Molekulargenetische Untersuchungen des SPG31-Gens bei der Hereditären Spastischen Paraplegie

Molecular genetic investigations on SPG31 gene in heriditäry spastic paraplegia

by Saskia Wedegärtner
Doctoral thesis
Date of Examination:2014-10-18
Date of issue:2014-10-21
Advisor:Prof. Dr. Dr. Wolfgang Engel
Referee:Prof. Dr. Wolfgang Engel
Referee:Prof. Dr. Ekkehard Wilichowski
Persistent Address: http://dx.doi.org/10.53846/goediss-4735

 

 

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Abstract

English

The term hereditary spastic paraplegia describes a group of rare, clinically and genetically heterogeneous disorders. Until today more than 48 different genes have been identified whose variant forms lead to this clinical picture. One of these genes is the REEP1-gene (SPG31). Mutations in this gene are regarded as being the third most common cause of autosomal dominant hereditary spastic paraplegia, with an incidence of 2-6 %. In our study, genetic testing of the REEP1-gene was performed on a group of 64 unrelated patients with autosomal dominant spastic paraplegia. Patients with mutations in the two most commonly affected genes (SPG4 and SPG3A) had been previously excluded. In two patients, three different genetic changes were detected overall. The incidence rate described could be confirmed with a frequency of 3.13 %. As the literature shows, the onset of the illness manifested itself in the patient cohort of the present paper in childhood and adolescence. We were able to detect a splice site mutation at the junction of intron-exon 4, a missense mutation within a stop codon and a mutation affecting the regulatory 3'UTR. Two of these changes have already been described. Due to the small number of patients with identical genetic changes, an exact genotype-phenotype correlation is not yet possible. To investigate the effect of splice site mutations we performed an expression analysis on different human materials obtained non-invasively. It was shown that the roots of human hair are well suited for the isolation of REEP1-mRNA. However, the process must be further standardized before patient studies can be conducted. To investigate the effect of mutations in the 3'UTR of SPG31, a luciferase assay was established. There were indications that due to these mutations the translation is down-regulated, and thus it reinforces the predicted loss of function-phenomenon. Further investigations may allow statements on the impact of changes not only in the 3'UTR miRNA binding sites but also in the 5'UTR in spastic paraplegia type 31 and other diseases.
Keywords: heriditary spastic paraplegia; SPG31; REEP1; miRNA
Schlagwörter: Hereditäre Spastische Paraplegie; SPG31; REEP1; miRNA
 
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