Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Rupp, V.
Identification and characterization of Kif1bß and hsSASS-6 as novel disease genes for two hereditary neurological disorders
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2018. pp. 139
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Heitzer Ellen
- Speicher Michael
- Windpassinger Christian
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- Abstract:
- Normal corticogenesis is guaranteed by a sequence of tightly regulated processes and interruption of any of these can eventually lead to the development of severe neurological disorders. In this thesis, two consanguineous families with autosomal recessive primary microcephaly (MCPH) and a novel, autosomal recessive syndromal form of intellectual disability with agenesis of the corpus callosum are described. Such rare autosomal recessive diseases occur more frequently in consanguineous families, since the likelihood of inheriting two of the diseased alleles is strongly increased. By homozygosity mapping, we identified potential candidate loci on chromosome 1p21.3-p13.1 in the MCPH family, and on chromosome 1p36.31-p36.21 in the family with the syndromal form of mental disability. By Next Generation Sequencing and Sanger Sequencing, we identified mutations in two novel genes for each disease. For the novel MCPH14 locus, a single missense mutation, located in a highly conserved domain of the hsSASS-6 gene, was found. This gene encodes for a protein required for procentriole formation. By performing a variety of knock-down and co-localization studies, we were able to prove the reduced function of the mutated protein, depicted by the higher incidence of monopolar spindles in U2OS cells, as well as the increased amount of cells with less than 4 centrioles. Since cell divisions in neuronal stem cells are essential for establishing a sufficient pool of progenitors, we suggest that this malfunction of hsSAS-6 has led to the described disease phenotype. In the second family with the novel syndrome, we discovered a splice site mutation in the ß-isoform of Kif1b resulting in skipping of the second to last exon and a thus induced frameshift in the remaining gene sequence. Kif1B is a kinesin-3 member highly important for the transport of synaptic vesicle precursors. Here we show that the partial loss of the vesicle-interacting PH-domain induced by the alternative splicing, alters the cellular localization of Kif1Bß and completely abrogates the co-localization with p75NTR-containing vesicles. As many previous studies have proven the need for Kif1Bß in neuronal outgrowth, our discoveries confirm the importance of Kif1Bß during embryonic brain development.