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Öğe Bialelic Pathogenic (c.830G>A(p.R277Q)) Variant Disrupting the GNE Gene Function and Causes Nonaka myopathy Phenotype(Pleiades Publishing Ltd, 2023) Dogan, Mustafa; Akbulut, Ekrem; Gezdirici, Alper; Eroz, Recep; Bozdogan, Sevcan TugNonaka myopathy (MIM 605820) is caused by homozygous pathogenic variants in the GNE gene. It is a recessively inherited early adult-onset myopathy that usually preserves the quadriceps and presents with bilateral foot drop, usually caused by anterior tibialis weakness. In patients with Nonaka myopathy, serum creatine kinases are slightly elevated, muscle weakness progresses slowly, and ambulation loss develops after 15-20 yr. The current study aims to raise awareness of Nonaka myopathy that occurs as a rare phenotype due to pathogenic variants in GNE gene. Detailed family histories and clinical data were recorded. Whole exome sequencing was performed and co-segregation analysis of the family were done by Sanger sequencing. Also the homology model of the mutant protein was created with the ProMod3 algorithm. We identified a bialelic pathogenic variant (c.830G>A) in GNE gene, which explain the patients' clinical status. We present the main findings of two siblings with Nonaka myopathy together with detailed clinical and genetic profiles of the patients together with a three-dimensional mutant GNE protein model. We think that the clinical characteristics and the effect of the (c.830G>A) variant will facilitate our understanding of GNE gene in Nonaka myopathy pathogenesis.Öğe Biallelic novel CCDC186 loss-of-function variant disrupting the gene function causes neurodevelopmental phenotype and review of the literature(Elsevier, 2025) Gezdirici, Alper; Turk, Sultan Buse; Esen, Tuna Eren; Yavas, Cuneyd; Akbulut, Ekrem; Yilmaz, Halil Ibrahim; Dogan, MustafaBackground: Coiled-coil domain-containing protein 186 (CCDC186) is essential for the transport of secretory dense-core vesicles (DCVs), specialized organelles responsible for storing and releasing neurotransmitters and other modulatory molecules in neurons and endocrine cells, thereby playing a crucial role in physiological processes such as synaptic plasticity, neurotransmission, and hormonal regulation. Resent reports have suggested that biallelic loss-of-function (LOF) variants in CCDC186 may be associated with neurodevelopmental disorders and a range of systemic manifestations. Methods: Whole exome sequencing (WES) was performed, and co-segregation analysis of the family was conducted using sanger sequencing. Additionally, five patients with CCDC186-associated phenotypes previously described in the literature were evaluated. Followed by cDNA synthesis and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to analyze gene expression levels. Bioinformatics tools, including RoseTTAFold for protein modeling and STRING for protein-protein interaction networks, were employed to assess the structural and functional consequences of the mutation. Results: We identified a homozygous NM_018017.4:c.535C>T (p.Arg179Ter) nonsense variant in the CCDC186 gene. This variant was associated with a marked downregulation of CCDC186 expression in the proband, with moderate reductions observed in heterozygous family members, suggesting dysregulated gene expression resulting from the mutation. Protein modeling indicated structural alterations, including a shift from intrinsically disordered regions to helix-loop-helix motifs in the mutant protein, as well as reduced binding probabilities for most interacting partners. Conclusion: In this study, we presented the comprehensive clinical and genetic profiles of a Turkish child with a novel CCDC186 variant, along with five previously reported patients from the literature. Our findings support that the homozygous LOF variants of the CCDC186 gene are associated with a novel neurodevelopmental phenotype.Öğe Biallelic Novel USP53 Splicing Variant Disrupting the Gene Function that Causes Cholestasis Phenotype and Review of the Literature(Karger, 2023) Gezdirici, Alper; Sengul, Ozlem Kalaycik; Dogan, Mustafa; Ozguven, Banu Y.; Akbulut, EkremIntroduction: Hereditary cholestasis is a heterogeneous group of liver diseases that mostly show autosomal recessive inheritance. The phenotype of cholestasis is highly variable. Molecular genetic testing offers an useful approach to differentiate different types of cholestasis because some symptoms and findings overlap. Biallelic variants in USP53 have recently been reported in cholestasis phenotype. Methods: In this study, we aimed to characterize clinical findings and biological insights on a novel USP53 splice variant causing cholestasis phenotype and provided a review of the literature. We performed whole-exome sequencing and then confirmed it with Sanger sequencing. In addition, as a result of in silico analyses and cDNA analysis, we showed that the USP53 protein in our patient was shortened. Results: We report a novel splice variant (NM_019050.2:c.238-1G>C) in the USP53 gene via whole-exome sequencing in a patient with cholestasis phenotype. This variant was confirmed by Sanger sequencing and was a result of family segregation analysis; it was found to be in a heterozygous state in the parents and the other healthy elder brother of our patient. According to in silico analyses, the change in the splice region resulted in an increase in the length of exon 2, whereas the stop codon after the additional 3 amino acids (VTF) caused the protein to terminate prematurely. Thus, the mature USP53 protein, consisting of 1,073 amino acids, has been reduced to a small protein of 82 amino acids. Conclusion: We propose a model for the tertiary structure of USP53 for the first time, and together with all these data, we support the association of biallelic variants of the USP53 gene with cholestasis phenotype. We also present a comparison of previously reported patients with USP53-associated cholestasis phenotype to contribute to the literature.Öğe Clinical and Molecular Findings in a Turkish Family Who Had a (c.869-1G>A) Splicing Variant in PSEN1 Gene with A Rare Condition: The Variant Alzheimer's Disease with Spastic Paraparesis(Bentham Science, 2022) Doğan, Mustafa; Eröz, Recep; Tecellioğlu, Mehmet; Gezdirici, Alper; Çevik, Betül; Barış, İbrahimBackground: Early-onset Alzheimer's disease (EOAD) is commonly diagnosed with an onset age of earlier than 65 years and accounts for 5–10% of all Alzheimer's disease (AD) cases. To date, although only 10-15% of familial EOAD cases have been explained, the genetic cause of the vast proportion of cases has not been explained. The variant Alzheimer's disease with spastic paraparesis (var- AD) is defined as a rare clinical entity characterized by early-onset dementia, spasticity of the lower extremities, and gait disturbance. Although the disease was first associated with variants in exon 9 of the PSEN1 gene, it was later shown that variations in other exons were also responsible for the disease. Objective: The current study aims to raise awareness of varAD, which occurs as a rare phenotype due to pathogenic variants in PSEN1. In addition, we aimed to evaluate the spectrum of mutations in varAD patients identified to date. Methods: Detailed family histories and clinical data were recorded. Whole exome sequencing was performed and co-segregation analysis of the family was done by Sanger sequencing. Also, a review of the molecularly confirmed patients with (varAD) from the literature was evaluated. Results: We identified a heterozygous splicing variant (c.869-1G>A) in the PSEN1 gene, in a family with two affected individuals who present with varAD. We reported the clinical and genetic findings from the affected individuals. Conclusion: We present the detailed clinical and genetic profiles of a Turkish patient with the diagnosis of varAD together with subjects from the literature. Together, we think that the clinical characteristics and the effect of the (c.869-1G>A) variant will facilitate our understanding of the PSEN1 gene in AD pathogenesis.Öğe Clinical, radiological and computational studies on two novel GNPTG variants causing mucolipidosis III gamma phenotypes with varying severity(Springer, 2021) Doğan, Mustafa; Eröz, Recep; Terali, Kerem; Gezdirici, Alper; Bolu, SemihMucolipidosis III gamma (ML III gamma) is a slowly progressive disorder that affects multiple parts of the body such as the skeleton, joints, and connective tissue structures. It is caused by pathogenic variants in the GNPTG gene that provides instructions for producing the gamma subunit of GlcNAc-1-phosphotransferase. In this study we aim to characterize clinical findings and biological insights on two novel GNPTG variants causing ML III gamma phenotypes with varying severity. We report on two siblings with ML III gamma bearing the previously undescribed c.477C > G (p.Y159*) nonsense variant in a homozygous state as well as a patient with ML III gamma bearing the novel c.110 + 19_111-17del variant in a homozygous state. These variants were revealed by whole-exome sequencing and Sanger sequencing, respectively. Their parents, who are heterozygotes for the same mutation, are healthy. The clinical and radiographic presentation of ML III gamma in our patients who had c.477C > G (p.Y159*) variant is consistent with a relatively severe form of the disease, which is further supported by a working three-dimensional model of the GlcNAc-1-phosphotransferase gamma subunit. On the other hand, it is seen that our patient who carries the c.110 + 19_111-17del variant has a milder phenotype. Our findings help broaden the spectrum of GNPTG variants causing ML III gamma and offer structural and mechanistic insights into loss of GlcNAc-1-phosphotransferase gamma subunit function.Öğe Functional evaluation of NAA10 variants in patients with Ogden syndrome(Lippincott Williams & Wilkins, 2026) Aydin Gumus, Aydeniz; Dogan, Mustafa; Gezdirici, Alper; Akbulut, Ekrem; Kinay Ermis, DuyguObjectives The catalytic subunit of NatA, the main component of the N-terminal acetyltransferase complex, which is involved in most of the acetylation of the human proteome, is encoded by the NAA10 gene. Mutations in the NAA10 gene lead to neurodegenerative diseases associated with disruption of acetylation. Ogden syndrome (OS) is a rare X-linked recessive or dominantly inherited disorder associated with NAA10 gene mutations, characterized by variable findings such as autism spectrum disorder, intellectual disability, and cardiac anomalies. In this article, it is aimed to clarify the functionality of two novel NAA10 gene variants in two female patients with OS. Methods A whole-exome sequencing (WES) study was performed from the blood samples of the patients. The effects of the two variants found by tertiary structure modeling, protein stability analysis, and molecular docking analyses on NAA10 were examined. Results Autism, intellectual retardation, and epilepsy were prominent in the patients, and heterozygous variants c.346C>T and c.439A>T in the NAA10 gene were detected in WES. The clinical findings were compatible with OS. The p.Arg116Trp and p.Met147Leu changes in the NAA10 gene caused changes in the overall topological structure of NAA10, including the substrate and ligand binding site. Conclusion In this study, c.346C>T and c.439A>T variants were found to alter the functional stability, structure, and energy of NAA10. Functional analyses of NAA10 variants in two rare OS patients have once again demonstrated that novel variants are essential studies for phenotype-genotype correlation association steps.Öğe An integrated clinical and molecular study of a cohort of Turkish patients with Marfan syndrome harboring known and novel FBN1 variants(Springer, 2021) Gezdirici, Alper; Teralı, Kerem; Yılmaz Güleç, Elif; Bornaun, Helen; Doğan, Mustafa; Eröz, RecepMarfan syndrome (MFS) is an autosomal dominant genetic condition that mainly affects connective tissue in many parts of the body. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. The diagnosis of MFS relies on the revised Ghent criteria, outlined by international expert opinion to facilitate accurate recognition of this syndrome as well as to improve patient management and counseling. However, it may not always be possible to make a definitive diagnosis according to these criteria in each patient and thus molecular confirmation is necessary in subjects with suspected MFS. This debilitating, if not fatal, disorder is caused by mutations in FBN1, which encodes a major constitutive element of extracellular microfibrils. Here, we present a detailed clinical and molecular analysis of 76 Turkish patients with definitive or suspected MFS diagnosed at our center between 2014 and 2019. We were able to identify a total of 51 different FBN1 variants in our cohort, 31 of which have previously been reported in the relevant scientific literature. The remaining 20 variants have not been documented to date. In one patient, we detected a large deletion including the entire FBN1 gene using the array CGH approach. Currently, there are very few studies on the genotype–phenotype correlation of patients with MFS, and no clear genotype–phenotype maps for MFS have been constructed so far, except for some cases. We believe that our findings will make a rich and peculiar contribution to the elusive genotype–phenotype relationship in MFS, especially in this large and populous ethnic group.Öğe The role of ATP9A (c.1091G > C; p.(Arg364Thr)) variant in cognitive impairment: diagnostic insight from whole exome sequencing(Springer, 2026) Yavas, Cuneyd; Abuaisha, Asmaa; Nekay, Emir; Gezdirici, Alper; Yilmaz, Halil Ibrahim; Akbulut, Ekrem; Arican, PinarBackground The ATP9A gene encodes a P4-type ATPase involved in phospholipid translocation, essential for vesicular trafficking and neuronal development. Pathogenic ATP9A variants cause autosomal recessive neurodevelopmental disorders characterized by intellectual disability and microcephaly, yet the impact of missense variants remains poorly understood. Methods A 7-year-old female patient with cognitive impairment, microcephaly, and developmental delay was admitted to Ba & scedil;ak & scedil;ehir & Ccedil;am and Sakura City Hospital. Whole exome sequencing (WES) using Illumina technology identified a novel homozygous ATP9A variant, confirmed by Sanger sequencing and segregation analysis. In silico tools (RosettaFold, DynaMut, mCSM, SDM, DUET, AggreScan3D) assessed its structural impact. Quantitative real-time polymerase chain reaction (RT-qPCR) was conducted to evaluate the relative expression levels of ATP9A. Results WES revealed a homozygous missense variant, ATP9A: NM_006045.3:c.1091G > C:p.(Arg364Thr), classified as variant of uncertain significance based on ACMG guidelines (PP2, PM2, PM3). Protein modeling demonstrated reduced stability (Delta Delta G = - 1.51 to - 0.26 kcal/mol), increased flexibility, and a 2.4-fold decrease in solvent accessibility. The variant disrupted polar and hydrophobic interactions within the P-type ATPase IV domain, thereby increasing aggregation propensity. Expression analysis revealed elevated ATP9A mRNA levels, suggesting a compensatory cellular response. Conclusion This novel ATP9A variant broadens the mutational spectrum of ATP9A-related neurodevelopmental disorders. Structural destabilization of the p.(Arg364Thr) protein may contribute to the patient's cognitive impairment and microcephaly, warranting further functional studies.
