Browsing by Author "Onat, Onur Emre"
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Item Open Access Abnormal subcortical activity in congenital mirror movement disorder with RAD51 mutation(Turkish Society of Radiology, 2018) Demirayak, Pınar; Onat, Onur Emre; Gevrekci, A. Ö.; Gülsüner, S.; Uysal, H.; Bilgen, R.; Doerschner, Katja; Özçelik, Tayfun; Boyacı, HüseyinPURPOSE Congenital mirror movement disorder (CMMD) is characterized by unintended, nonsuppressible, homologous mirroring activity contralateral to the movement on the intended side of the body. In healthy controls, unilateral movements are accompanied with predominantly contralateral cortical activity, whereas in CMMD, in line with the abnormal behavior, bilateral cortical activity is observed for unilateral motor tasks. However, task-related activities in subcortical structures, which are known to play critical roles in motor actions, have not been investigated in CMMD previously. METHODS We investigated the functional activation patterns of the motor components in CMMD patients. By using linkage analysis and exome sequencing, common mutations were revealed in seven affected individuals from the same family. Next, using functional magnetic resonance imaging (fMRI) we investigated cortical and subcortical activity during manual motor actions in two right-handed affected brothers and sex, age, education, and socioeconomically matched healthy individuals. RESULTS Genetic analyses revealed heterozygous RAD51 c.401C>T mutation which cosegregated with the phenotype in two affected members of the family. Consistent with previous literature, our fMRI results on these two affected individuals showed that mirror movements were closely related to abnormal cortical activity in M1 and SMA during unimanual movements. Furthermore, we have found previously unknown abnormal task-related activity in subcortical structures. Specifically, we have found increased and bilateral activity during unimanual movements in thalamus, striatum, and globus pallidus in CMMD patients. CONCLUSION These findings reveal further neural correlates of CMMD, and may guide our understanding of the critical roles of subcortical structures for unimanual movements in healthy individuals.Item Open Access The genetic structure of the Turkish population reveals high levels of variation and admixture(National Academy of Sciences, 2020-12-18) Kars, Meltem Ece; Başak, A. N.; Onat, Onur Emre; Bilguvar, K.; Choi, J.; Itan, Y.; Çağlar, C.; Palvadeau, R.; Casanova, J.-L.; Cooper, D. N.; Stenson, P. D.; Yavuz, A.; Buluş, H.; Günel, M.; Friedman, J. M.; Özçelik, TayfunThe construction of population-based variomes has contributed substantially to our understanding of the genetic basis of human inherited disease. Here, we investigated the genetic structure of Turkey from 3,362 unrelated subjects whose whole exomes (n = 2,589) or whole genomes (n = 773) were sequenced to generate a Turkish (TR) Variome that should serve to facilitate disease gene discovery in Turkey. Consistent with the history of present-day Turkey as a crossroads between Europe and Asia, we found extensive admixture between Balkan, Caucasus, Middle Eastern, and European populations with a closer genetic relationship of the TR population to Europeans than hitherto appreciated. We determined that 30% of TR individuals had high inbreeding coefficients (≥0.0156) with runs of homozygosity longer than 4 Mb being found exclusively in the TR population when compared to 1000 Genomes Project populations. We also found that 28% of exome and 49% of genome variants in the very rare range (allele frequency < 0.005) are unique to the modern TR population. We annotated these variants based on their functional consequences to establish a TR Variome containing alleles of potential medical relevance, a repository of homozygous loss-of-function variants and a TR reference panel for genotype imputation using high-quality haplotypes, to facilitate genome-wide association studies. In addition to providing information on the genetic structure of the modern TR population, these data provide an invaluable resource for future studies to identify variants that are associated with specific phenotypes as well as establishing the phenotypic consequences of mutations in specific genes.Item Open Access Identification of a novel missense mutation in RAD51 in a large family with congenital mirror movements(American Society of Human Genetics, 2012-11) Onat, Onur Emre; Gülsüner, Süleyman; Bilgen, R.; Dal, G. M.; Bilguvar, K.; Boyacı, Hüseyin; Doerschner, Katja; Uysal, H.; Günel, M.; Özçelik, TayfunCongenital mirror movements (CMM) are a rare and heterogeneous group of disorders characterized by involuntary contralateral movements of mainly the upper extremities during intentional movements on the opposite side. Isolated cases are usually familial and suggest autosomal dominant inheritance with incomplete penetrance. In two chromosome 18 linked families, causative mutations were identified in DCC (Science 328:592, 2010; MRMV1; MIM:157600). Here, we describe a three-generation consanguineous Turkish family with six members affected by CMM. Linkage analysis with a dominant model and 90 percent penetrance parameters resulted in peaks on 15q13.3-q21.1, 15q26.2, and 19q12 with maximum multipoint LOD scores of 3.6, 2.6, and 2.6, respectively. However, a region of homozygosity segregating with the phenotype was not observed, and thus excluded the possibility of recessive inheritance of the disease allele in this consanguineous family. Whole-exome sequencing of an affected individual uncovered 7 coding, 33 intronic and 3 intergenic novel variants located within the three linkage intervals, which were filtered against the dbSNP132 dataset. Segregation analysis, population filtering using 1000 genomes and EVS data sets, and conservation considerations using prediction tools revealed a novel missense mutation (c.404C>T [p.T134N], RefSeq accession number NM_002875) in exon 5 of RAD51 (MIM:179617), consistent with the dominant inheritance of the disease allele in the family. The mutation resides in the highly conserved AAA (ATPases associated with diverse cellular activities) domain of the protein, and it was not observed in 436 chromosomes from healthy individuals coming from a geographical matched region. Recently, truncating mutations in RAD51 were identified in two families with CMM (Am J Hum Genet 90:301,2012; MRMV2; MIM:614508). Our findings support the totally unexpected role of RAD51 in neurodevelopment and further suggest that alterations of this gene may lead to neurological phenotypes.Item Open Access Identification of ATP8A2 gene mutation in a consaguineous family segregating cerebellar atrophy and quadrupedal gait(Bilkent University, 2012) Onat, Onur EmreCerebellar ataxia, mental retardation, and dysequilibrium syndrome is a rare and heterogeneous neurodevelopmental disorder characterized by cerebellar atrophy, dysarthric speech, and quadrupedal locomotion. Here, a consanguineous family with four affected individuals which suggest an autosomal recessive inheritance was investigated. Homozygosity mapping analysis using high-resolution genotyping arrays in two affected individuals revealed four shared homozygous regions on 13q12, 19p13.3, 19q13.2, and 20q12. Target enrichment and next-generation sequencing of these regions in an affected individual was uncovered 11 novel protein altering variants which were filtered against dbSNP132 and 1000 genomes databases. Further population filtering using personal genome databases and previous exome sequencing datasets, segregation analysis, geographically-matched population screening, and prediction approaches revealed a novel missense mutation, p.I376M, in ATP8A2 segregated with the phenotype in the family. The mutation resides in a highly conserved C-terminal transmembrane region of E1-E2 ATPase domain. ATP8A2 is mainly expressed in brain, in particular with the highest levels at cerebellum which is a crucial organ for motor coordination. Mice deficient with Atp8a2 revealed impaired axonal transport in the motor neurons associated with severe cerebellar ataxia and body tremors. Recently, an unrelated individual with a de novo t(10;13) balanced translocation whose one of the ATP8A2 allele was disrupted has been identified. This patient shares similar neurological phenotypes including severe mental retardation and hypotonia. These findings suggest a role for ATP8A2 in the neurodevelopment, especially in the development of cerebro-cerebellar structures required for posture and gait in humans.Item Open Access In silico identification of candidate MECP2 targets and quantitative analysis in rett syndrome(Bilkent University, 2006) Onat, Onur EmreRett syndrome (RTT) is an X-linked neuro-developmental disorder seen exclusively girls in the childhood. It is one of the most common causes of mental retardation with an incidence rate of 1/10,000-1/15,000. Mutations in MECP2 gene was described as a common cause of RTT. MECP2 is a transcriptional repressor that regulates gene expression. It is not fully understood which MECP2 targets are affected in RTT and therefore contribute to disease pathogenesis. Researchers approached the problem in two directions: a) Global expression profile analysis and b) Candidate gene analysis. Global expression profile analysis revealed which a limited number of genes including those on the X-chromosome are de-regulated. Candidate gene analysis studies showed that loss of imprinting as exemplified by DLX5 could also contribute to disease pathogenesis. We hypothesize that Xchromosome inactivation (XCI) is an important physiological epigenetic mechanism that could be involved in Rett pathogenesis. We predicted a MECP2 binding motif by a distinctive bioinformatic approach. Using this algorithm we searched for the candidate MECP2 target genes on the X-chromosome and whole genome. The genes FHL1 and MPP1, whose interaction with MECP2 were heuristically displayed were predicted by our algorithm. We identified more than 100 genes which are on the Xchromosome. 10 genes from the list were selected according to their MECP2 binding homology score and X-inactivation status. In order to test this hypothesis we analyzed these genes with quantitative RT-PCR .We expect to identify the key genes that potentially contribute to RTT pathogenesis via disturbances in X-chromosome inactivation.Item Open Access Mitochondrial serine protease HTRA2 p.G3999S in a kindred with essential tremor and Parkinson disease(National Academy of Sciences, 2014) Gülümser, Hilal Ünal; Gulsuner, S.; Mercan, F. N.; Onat, Onur Emre; Walsh, T.; Shahin, H.; Lee, M. K.; Dogu, O.; Kansu, T.; Topaloglu, H.; Elibol, B.; Akbostanci, C.; King, M. C.; Özçelik, Tayfun; Tekinay, Ayşe B.Essential tremor is one of the most frequent movement disorders of humans and can be associated with substantial disability. Some but not all persons with essential tremor develop signs of Parkinson disease, and the relationship between the conditions has not been clear. In a six-generation consanguineous Turkish kindred with both essential tremor and Parkinson disease, we carried out whole exome sequencing and pedigree analysis, identifying HTRA2 p.G399S as the allele likely responsible for both conditions. Essential tremor was present in persons either heterozygous or homozygous for this allele. Homozygosity was associated with earlier age at onset of tremor (P < 0.0001), more severe postural tremor (P < 0.0001), and more severe kinetic tremor (P = 0.0019). Homozygotes, but not heterozygotes, developed Parkinson signs in the middle age. Among population controls from the same Anatolian region as the family, frequency of HTRA2 p.G399S was 0.0027, slightly lower than other populations. HTRA2 encodes a mitochondrial serine protease. Loss of function of HtrA2 was previously shown to lead to parkinsonian features in motor neuron degeneration (mnd2) mice. HTRA2 p.G399S was previously shown to lead to mitochondrial dysfunction, altered mitochondrial morphology, and decreased protease activity, but epidemiologic studies of an association between HTRA2 and Parkinson disease yielded conflicting results. Our results suggest that in some families, HTRA2 p.G399S is responsible for hereditary essential tremor and that homozygotes for this allele develop Parkinson disease. This hypothesis has implications for understanding the pathogenesis of essential tremor and its relationship to Parkinson disease.Item Open Access Multiscale analysis of SRY‐positive 46,XX testicular disorder of sex development: Presentation of nine cases(Wiley, 2020-06-04) Akar, Ö. S.; Güneş, S.; Abur, U.; Altundağ, E.; Aşçı, R.; Onat, Onur Emre; Özçelik, Tayfun; Oğur, G.46,XX testicular disorder of sex development (46,XX TDSD) is a relatively rare condition characterised by the presence of testicular tissue with 46,XX karyotype. The present study aims to reveal the phenotype to genotype correlation in a series of sex‐determining region Y (SRY)‐positive 46,XX TDSD cases. We present the clinical findings, hormone profiles and genetic test results of six patients with SRY‐positive 46,XX TDSD and give the details and follow‐up findings of our three of previously published patients. All patients presented common characteristics such as azoospermia, hypergonadotropic hypogonadism and an SRY gene translocated on the terminal part of the short arm of one of the X chromosomes. Mean ± standard deviation (SD) height of the patients was 164.78 ± 8.0 cm. Five patients had decreased secondary sexual characteristics, and three patients had gynaecomastia with varying degrees. Five of the seven patients revealed a translocation between protein kinase X (PRKX) and inverted protein kinase Y (PRKY) genes, and the remaining two patients showed a translocation between the pseudoautosomal region 1 (PAR1) of X chromosome and the differential region of Y chromosome. X chromosome inactivation (XCI) analysis results demonstrated random and skewed XCI in 5 cases and 1 case, respectively. In brief, we delineate the phenotypic spectrum of patients with SRY‐positive 46,XX TDSD and the underlying mechanisms of Xp;Yp translocations.Item Open Access Reply to tzoulis et al.: genetic and clinical heterogeneity of essential tremor(National Academy of Sciences, 2015) Gülsuner, Hilal Ünal; Gülsuner, S.; Mercan, F.; Onat, Onur Emre; Walsh, T.; Shahin, H.; Lee, M.; Dogu, O.; Kansu, T.; Topaloglu, H.; Elibol, B.; Akbostanci, C.; King, M. -C.; Özçelik, Tayfun; Tekinay, Ayse B.In addressing our recent report of HTRA2 p.G399S as the gene and mutation responsible for essential tremor and subsequent Parkinson disease in a large kindred (1), Tzoulis et al. (2) screened this mutation in patients with Parkinson disease, essential tremor, tremulous cervical dystonia, and nontremulous cervical dystonia patients, and did not find a significant difference in carrier frequency compared with the general population. Their observation replicates our experience, in that in the kindred of our study, HTRA2 p.G399S was responsible for essential tremor and, among homozygotes, for Parkinson disease, but as we reported, this allele was not responsible for essential tremor in other families from the same population. Both these observations support the conclusion that essential tremor is a heterogeneous disease, both clinically and genetically (3). In addition to HTRA2, two other genes for essential tremor have been identified: DNAJC13 and FUS, and still other responsible genes have been mapped to chromosomes 2p22-24, 3q13, and 6p23 (1, 4). In any one patient, mutation at only one of these genes is sufficient for development of essential tremor, but the responsible gene differs among patients. These two features—the severity of individual causal mutations and different responsible genes in different families—are characteristic of genetic heterogeneity of complex diseases generally (5). Phenotypic features of a genetically heterogeneous disease may offer clues as to the responsible gene. In the family harboring mutation in HTRA2, Parkinson disease appeared after more than a decade of essential tremor. Also, cervical dystonia was not among the presenting signs in any of the family members. These clinical features differ from the series of patients screened by Tzoulis et al. Some of the patients screened by Tzoulis et al. may harbor HTRA2 mutations other than p.G399S that would be revealed by more complete sequencing; this would be interesting to learn. It is also possible that mutations in the other known genes for essential tremor may be present in these patients. If not, then these patients, like those from the other kindreds in our series, offer the opportunity to identify additional causal genes for essential tremor.