Ph.D. Theses

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Amyotrphic lateral sclerosis in Turkey : Studies on Familial and sporadic ALS using high-throughput genomic technologies
(Thesis (Ph.D.)-Bogazici University. Institute for Graduate Studies in Science and Engineering, 2010., 2010.) Özoğuz, Aslıhan.; Başak, A. Nazlı.
Amyotrophic Lateral Sclerosis (ALS) is a late-onset neurodegenerative disease, characterized by death of motor neurons in cortex, brainstem and spinal cord. It is a multifactorial disease with interacting pathogenic mechanisms. Most incidences are sporadic (SALS), while 10 per cent of cases have a family history (FALS). The genetics of ALS is complex; eight genes and six loci with autosomal dominant (AD), autosomal recessive and X-linked patterns of inheritance have been identified thus far. In the framework of this study, 198 Turkish ALS cases were investigated for possible mutations in the SOD1 gene. Five FALS cases were shown to carry disease-causing SOD1 mutations, while six were carriers of a rare polymorphism. In the next step, AD, nonconsanguineous FALS and juvenile cases were analyzed for the TDP-43, FUS and ANG genes via DNA sequencing. One homozygous D90A case, represented as recessive, was investigated by haplotype analysis and was compared to 21 Scandinavian ALS cases in search of a common ancestry. Additionally, 15 FALS and 13 juvenile cases, who were negative for the tested genes, were analyzed by whole genome genotyping for identification of new ALS genes. While no significant regions were obtained, a recessive family was preselected for the identification of homozygosity regions. Five candidate genes located within homozosity regions were examined in one of the family member; no mutations were identified. The same individual was also assessed by whole exome resequencing. Furthermore, this study also contributed to a collaborative genome-wide association study in SALS, where 14 month-survival advantage was shown for homozygous CC allele at rs1541160 SNP in the gene coding KIFAP3. This is the most comprehensive study performed in Turkey on the molecular genetics of ALS. The high-throughput methodologies used and the findings presented in this thesis are expected to shed light to the complex pathogenesis of amyotrophic lateral sclerosis.
Beta thalassemia in Turkey: |distribution, diversity, evolution and phenotype-genotype correlations
(Thesis (Ph.D.)- Bogazici University. Institute for Graduate Studies in Science and Engineering, 1999., 1999.) Tadmouri, Ghazi Omar.; Başak, A. Nazlı.
The present study illustrates the results of years of research on different aspects of beta-thalassemia in Turkey. Methods to detect the C-T change at position -158 upstream of the Gy-globin gene and the (AT)xTy motif 5' to the beta-globin gene were established and implemented. Analysis of these polymorphisms explained the reason behind the increased levels of fetal hemoglobin in nine out of 31 beta-thalassemia patients analyzed and demonstrated a dominant effect exerted by the XmnI Gy-globin polymorphism. Molecular screening of beta-globin genes in 19 beta-thalassemia individuals by genomic DNA sequencing uncovered the presence of 14 mutations; three of these are seen for the first time in Turkey. Another achievement made during this study is the compilation of beta-globin gene data collected since 1988 in a single repository. This allowed an easy mean to investigate the distribution of beta-globin gene mutations in various regions and towns of Turkey. This also demonstrated that the distribution of beta-thalassemia mutant alleles differed within each geographical area with a decreased gradient of mutation numbers from the East to the West of Anatolia. Analysis of nine polymorphic nucleotides and the (AT)xTy motif 5' to the beta-globin gene in 204 non-related beta-globin genes from Turkey exhibited 12 sequence haplotypes. Samples from the Black Sea region demonstrated a remarkable level of genetic heterogeneity in contrast to the homogeneity in Central Anatolian samples. Of the 22 beta-globin mutations analyzed, 18 were related with single sequence haplotypes and each of the other four were associated with a minimum of two sequence haplotypes. Our results demonstrate that the heterozygote advantage against malaria in Anatolia may have occurred at 6500-2000 BC by the oldest beta-thalassemia allele (i.e.,IVS-I-110 G-A). From that date on, most of the common beta-thalassemia mutations in Turkey were established and by the 13th century AD most of them were brought to frequencies close to what is observed at present.
Effects of extremely low frequency electromagnetic fields on caspase activities
(Thesis (Ph.D.)-Bogazici University. Institute for Graduate Studies in Science and Engineering, 2006., 2006.) Ozansoy, Mehmet.; Başak, A. Nazlı.; Denizhan, Yağmur.
All life on Earth is bathed in a sea of natural low-frequency electromagnetic fields from conception to death. Since the World Health Organization (WHO) launched its international electromagnetic fields (EMF) project in 1996, it has conducted international reviews of the evidence on whether exposure to static and extremely low frequency (ELF) fields might be harmful to health. ELF fields for WHO’s EMF project are defined as those having frequencies above zero and below 300 Hz. In the framework of this study, the activation of seven different caspases will be investigated systematically, when extremely low frequency electromagnetic fields, which are thought to be an environmental hazard according to WHO, are applied to the HEK 293 cell line. The selected frequency will be 50 Hz, which is the power transmission line frequency in most parts of the world. Two different magnetic field strengths will be applied to HEK 293 cells, and two different exposure durations will be chosen. Caspase activity levels are to be measured at different time points after exposure. The common pattern seen in all of them was the oscillation of enzyme activities from the beginning. At 100 μT, caspases gave four peaks at four, eight, 16 and 34-hour incubation periods. This oscillatory behavior can also be seen when 25 μT magnetic field was applied, but the behaviors of the enzymes were different in a certain extent. The location and the number of the peaks at 25 μT exposure were quite variable, but the activity periods of all caspases seemed to be shorter than those exposed to 100 μT. The data presented here indicate that when ELF-EMF is applied to the HEK 293 cells, all seven caspases investigated are found to be activated, but this activation shows an oscillatory pattern, and in the long run it seems to be damped by some intracellular mechanisms.
Parkinson's disease in a large Turkish pedigree with SNCA duplication (PARK4): complexin-1 as a potent biomarker for predictive diagnosis
(Thesis (Ph.D.)-Bogazici University. Institute for Graduate Studies in Science and Engineering, 2015., 2015.) Lahut, Suna.; Başak, A. Nazlı.; Auburger, Georg.
Accumulation and aggregation of alpha-synuclein (SNCA) is a hallmark of Parkinson’s disease (PD). Considering the roles of SNCA in both idiopathic and familial PD, we studied blood samples from a large pedigree with SNCA duplication (PARK4), to identify effects of SNCA gain-of-function on expression levels of downstream genes as potential disease biomarkers. Downregulation of complexin-1 (CPLX1) expression level was found to be correlated with PARK4 and also the further investigated cohort with REM sleep behavior disorder (RBD), which resembles presymptomatic PD. In global RNAseq profiling of blood from presymptomatic PARK4, significant upregulations for immune system, lysosome, lipid and platelet activation pathways were detected. The representative genes of upregulated pathways, SPP1, GZMH, and PLTP, were validated in PARK4. However, unlike CPLX1, they failed to distinguish presymptomatic PD from healthy individuals. The longest size variant (allele 2) of the Rep1 repeat region of the SNCA promoter is known to be associated with PD risk. This region was analyzed in idiopathic PD and restless leg syndrome (RLS). Rep1 allele 2 frequency was found significantly decreased in RLS, suggesting reduced SNCA levels contributing to disease. The WW Domain Containing E3 Ubiquitin Protein Ligase (WWP2) mRNA expression level was tested in PARK4 and RBD and was observed to mimic SNCA expression profiles in both cohorts. Western blot analyses of double transfected cells suggested that in the presence of WWP2, SNCA-wildtype, but not SNCA-A53T-mutant, to be degraded.
Parkinson's disease in Turkish patients: molecular defects in familial and isolated cases
(Thesis (Ph.D.)-Bogazici University. Institute for Graduate Studies in Science and Engineering, 2009., 2009.) Pirkevi, Caroline Selma.; Başak, A. Nazlı.
Parkinson's disease (PD) is worldwide the second most common neurodegenerative disorder after Alzheimer's disease. Recently, several genes have been shown to result in PD phenotype. Mutations in these genes may lead to autosomal dominant ( -synuclein, LRRK2), autosomal recessive (Parkin, PINK1, DJ1) or sporadic PD. In the framework of this study, the above five genes were investigated in Turkish patients. For the Parkin gene, we have performed dHPLC analysis prior to sequencing. The high percentage of abnormal dHPLC profiles observed in the patient population revealed only one mutation and 136 polymorphisms. Exon rearrangements were investigated by semi-quantitative multiplex PCR and by MLPA; 12 rearrangements were described in the Parkin gene. PINK1 and DJ1 exons were also sequenced; 75 variations were identified, two being heterozygous mutations. Point mutations in -synuclein are a rare cause of PD and were not found in our patient population. In contrast, triplications and duplications of the whole gene are found more frequently in autosomal dominant forms of the disease. A heterozygous duplication of exons 3 and 4 was described in several patients of a large kindred, and the whole family was subjected to haplotype analysis for chromosome 4q. LRRK2 consists of 51 exons and most mutations are seen in 15 of these. Sequencing of these exons revealed a novel S1508R and a G2019S mutation. G2019S frequency differs among populations and it is associated with three different haplotypes so far. The haplotype of our patient has been shown to have a great homology with the Japanese haplotype. Although an independent origin of the Turkish haplotype cannot be excluded at this point, the huge and centurieslong migration of the Turkic people in Central Asia rather supports a common origin.
The molecular landscape of ALS in Turkey: A multifaceted approach to the complex genetics of ALS
(Thesis (Ph.D.)-Bogazici University. Institute for Graduate Studies in Science and Engineering, 2018., 2018.) İskender, Ceren.; Çağlayan, S. Hande.; Başak, A. Nazlı.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease (NDD), characterized by degeneration of both upper and lower motor neurons leading to muscle wasting. With an incidence of two and a prevalence of four in 100.000/year, it is the third most common NDD after Alzheimer’s and Parkinson’s diseases. The last decade has proven that the ‘condition’ called ALS is both clinically and genetically heterogenous, and that the genetic component in 90% of the cases that are considered as sporadic, might be stronger than expected. In this thesis, we investigated the complex genetics of ALS in the ethnically heterogeneous yet inbred Turkish population. Familial ALS account for 22% of our cases (159/722) and 563 cases were classified as sporadic (78%). Consanguinity is calculated as 25% among familial and 17% in sporadic cases. Conventional screening of the most common ALS genes (C9orf72, SOD1, TARDBP and FUS) in patients with a family history of disease, explained the disease cause in only 33%, pointing towards marked locus heterogeneity within the population. C9orf72 hexanucleotide repeat expansion was further detected in 3% of ‘apparently sporadic’ patients. Application of whole exome sequencing (WES) in dominant and recessive Turkish pedigrees presenting with ALS or non-ALS motor neuron diseases (MNDs), revealed distinct rare or novel mutations in 20 out of 39 families and enabled differential diagnosis in cases with atypical ALS features. Common current themes in ALS, like oligogenic inheritance and possible genetic modifiers are addressed in families with incomplete penetrance and in C9orf72 expansion carriers. Oligogenic inheritance of known ALS genes was not prominent in the Turkish C9orf72-positive cases. Hypermethylation in the promoter region of C9orf72 was confirmed in Turkish patients, however it did not seem to modify age of onset. Finally, analyses of whole genome sequencing data of 625 Turkish ALS patients and 152 healthy controls in the framework of Project MinE showed population-specific aspects and once more substantiated the concept of low penetrance of rare ALS genes among sporadic patients.

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Browsing Ph.D. Theses by Author "Başak, A. Nazlı."

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