Publikationsserver der RWTH Aachen University
Molekulargenetische und funktionelle Untersuchungen zu autosomal-rezessiv erblichen Neuropathien
Abstract
dc:descriptionThe hereditary motor and sensitive neuropathy (HMSN), also called Charcot-Marie-Tooth neuropathy, represents the most frequent inherited neuromuscular disorder. In most cases HMSN is of autosomal dominant or X-chromosomal trait. Yet, the autosomal recessive inherited form (AR-HMSN) is less frequent in Western industrialized countries. However, in regions and population groups with a high rate of consanguinity, this form counts for 50% of the affected cases. The AR-HMSN is known to be a very heterogeneous disorder. In the present study, moleculargenetic as well as cell- and molecularbiological investigations of the pathogenesis of AR-HMSN were performed. Thereby two main aims were followed:1) Characterization of the so far unknown function of the KIAA1985 (SH3TC2) gene product responsible for the Charcot-Marie-Tooth subtype 4C. 2) Verification, based on published data, of the hypothesis that mutations in genes coding for Rho-GTPases (or their regulators) cause peripheral neuropathies.The product of the CMT4C gene, KIAA1985 (SH3TC2), is a novel protein of so far unknown function. This study was able to show that Kiaa1985 is exclusively expressed in Schwann cells, the myelinating glia cells of the peripheral nervous system. The pattern of expression correlates with the affected tissue in patients with CMT4C. Investigations of the subcellular localization of KIAA1985 revealed that KIAA1985 can be bound to cellular membranes due to posttranslational lipid modification. KIAA1985 could be detected in the plasma membrane and colocalizes with marker proteins of the pericentriolar recycling endosome. Given its predicted domain structure, KIAA1985 belongs to a group of possible adapter proteins. Therefore interaction partners of KIAA1985 should be identified. One of these identified interactors was the small GTPase Rab11, a key regulator of endozytotic and exocytotic transport processes between plasma membrane, recycling endosome and the trans-golgi-network. Further results suggest that KIAA1985 functions as a Rab11 effector molecule, which regulates Rab11-dependent transport processes. The observation that KIAA1985 mutants which cause CMT4C do not interact with Rab11 leads to the assumption of a significant role of the KIAA1985-Rab11-interaction in the pathogenesis of the CMT4C. Further studies will have to clarify the Rab11-dependent transport processes influenced by KIAA1985, as well as the role of the endosomal recycling in the myelinization. In the context of the research for neuropathy-associated mutations in genes for Rho-GTPases and Rho-GTPase regulators, the FGD4-gene (for the Cdc42-guanine-nucleotide-exchange factor Frabin) represented as the most promising candidate, since FGD4 was also a positional candidate gene due to its localization within the CMT4H interval. In the first step, 63 patients were selected with regard to clinical, neurophysiological and histopathological criteria that were orientated by already published findings in CMT4H-families. Sequence analysis of the FGD4-gene revealed pathogenetic mutations in four cases. Analyses of the expression pattern and first functional studies with overexpressed FGD4-protein in Schwann cells presented an expression of FGD4 in the target-cells of a peripheral neuropathy as well as a biological activity within these cells. Considering the diverse functions of Rho-GTPases during the genesis, degeneration and regeneration of the peripheral nervous system, further investigations are essential to identify the precise function of Frabin in the peripheral nervous system. A possible strategy could be the clarification of the role of Frabin in important, Rho-GTPases-regulated cellular processes like the development of cell-polarity, vesicle transport, neurotrophin signaling and the communication with the extracellular matrix. The present study, thus successfully applied two effective strategies for the elucidation of the pathogenesis of inherited disorders. Through the investigation of expression, localization and protein-protein-interaction of the HMSN-gene KIAA1985, a possible role of Rab11 and of the vesicular recycling in the pathogenesis of demyelinating neuropathies could be ruled out (from the gene to the biological mechanism). On the other hand, the knowledge on the function of Rho-GTPase-dependent pathways in the genesis, degeneration and regeneration of the PNS allowed the specific choice of a candidate gene, FGD4, for a so far not clarified HMSN-type in molecular genetics (from the biological mechanism to the gene-identification).
Degree
thesis:*- Grantor dc:publisher
- Publikationsserver der RWTH Aachen University
- Year dc:date
- 2009
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Roos, Andreas
- Contributors dc:contributor
-
- Zerres, Klaus
Subjects
dc:subject × 9Rights
dc:rights- Statement dc:rights
-
- info:eu-repo/semantics/openAccess
- Language dc:language
- ger