TY  - THES
AB  - Human motoneuron diseases can be classified according to their etiology (sporadic, familial), the appearance of clinical signs and disease progression. Corresponding to the disease patterns, one can distinguish diseases of the first motoneuron (e.g. spastic spinal paralyses), the second motoneuron (e.g. spinal muscular atrophy) and diseases under participation of both systems (e.g. amyotrophic lateral sclerosis). Insights into the underlying pathomechanism were gained through the identification of disease-causing genes in rare heritable forms. The goal of this work was to identify the causative mutation in a mouse model for human spinal muscular atrophy and amyotrophic lateral sclerosis.
The mouse model examined in this work was first described in 1956 as the recessive Wobbler mutation (gene symbol: wr) and was mapped to mouse chromosome 11 in 1992. Homozygous Wobbler mice show a tremor in the forelimbs and a wobbling gait. In spinal cord and brain stem degeneration of motoneurons can be observed, which leads to a muscular atrophy in shoulder and neck areas. Due to the progressive character of this disease, Wobbler animals can grasp no longer at the age of six weeks. Additionally, Wobbler males suffer from a spermatogenesis defect and are sterile.
New candidate genes could be identified and characterized for wr by the detailed analysis of the wr critical interval. Tmem17 codes for an intracellular localized transmembrane protein that is evolutionary highly conserved. NM_172792 is a putative serine/threonine kinase without a human ortholog. Both genes could be excluded as candidates on the basis of sequence and expression analyses. Furthermore, the wr critical interval could be reduced so that six genes remained in the candidate region. The discovery of a point mutation in Vps54 led finally to the breakthrough. The Wobbler phenotype could be compensated by the transgenic overexpression of Vps54. This result proved the identity of wr. Possible interaction partners for Vps54 could be identified by the yeast two hybrid system. Many of these proteins function in intracellular vesicle trafficking. Further investigations showed that the point mutation in Vps54 negatively influences the binding of the interaction partners. By genome-wide expression profiling experiments it was possible to identify many genes that are involved in the disease progression in this mouse model.
The identification of Vps54 as the disease-causing Wobbler gene connects possibly disturbed intracellular vesicle traffic with motoneuron disease and could contribute to the clarification of the involved pathomechanism in human diseases.
DA  - 2005
LA  - ger
PY  - 2005
TI  - Identifizierung und Charakterisierung des krankheitsauslösenden Gens in einem Mausmodell für humane Motoneuronerkrankungen
UR  - https://nbn-resolving.org/urn:nbn:de:hbz:361-7242
Y2  - 2024-11-25T01:06:44
ER  -