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Development of the human nervous system involves complex interactions between fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to mostly consanguineous families with neurogenetic disorders that often included brain malformations. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations.

Human brain development is a precisely orchestrated process requiring multiple genetic and epigenetic febi and the coordination of cellular and molecular mechanisms, perturbation of which leads to a plethora of neurodevelopmental phenotypes depending on the spatial and temporal effect of csbi disturbance. Neuronal development has been categorized into three main processes: Classification of the various malformations of cortical development has evolved to reflect these underlying developmental processes Barkovich et al.

Although such classifications recapitulate the main developmental steps in brain formation, recent advances challenge the implied boundaries between these clearly defined stages and suggest that the genes implicated in many developmental stages are genetically and functionally interdependent. Ultimately, this can lead to a more pragmatic classification of neurodevelopmental phenotypes that relies primarily on knowledge of genes and gene networks and manifests as dysfunction s in mechanisms of protein and pathway actions Barkovich et al.

A fundamental question in the study of brain malformations is the role of structural abnormalities in promotion of intellectual disability.

The two have long been studied together, with particular focus on X-linked intellectual disability XLID and more recent studies on both autosomal recessive intellectual disability ARID and dominant de novo mutations. Genes involved in intellectual disability play a role in diverse basic cellular functions, such as DNA transcription and translation, protein degradation, mRNA splicing, chromatin remodeling, energy metabolism and fatty-acid synthesis and turnover de Ligt et al.

Further coordinated study of brain malformations and intellectual disability offers the opportunity to potentially relate basic developmental features to elements of higher level cognitive function.

The advent of next generation sequencing has enabled rapid identification of numerous genes and mechanisms that underlie disorders of brain malformation and intellectual disability Alazami et al. Further advances are often limited by the availability of well characterized and rigorously phenotyped patients and the capacity for detailed analyses of gene function.

Due to the possibility that some post-migrational brain malformations may not be evident on imaging, we did not exclude patients with isolated profound intellectual disability from this study. We describe the genes identified by rare variant analyses and highlight candidate novel genes that were either present in more than one family with a similar phenotype; clearly fit into known biological processes perturbed in neurodevelopment; or harbored homozygous loss of function LOF i.

The central nervous system CNS features and pedigree structures of the families are shown as Figure 1 and S1respectively. According to their foremost central nervous system findings and accompanying clinical features dysmorphic and additional systemic findings we further classified probands into seven major groups: Multiple affected members proband and 1—2 siblings or cousins were sequenced when available, and in singleton cases, either the trio unaffected parents and affected proband or only the proband were sequenced.

Venn diagram of clinical and neuro-radiological features. The font size of the numbers correlates with the number of individuals that represent any given category. Phenotypic clustering of the probands according to their most outstanding feature revealed seven major groups: Figure S2 describes the workflow used to identify candidate disease genes.

We identified known variants in 5 known disease genes and 47 novel variants in 42 known disease genes; of these, 19 represented phenotypic expansions wherein trait manifestations were distinct from those previously reported in association with variation in that given gene Table S1Figure 1C.

Variants of unknown significance VUS in known disease genes were considered probably associated with the disease if they segregated with the phenotype and were determined damaging or likely damaging by bioinformatic predictions by a majority of five different tools see Experimental Procedureswith evolutionary conservation of the affected amino acid being a prerequisite for missense variants. The above criteria were then used to screen for the strongest candidate genes in the remaining cases, with the addition of two factors: Unsupervised clustering based on mRNA levels in the brain tissue partitioned the known and candidate genes into 4 subgroups: Biological functional annotation of the novel and known mutated genes in our cohort revealed that they were most significantly enriched in neurogenesis, tRNA metabolic process, forebrain development, pattern specification process, and cell-cell adhesion.


This network revealed 3 highly interconnected protein networks, consisting of genes significantly enriched in brain development, RNA metabolism, and cytoskeletal organization.

Unsupervised clustering of the novel candidate and known mutated disease genes based on their mRNA levels in the brain tissue partitioned them into 4 subgroups: Biological functional annotation of the novel and known mutated genes in our cohort revealed enrichment of the collection in neurogenesis, tRNA metabolic processes, forebrain development, pattern specification process, and cell-cell adhesion Figure 2B. We next tested whether the novel and known mutated genes have a greater than expected degree of connectivity within a protein-protein interaction network, based upon the known and predicted protein-protein interaction score retrieved from the STRING database http: Among these families, we identified homozygous deletions in three consanguineous families.

Second, a kb homozygous deletion encompassing almost the entire AP4E1 gene, previously associated with spastic paraplegia 51 MIMwas found in patient BAB with intellectual yimlaz, microcephaly, seizures, spasticity, and hyperintensity changes in both cerebellar hemispheres and subcortical deep white matter Figure 3A. Interestingly, his brother BAB was not homozygous for this same deletion and retrospective analysis of their phenotypes indicated that unlike his brother, BAB had neither abnormalities on MRI nor spasticity.

Hemizygous intragenic deletion of DMD interrupting exons 46 and 47; C. Homozygous deletion almost entirely encompassing SNX PCR validation underneath each pedigree shows amplification or lack thereof of the deletion region and a positive control PCR of an yilmax locus. Amplification of the deletion region in parents and unaffected siblings indicates either a heterozygous assumed for parents, as obligate carriers or homozygous wild type state.

Upper panel represents CNV as predicted from WES data; middle panel represents validation by array studies; and lower panel shows chromosomal position and RefSeq genes involved.

Parental yilmaaz for CNVs were beyond the scope of this article. Review of the SNVs on the complementary chromosome did not reveal any reduction to homozygosity of a recessive variant cwbi a known disease-associated gene in these loci. Two patients BAB yilmz BAB had both a terminal deletion and a terminal duplication, possibly suggestive of an unbalanced translocation. Patient BAB had a 17q Detected CNVs in the study cohort. In our cohort, 48 families showed cortical dysplasia atrophy, heterotopia, pachygyria or schizencephaly with or without microcephaly, callosal abnormalities, and hindbrain involvement Figures 1A and 1B.

In this clinical phenotypic category, we highlight novel candidate genes in which likely deleterious variants were identified in more than cbi family: Available patient images reveal some dysmorphic features most probably a result of microcephaly.

LF and RQ substitutions occur in the latter two domains respectively.

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NK substitution occurs nearby the DEAD domain, which plays a hakzn in several aspects of RNA metabolism processes such as cebj initiation and pre-mRNA splicing, whereas the other substitution p. Model structure for human PRUNE protein from SwissModel repository suggests that negatively charged D30 and D interact directly with the positively charged cofactor, while R and G are in close proximity to the catalytic site.

Based on the proximity of the villages of the two families and the shared AOH surrounding yilmz mutation data not shownwe suggest that a founder effect likely played a role in the etiology Karaca et al. GX variants shared by the two affected siblings. PRUNE prune homolog, drosophila is a phosphodiesterase member of the DHH phosphoesterase superfamily and highly expressed in the human fetal brain haian fully confined to the hhakan system in mouse embryos Reymond et al.

The Turkish variant p. DN changes ha,an of the three conserved amino acids Ceb that form the active site of the protein.

We detected two different homozygous potentially pathogenic variants in VARS that encodes valyl-tRNA synthetase, in two unrelated consanguineous pedigrees: All affected individuals presented with severe developmental delay, microcephaly, seizures, and cortical atrophy on MRI Figure 5B. The phenotype of these affected individuals was similar to that of the families with the homozygous PRUNE variant and to the previously published patients with CLP1 mutations Karaca et al.

Selected genes and their protein-protein interactions are shown in terms of correlation with neurodevelopmental process and resultant phenotype. BAB presented with severe microcephaly, developmental delay, seizures, and cortical atrophy and BAB presented with severe microcephaly, polymicrogyria, and dysgenesis of the corpus callosum Figure 5B. DEAD box proteins are known to be implicated in embryogenesis, spermatogenesis, and cellular growth and division de la Cruz et al.

In a recent study, it was shown that Dhx37 is required for the biogenesis of glycine receptors in zebrafish and thereby regulates glycinergic synaptic transmission and associated motor behaviors Hirata et al.


The authors do not comment on a central nervous system phenotype in the mutants. We further screened for any homozygous or hemizygous loss of function variants in our cohort. We verified that the observed loss of function variants affected all transcripts, checked whether it was in the last exon or last 55 bp of the penultimate exon which may escape nonsense mediated cebu, and reviewed internal and publicly available databases e.

We identified homozygous loss of function variants in five families in the following genes: Consanguinity between parents is indicated in each pedigree. Brain MRI of BAB revealed severe cortical dysplasia, diffuse hypoplastic corpus callosum, dilated lateral ventricles, simplified gyral pattern, and dysmorphic basal ganglia.

RX variant, to tubulinopathy-related cortical dysplasia syndromes. Patient image illustrates her severe dystonia.

Çebi, Hakan Yılmaz [WorldCat Identities]

BAB with homozygous stop gain p. Patient image underlines the coarse face, bushy eyebrows, facial hypertrichosis, and long eye lashes which resembles the facial dysmorphism in Coffin-Siris syndrome. A homozygous frameshift mutation p. LR mutation is provided and which also revealed a coarse face in the patient. Patient BAB presented with microcephaly, spasticity, and intellectual disability.

Family history was negative. The encoded ubiquilin 1 protein and related ubiquitin-like family members are proposed to functionally link the ubiquitination machinery to the proteasome to facilitate in vivo protein degradation Kleijnen et al.

Gfs encoding the vesicular monoamine transporter 2 VMAT2 crbi regulates the release and metabolism of the monoamine neurotransmitters; this finding offers a potential avenue for experimental treatment of the associated disease with direct dopamine agonists Tables 1 and S1Figures 6B and S4B Ohara et al. We utilized the type of brain malformation in a given individual and an understanding of its underlying molecular pathogenesis in the prioritization of the potential candidate genes identified in this study.

KIF23 encodes a kinesin family member localized at the interzone of the mitotic spindle Mishima et al. DN segregated with the phenotype in 2 affected and 4 unaffected family members.

The encoded protein is a component of the triple T complex which has been shown to play a role in PIKK signaling in brain development and functioning Hurov et al. Another component of the triple T complex is encoded by TTI2and this gene has been shown to be mutated in a large consanguineous family with microcephaly, severe cognitive impairment, skeletal anomalies, and facial dysmorphism MIM Langouet et al.

In order to further clarify the role of RNA processing factors in brain malformations, we screened our cohort for potentially pathogenic variants in genes whose encoded proteins were predicted to interact with VARS, CLP1, and other RNA cleavage and polyadenylation specific factors Figure 7. TUT1 plays a role in post-transcriptional modification of miRNAs, primarily as a poly A polymerase, and is essential for cell proliferation Knouf et al.

Exome sequencing, accompanied by an informatics pipeline and analyses tools, and followed by Sanger validation and yilmas studies, enabled detection of rare variants of potential pathologic significance. In silico analyses of the genes for brain developmental expression, and interactome and pathway analysis of gene products, further prioritized variants potentially associated with the Mendelizing traits that were studied.

The study of a large cohort of over families, rather hakna a small number of larger families aided the discovery process.

Hakan Yilmaz Cebi “Hazir Kita” (MPL)

Two similar large scale genomic studies have been published recently Alazami et al. Interestingly, none of the genes proposed yulmaz potential candidates in these two studies overlapped with those proposed herein. This may be attributed to the selection of different ethnic groups and yjlmaz accumulation of private variants which occurred in recent ancestral generations Lupski et al.

Finally, the multitude of prospective novel candidate genes highlights the magnitude and complexity of the mechanisms involved in human nervous system development and maintenance. Our findings converge on three cellular processes: As anticipated, some genes are involved in more than one of these processes. This is consistent with the well-established association between defective neurogenesis, loss of neuroprogenitor cells, and resultant decreased volume of the brain.

Proposed candidates found in patients with structural brain malformations e. Our hypothesis that VARS may lead to microcephaly and cortical dysgenesis is in accordance with the emerging class of neurological disorders resulting from mutations in genes encoding various aminoacyl tRNA synthetases Taft et al. We identified two potential candidate genes which function as RNA helicases: