Untersuchungen zur Pathogenese der Spinocerebellären Ataxien (SCA) mit Fokus auf Ionenkanal-Defekten (SCA13 und SCA19/22) und anderen verursachenden Mechanismen.
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Philipps-Universität Marburg
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Abstract
Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of neurodegenerative diseases with autosomal-dominant inheritance. Typical symptoms are ataxia, oculormotor dysfunction and dysarthria, but other movement disorders and cognitive impairment can also occur. In SCAs, there is only a weak genotype-phenotype-correlation. In the more common subtypes, repeat expansions in the associated genes are responsible for the disease. In rarer cases, deletions, insertions or substitutions of one or a few bases in coding or non-coding regions are causative. The affected genes and gene products have various func-tions, but some of them encode ion channels, that are necessary and important for neuronal function in the cerebellum.
In this work, five previously undescribed variants in SCA-associated genes were investigated. They were identified in cohorts of ataxia and dementia. Firstly, a splice acceptor variant in the STUB1-gene, coding for the E3-ubiquitin-ligase CHIP and associated with SCA48, was identified. It was shown that the c.524+1G>A variant can either lead to an intron retention or, more rarely, activate cryptic splice acceptors. This results in added amino acids or a frameshift with a truncating stop codon. In addition to the STUB1-variant, the index patient carries two intermediate TBP alleles. Repeat expansions in TBP are associated with SCA17. Therefore, the expanded alleles might exacerbate the phenotype of the patient and his also affected mother to a dementia-like syndrome.
Further variants were identified in the voltage-gated potassium channels Kv3.3 (KCNC3) and Kv4.3 (KCND3). These channels are essential for neuronal function in the cerebellum. Pathogenic variants that cause impaired channel function result in SCA13 (KCNC3) and SCA19/22 (KCND3).
In Kv3.3, the variant c.-6C>A in the Kozak sequence of KCNC3 was investigated. Due to its location, the variant could interfere with the regulatory functions of the Kozak sequence. Strikingly, promoter expression analysis showed that the base change increased translation efficiency and thus protein expression. Since SCA13 is generally caused by non-functional channels or an impaired channel conductance, this might be a new pathomechanism for this subtype. However, the severity of the patient’s phenotype suggests other, as yet uni-dentified genetic factors. In addition, the effects of the amino acid substitutions p.S591G and p.R625S in Kv3.3 on ion channel function were investigated by patch-clamping. No effect on channel conductance was seen for the variants. In these cases, other, unidentified genetic factors might be causative for the patients’ diseases.
In the Kv4.3 channel (SCA19/22), the N-terminal variant p.D152G was identified. p.D152G impairs channel function by decreasing the ionic current in a dominant-negative manner. Confocal microscopy showed impaired membrane localization of the channel, which may contribute to this effect.
This work demonstrates the importance of functional analysis of so far undescribed genetic variants. It was shown that functional studies are useful for the diagnosis of ataxia patients. Furthermore, in several cases, more than one variant was responsible for the pa-tient’s phenotype. This shows that digenic effects should be considered in cases of ataxia, especially when dementia-like symptoms are involved.
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Created: 2025Issued: 2025-04-23Updated: 2025-04-23
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
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DoctoralThesis
DFG-subjects
KaliumkanalSpinocerebelläre AtaxieHumangenetikChannelopathie
DDC-Numbers
610
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Reis, Marlen Colleen: Untersuchungen zur Pathogenese der Spinocerebellären Ataxien (SCA) mit Fokus auf Ionenkanal-Defekten (SCA13 und SCA19/22) und anderen verursachenden Mechanismen.. : Philipps-Universität Marburg 2025-04-23. DOI: https://doi.org/10.17192/z2025.0185.
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This item has been published with the following license: In Copyright