cause of a novel syndrome featuring joint dislocation. A neurocutaneous phenotype segregated in a consanguineous New Zealand family, and through a genetic mapping strategy, a significantly linked locus was identified at 10q23 (Z = 3.63), in which segregation of a common ancestral haplotype fits the linkage hypothesis of homozygosity by descent. Candidate gene analysis and subsequent screening identified a missense mutation 2350C>T in ALDH18A1, which predicts the substitution H784Y in the encoded protein [Delta]�-pyrroline-5-carboxylate synthase (P5CS). The known function of P5CS in proline and ornithine biosynthesis was not affected by the presence of H784Y in an indirect assay, and therefore the hypothesis proposed was that a novel, unknown moonlighting function of P5CS is perturbed causing the phenotype segregating in the family. As an initial exploration of functions of P5CS in the cell, yeast two-hybrid analysis was undertaken. This project examined the contribution of two genes, FLNB and ALDH18A1, to Mendelian congenital joint dislocations. How the cellular functions of the encoded proteins in the cytoskeleton, metabolism, or signal transduction, are critical for joint development is ill understood. Future investigations aimed at identifying candidate genes that confer susceptibility to developmental dysplasia of the hip should consider candidate genes that encode proteins related in function to the products of the FLNB and ALDH18A1 genes.

Understanding the molecular basis of Mendelian disorders featuring joint dislocation can enhance the knowledge of genetic or cellular pathways required in joint development, and provide candidate genes for studying related complex disorders, such as developmental dysplasia of the hip. Two strategies were employed in this project to investigate Mendelian contributors to congenital joint dislocation. The first strategy was to investigate in-depth a gene known to be associated with joint dislocation. Missense mutations or small in-frame deletions in FLNB, encoding filamin B, have previously been associated with a spectrum of osteochondrodysplasias. Screening a larger cohort established FLNB as the sole underlying disease gene for atelosteogenesis type I and III and also boomerang dysplasia, which was previously thought clinically to be allelic to AOI. Mutations in FLNB cause a large proportion of Larsen syndrome cases with phenotypes reminiscent of the early case series reported. Atypical or "recessive" Larsen syndrome may therefore be due to a different underlying genetic aberration. The disease-associated amino acid substitutions or in-frame deletion/insertions cluster to two main regions of the filamin B protein: the calponin homology 2 domain of the actin-binding domain, and repeats 13-17 of the rod domain. To analyse the functions of these regions, yeast two-hybrid analyses were performed. No interactors were identified with the calponin homology 2 domain, which suggests the amino acid substitutions may disrupt actin binding or the regulation thereof. A candidate interactor, centromere protein J, was identified that binds to repeats 13-15, and could suggest a model for aberrant cell division seen in growth plates of bones of individuals with atelosteogenesis types I and III and boomerang dysplasia. The second strategy used in this project was to investigate the genetic cause of a novel syndrome featuring joint dislocation. A neurocutaneous phenotype segregated in a consanguineous New Zealand family, and through a genetic mapping strategy, a significantly linked locus was identified at 10q23 (Z = 3.63), in which segregation of a common ancestral haplotype fits the linkage hypothesis of homozygosity by descent. Candidate gene analysis and subsequent screening identified a missense mutation 2350C>T in ALDH18A1, which predicts the substitution H784Y in the encoded protein [Delta]�-pyrroline-5-carboxylate synthase (P5CS). The known function of P5CS in proline and ornithine biosynthesis was not affected by the presence of H784Y in an indirect assay, and therefore the hypothesis proposed was that a novel, unknown moonlighting function of P5CS is perturbed causing the phenotype segregating in the family. As an initial exploration of functions of P5CS in the cell, yeast two-hybrid analysis was undertaken. This project examined the contribution of two genes, FLNB and ALDH18A1, to Mendelian congenital joint dislocations. How the cellular functions of the encoded proteins in the cytoskeleton, metabolism, or signal transduction, are critical for joint development is ill understood. Future investigations aimed at identifying candidate genes that confer susceptibility to developmental dysplasia of the hip should consider candidate genes that encode proteins related in function to the products of the FLNB and ALDH18A1 genes.

This thesis analyses the representation of so-called human curiosities in recent visual art, by drawing a connection to historical practices of exhibiting 'monstrous' and deformed bodies within institutions such as freak shows, anatomical collections and medical museums. The last two decades have witnessed a surge of scholarly interest in the histories of these institutions, particularly through the work of Robert Bogdan, Rosemarie Garland-Thomson, Rachel Adams, Richard Sandell and Samuel J.M.M Alberti, whose research can be situated in interdisciplinary humanities fields such as disability studies, museology, history of science and literary and visual studies. Concurrently, a remarkable number of contemporary artists have also turned to the history and imagery of these spaces to explore the politics of display in exhibitions of non-normative bodies. This study addresses the critical gap between these two parallel domains of inquiry, drawing upon recent studies concerning historical exhibitions of monstrous bodies to analyse how contemporary artists have simultaneously confronted and extended these traditions through their artworks. In order to show that the very notion of 'monstrous bodies' is inextricably bound up in the curious display practices that frame them, I analyse the representation of human curiosities in the work of Zoe Leonard, Joanna Ebenstein, Diane Arbus, Mat Fraser, Pauline Boudry & Renate Lorenz, Marc Quinn and John Isaacs. Each chapter examines a distinct institutional context – the anatomical collection, the freak show, the art gallery, and the contemporary medical museum – to investigate how these artists challenge the meanings conferred upon extraordinary bodies within each space, bestowing new significance upon these forms within the context of their various art practices. I argue that, by doing so, artists themselves can take on roles like curious collectors, freak show talkers and teratologists, revealing the potential for 'art' to act as yet another display framework that imposes a particular set of meanings onto anomalous bodies.

Currently, there is little research on self-perception and the psychological impact of concealable deformities such as pectus excavatum (PE). The current study addresses this gap by comparing self-perceived severity, actual physical severity, and depressive symptoms in youth with PE. Substantiating parents' and physicians' concerns, participants' scores on the Youth Self-Report depression subscales were significantly higher than non-clinical normative samples, indicating more depressive symptoms. Analyses of self-perceived severity, the Haller Index (HI; a medical measure of PE severity), and depressive symptoms substantiated the importance of subjective self-perception. There were no significant correlations between the HI of physical severity and depressive affect; however, youths' perceptions of severity correlated strongly and predicted depressive affect. The results suggest that youth with PE may be at risk for depressive disorders, and that self-perception, not actual physical severity, is the better predictor of the psychosocial impact of the deformity.