Researcher:
Başak, Ayşe Nazlı

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Ayşe Nazlı

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Başak

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Başak, Ayşe Nazlı

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2018 - 201952020 - 202347

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    The first biallelic missense mutation in the fxn gene in a consanguineous turkish family with charcot-marie-tooth-like phenotype
    (2020) Candayan, Ayşe; Yunisova, Gülşhan; Çakar, Arman; Durmuş, Hacer; Parman, Yeşim; Battaloğlu, Esra; N/A; Başak, Ayşe Nazlı; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 1512
    Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy with a prevalence of 1 in 2500 individuals worldwide. Here, we report three Turkish siblings from consanguineous parents presenting with a CMT-like phenotype who carry a homozygous c.493C>T, p.Arg165Cys mutation in the FXN gene that is the only known causative gene for Friedreich’s ataxia (FRDA). The identified missense mutation has been reported previously in two FRDA cases in compound heterozygosity with the common GAA repeat expansion in the first intron of the FXN gene. Analysis of skin biopsy samples from our family indicated that the mutation does not affect the expression levels of the frataxin, pointing to functional impairment of the corresponding protein. The CMT phenotype in the siblings was associated with visual impairment, optic nerve atrophy, and dysarthria. To the best of our knowledge, this family represents the first FXN missense mutation in homozygosity and challenges the notion that missense mutations have not been reported yet due to their embryonic lethality. Furthermore, this finding poses an interesting genetic overlap between autosomal recessive CMT and FRDA that we believe may have important implications on understanding the pathogenesis of these neurological disorders.
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    Long-term follow-up of five families from Turkey with UBQLN2 variants
    (Wiley, 2022) Durmus, Hacer; Cakar, Arman; Aysal, Fikret; Ertas, Mustafa; Parman, Yesim; N/A; Başak, Ayşe Nazlı; Faculty Member; School of Medicine; 1512
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    Co-existence of mutations in PRRT2 and ABCC6 genes in a Turkish family
    (Türkiye Klinikleri, 2020) Şenel, Gülçin Benbir; Tezen, Didem; Apaydın, Hülya; Tekgül, Şeyma; Başak, Ayşe Nazlı; Master Student; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Sciences and Engineering; School of Medicine; 63142; 1512
    Paroxysmal kinesigenic choreoathetosis (PKC) is an inherited disorder with an autosomal dominant mode of inheritance, caused mostly by the mutations in PRRT2 (proline-rich transmembrane protein-2) gene, located on chromosome 16. Pseudoxanthoma elasticum (PXE) is a hereditary metabolic disease with autosomal recessive inheritance resulting from the mutations in the ABCC6 (ATP-Binding Cassette, Subfamily C, Member 6) gene, located also on chromosome 16. Here we present a female patient with familial paroxysmal kinesigenic dyskinesia and benign familial infantile convulsions (BFIC), in whom both a heterozygous truncating frameshift mutation in the PRRT2 gene and a heterozygous missense mutation in the ABCC6 gene were demonstrated. The co-existence of these two mutations has not been reported in the literature. Although the clinical symptomatology of PXE was not present in our patient, some family members of our index case had. Here we present a Turkish family with two different mutations on the same chromosome, namely PRRT2 and ABCC6 mutations. However, because these two mutations have separate parental inheritance and are not in linkage disequilibrium, the co-existence was reported as co-incidental.
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    Two cases of early-onset autosomal recessive spastic ataxia of charlevoix-saguenay diagnosed in adulthood
    (Elsevier, 2021) Şahin, Turgut; Karaarslan, Fatma Tuğra; Yılmaz, Rezzak; Akbostancı, Muhittin Cenk; Tekgül, Şeyma; Başak, Ayşe Nazlı; Master Student; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Sciences and Engineering; School of Medicine; 63142; 1512
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    Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): an important cause of late-onset ataxia with unique clinical features
    (Springer Heidelberg, 2022) Çakar, Arman; Şahin, Erdi; Tezel, Seden; Candayan, Ayşe; Samancı, Bedia; Battaloğlu, Esra; Bilgiç, Başar; Hanağası, Haşmet; Durmuş, Hacer; Parman, Yeşim; N/A; Başak, Ayşe Nazlı; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 1512
    Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slowly progressive disorder characterized by cerebellar ataxia, sensory neuropathy and bilateral vestibulopathy. Recently, a biallelic intronic AAGGG repeat expansion, (AAGGG)(exp), in the Replication Factor C1 (RFC1) gene was identified as the cause of this disorder. In this study, we describe the phenotypic features of five patients from five different families diagnosed as CANVAS. The mean age at onset was 49.00 +/- 9.05 years (between 34 and 56 years) and the most frequent presenting symptom in CANVAS was gait ataxia, followed by sensory disturbances. Persistent coughing was prominent in three patients, and it preceded the onset of ataxia and sensory symptoms in two patients. Parental consanguinity was present in three patients. Two patients showed symptoms or signs suggesting autonomic involvement. Sural nerve biopsy revealed axonal neuropathy in two patients. The mean age at onset was 49.00 +/- 9.05 years (between 34 and 56 years) and the most frequent presenting symptom in CANVAS was gait ataxia, followed by sensory disturbances. Persistent coughing was prominent in three patients, and it preceded the onset of ataxia and sensory symptoms in two patients. Parental consanguinity was present in three patients. Two patients showed symptoms or signs suggesting autonomic involvement. Sural nerve biopsy revealed axonal neuropathy in two patients. Our study describes clinical findings, histopathological features and diagnostic clues of CANVAS from Turkey, a country with a high consanguineous marriage rate. Repeat expansion in the RFC1 gene should be considered in all cases with late-onset ataxia, especially when sensory disturbances, vestibular involvement and persistent coughing coexist.
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    Ocular findings of oculomotor apraxia/ataxia type 1
    (Elsevier B.V., 2023) Sönmez, Hatice Kübra; Gülmez Sevim, Duygu; Gültekin, Murat; N/A; N/A; Şimşir, Gülşah; Başak, Ayşe Nazlı; Master Student; Faculty Member; Graduate School of Sciences and Engineering; School of Medicine; N/A; 1512
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    Ataxia telangiectasia like disorder: another dopa-responsive disorder look-alike?
    (Elsevier Sci Ltd, 2020) Ser, Merve Hazal; Gündüz, Ayşegül; Kızıltan, Meral E.; Kızıltan, Güneş; Tekgül, Şeyma; Başak, Ayşe Nazlı; Master Student; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Sciences and Engineering; School of Medicine; 63142; 1512
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    Author Correction: common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology (Nature Genetics, (2021), 53, 12, (1636-1648), 10.1038/s41588-021-00973-1)
    (Nature Research, 2022) van Rheenen, Wouter; van der Spek, Rick A. A.; Bakker, Mark K.; van Vugt, Joke J. F. A.; Hop, Paul J.; Zwamborn, Ramona A. J.; de Klein, Niek; Westra, Harm-Jan; Bakker, Olivier B.; Deelen, Patrick; Restuadi, Restuadi; Gawor, Klara; Westeneng, Henk-Jan; van Eijk, Kristel R.; Al Khleifat, Ahmad; Ticozzi, Nicola; Cooper-Knock, Johnathan; Gromicho, Marta; Chandran, Siddharthan; Orrell, Richard W.; Sendtner, Michael; Cereda, Cristina; Sproviero, Daisy; Ratti, Antonia; Siciliano, Gabriele; Filosto, Massimiliano; Moglia, Cristina; Grassano, Maurizio; Beghi, Ettor; Osmanovic, Alma; Lerner, Yossef; Zabari, Michal; Nefussy, Beatrice; Mora Pardina, Jesus S.; Dion, Patrick A.; Bensimon, Gilbert; Olsen, Catherine M.; Ceroni, Mauro; Diamanti, Luca; Ferrarese, Carlo; Tremolizzo, Lucio; Torrieri, Maria Claudia; Bombaci, Alessandro; Mazzini, Letizia; Corrado, Lucia; De Mattei, Marco; N/A; Başak, Ayşe Nazlı; Faculty Member; School of Medicine; 1512
    In the version of this article initially published, the affiliation for Nazli Başak appeared incorrectly. Nazli Başak is at Koç University, School of Medicine, KUTTAM-NDAL, Istanbul, Turkey, and not Bogazici University. The error has been corrected in the HTML and PDF versions of the article. © 2022, The Author(s).
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    A novel pathogenic variant in the 3ʹ end of the AGTPBP1 gene gives rise to neurodegeneration without cerebellar atrophy: an expansion of the disease phenotype?
    (Springer, 2021) Turay, Sevim; Eroz, Recep; N/A; Başak, Ayşe Nazlı; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 1512
    Childhood-onset neurodegeneration with cerebellar atrophy (CONDCA) is a recently described form of the large group of infantile hereditary lower motor neuron diseases (Teoh et al. 2017), resulting from biallelic damaging variants in the AGTPBP1 gene, first described by Shashi et al. in EMBO J 37(23):e100540, 2018. AGTPBP-related neurodegeneration is a severe neurodevelopmental disorder that progresses with global developmental delay and intellectual disability, often accompanied with peripheral nerve damage and lower motor degeneration and a fatal course in the early years of life. The encoded protein is ATP/GTP-Binding Protein1, also known as cytosolic carboxypeptidase 1 (CCP1) or nervous system nuclear protein induced by axotomy (NNA1). Here we report a consanguineous family with four offspring, two of whom are affected. The index patient is a 21-month-old male with global developmental delay and hypotonia. The proband's 17-year-old sister, diagnosed with cerebral palsy, had severe hypotonia accompanied by motor and cognitive retardation. WES analysis revealed a novel homozygous c.3293G > A variant in the AGTPBP1 gene with high pathogenicity scores. Targeted Sanger sequencing confirmed the variant in both affected children and in heterozygous form in the parents. The affected siblings present with hypotonia and motor and cognitive retardation, in line with the studies previously reported. However, in our patients, no signs of cerebellar atrophy in cranial MRI were present, so the acronym CONDCA is not applicable; lower motor neuron findings were also absent. The matching and distinguishing aspects of our patients will add to the present literature and expand our understanding of this rare genetic neurodegenerative disease of early childhood.
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    Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival
    (Frontiers Media S.A., 2023) Adey, Brett N.; Cooper-Knock, Johnathan; Al Khleifat, Ahmad; Fogh, Isabella; van Damme, Philip; Corcia, Philippe; Couratier, Philippe; Hardiman, Orla; McLaughlin, Russell; Gotkine, Marc; Drory, Vivian; Silani, Vincenzo; Ticozzi, Nicola; Veldink, Jan H.; van den Berg, Leonard H.; de Carvalho, Mamede; Pinto, Susana; Mora Pardina, Jesus S.; Povedano Panades, Mónica; Andersen, Peter M.; Weber, Markus; Shaw, Christopher E.; Shaw, Pamela J.; Morrison, Karen E.; Landers, John E.; Glass, Jonathan D.; Vourc’h, Patrick; Dobson, Richard J. B.; Breen, Gerome; Al-Chalabi, Ammar; Jones, Ashley R.; Iacoangeli, Alfredo; N/A; Başak, Ayşe Nazlı; Faculty Member; School of Medicine; 1512
    Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Methods: Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype. Results: We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days. Discussion: These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion. Copyright © 2023 Adey, Cooper-Knock, Al Khleifat, Fogh, van Damme, Corcia, Couratier, Hardiman, McLaughlin, Gotkine, Drory, Silani, Ticozzi, Veldink, van den Berg, de Carvalho, Pinto, Mora Pardina, Povedano Panades, Andersen, Weber, Başak, Shaw, Shaw, Morrison, Landers, Glass, Vourc’h, Dobson, Breen, Al-Chalabi, Jones and Iacoangeli.