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Aarskog-Scott Syndrome and Faciogenital Dysplasia Protein 1 (FGD1) : Treatment of Swan-Neck Deformity and FGD1/Fgd1 Characterization in Man and Mouse

Aarskog-Scott Syndrome and Faciogenital Dysplasia Protein 1 (FGD1) : Treatment of Swan-Neck Deformity and FGD1/Fgd1 Characterization in Man and Mouse

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ANGSTENBERGER, Jonas, 2012. Aarskog-Scott Syndrome and Faciogenital Dysplasia Protein 1 (FGD1) : Treatment of Swan-Neck Deformity and FGD1/Fgd1 Characterization in Man and Mouse [Dissertation]. Konstanz: University of Konstanz

@phdthesis{Angstenberger2012Aarsk-21628, title={Aarskog-Scott Syndrome and Faciogenital Dysplasia Protein 1 (FGD1) : Treatment of Swan-Neck Deformity and FGD1/Fgd1 Characterization in Man and Mouse}, year={2012}, author={Angstenberger, Jonas}, address={Konstanz}, school={Universität Konstanz} }

Angstenberger, Jonas Angstenberger, Jonas Aarskog-Scott synrdome (AAS) or Faciogenital Dysplasia (FGDY) is a developmental orphan disorder primarily characterized by skeletal dysplasia and genital abnormalities. The pathomechanism of the disease is poorly understood owing to genetic heterogeneity, clinical overlap with other disorders and the relatively low incidence. AAS is an X-chromosomelinked recessive disorder affecting mainly males, although autosomal dominant and autosomal recessive inheritance has been also reported. The only known disease causing factor responsible for the X-linked form of AAS is the Faciogenital Dysplasia Protein 1 (FGD1). FGD1 is a guanine nucleotide exchange factor for CDC42, a member of the Rho family of small GTPases. FGD1 has been reported to modulate secretion and cytoskeletal reorganization, however, the role of FGD1 in AAS syndrome is largely unknown.<br /><br /><br /><br />In this work, first the expression profile of the mouse Fgd1 was investigated during embryogenesis and in more than twenty adult tissues. According to the literature, Fgd1 exhibits an expression pattern restricted to differentiating osteoblasts in the mouse embryo. In contrast, using sensitive in situ hybridization and immunohistochemistry with newly developed anti-Fgd1 antibodies, a much broader expression spectrum of Fgd1 was identified in the present work. Strong Fgd1 expression was seen in the developing nervous system and in the limb bud as early as embryonic days 11.5. Detailed analysis at later embryonic stages confined Fgd1 to<br />multiple organs including cartilage, heart, kidney, muscle and the intestine. Confirming the ubiquitous expression pattern, Fgd1 was detected in nearly all postnatal organs. Fgd1 was found in neuronal and interneuronal cells of the central nervous system and nuclear layers of the retina. Primarily epithelial cells express Fgd1 in the endocrine (pancreas), the respiratory (trachea and lung) and the digestive (salivary glands, colon and liver) systems. Fgd1 was prominent in the cardiovascular system, the male (testis, epididymis and prostate) and the female (ovary and uterus) reproductive systems. Furthermore, Fgd1 was detected the genitourinary system (kidney and urinary bladder), the hematopoietic system (bone marrow and spleen), lymphatic system (thymus), in the skin and in the musculoskeletal system (bone, cartilage, ligaments and skeletal muscle). Thus, the previously unrecognized expression pattern<br />suggests that Fgd1 plays a general role in most organs of the body and its function is not restricted to osteoblasts.<br /><br /><br /><br />In order to elucidate the function of FGD1 in vitro, small hairpin RNA (shRNA)-mediated FGD1 knock down in various human cell lines was performed. Analysis of the osteoblastic SaOs2 and the fibroblastic HT1080 carcinoma cell lines demonstrated that FGD knock down impairs cell proli feration and adhesion to extracellular matrix proteins. FGD1-deficiency resulted in slow proli feration rate owing to reduced progression through the G1 phase of the cell cycle. The attachment assays revealed that a lack of FGD1 leads to reduced integrin mediated adhesion to fibronectin, collagen type I, lamin in and vitronectin in varying extent.<br /><br /><br /><br />Genetically modified mice are essential tools deciphering the pathomechanisms of human disorders. In order to correlate Fgd1 function with the clinical symptoms of AAS, establishing mouse model(s) for the disease was a general aim of this thesis. As a first attempt, a constitutive<br />gene targeting strategy was applied in murine R1 embryonic stem (ES) cells. Despite a large scale screening, no homologous recombinant ES cell clone was identif ied. The Fgd1 gene is localized on the X chromosome and its null mutation results in functional knock out already in R1 ES cells, which were derived from male embryos. The unsuccessful constitutive targeting implies that Fgd1 may play a role in stem cells and in preimplantation development. This hypothesis was proved by demonstrating the expression of Fgd1 in ES cells and in early stage embryoid bodies. To overcome the likely negative effect of Fgd1-deficiency in constitutively targeted ES cells, a conditional targeting strategy was applied. ES cells with the floxed Fgd1 gene were generated that can be used to establish transgenic mice.<br /><br /><br /><br />The expression pattern of Fgd1 in tendons and ligaments suggests that swan-neck deformity of the fingers, a primary criterion of AAS, can be treated by operating the ligaments. In this<br />work it is shown that Littler tenodesis, an operative intervention commonly used for rheumatoid swan-neck deformity, can also be applied to restore the oblique reticular ligament in Aarskog-Scott associated swan-neck deformity. A 28-year old AAS-patient was operated and<br />intensively analyzed after the operation. By monitoring the sensitivity, joint movement and grip strength, the full recovery of all parameters was demonstrated. 2013-02-11T07:11:17Z 2012 2013-02-11T07:11:17Z eng Aarskog-Scott Syndrome and Faciogenital Dysplasia Protein 1 (FGD1) : Treatment of Swan-Neck Deformity and FGD1/Fgd1 Characterization in Man and Mouse deposit-license

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