6 results on '"M. Gunel"'
Search Results
2. Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities.
- Author
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Cali E, Suri M, Scala M, Ferla MP, Alavi S, Faqeih EA, Bijlsma EK, Wigby KM, Baralle D, Mehrjardi MYV, Schwab J, Platzer K, Steindl K, Hashem M, Jones M, Niyazov DM, Jacober J, Littlejohn RO, Weis D, Zadeh N, Rodan L, Goldenberg A, Lecoquierre F, Dutra-Clarke M, Horvath G, Young D, Orenstein N, Bawazeer S, Vulto-van Silfhout AT, Herenger Y, Dehghani M, Seyedhassani SM, Bahreini A, Nasab ME, Ercan-Sencicek AG, Firoozfar Z, Movahedinia M, Efthymiou S, Striano P, Karimiani EG, Salpietro V, Taylor JC, Redman M, Stegmann APA, Laner A, Abdel-Salam G, Li M, Bengala M, Müller AJ, Digilio MC, Rauch A, Gunel M, Titheradge H, Schweitzer DN, Kraus A, Valenzuela I, McLean SD, Phornphutkul C, Salih M, Begtrup A, Schnur RE, Torti E, Haack TB, Prada CE, Alkuraya FS, Houlden H, and Maroofian R
- Subjects
- Humans, Obesity genetics, Phenotype, Protein-Arginine N-Methyltransferases genetics, Brachydactyly, Neurodevelopmental Disorders genetics, Intellectual Disability genetics, Dwarfism genetics, Musculoskeletal Abnormalities
- Abstract
Purpose: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder., Methods: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature., Results: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss., Conclusion: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities., Competing Interests: Conflict of Interest Megan Li is an employee of Invitae. Erin Torti, Amber Begtrup, and Rhonda E Schnur are employees of GeneDx, Inc. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
3. Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations.
- Author
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Shenkar R, Shi C, Rebeiz T, Stockton RA, McDonald DA, Mikati AG, Zhang L, Austin C, Akers AL, Gallione CJ, Rorrer A, Gunel M, Min W, De Souza JM, Lee C, Marchuk DA, and Awad IA
- Subjects
- 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine analogs & derivatives, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine pharmacology, Adolescent, Adult, Animals, Apoptosis Regulatory Proteins metabolism, Carrier Proteins genetics, Cells, Cultured, Central Nervous System Neoplasms enzymology, Central Nervous System Neoplasms genetics, Child, Child, Preschool, Disease Models, Animal, Hemangioma, Cavernous, Central Nervous System enzymology, Hemangioma, Cavernous, Central Nervous System genetics, Human Umbilical Vein Endothelial Cells, Humans, Infant, Intracellular Signaling Peptides and Proteins metabolism, Keratin-1 genetics, Membrane Proteins metabolism, Mice, Middle Aged, Prospective Studies, Proto-Oncogene Proteins metabolism, Stress Fibers drug effects, Stress Fibers metabolism, Young Adult, rho-Associated Kinases antagonists & inhibitors, Apoptosis Regulatory Proteins genetics, Central Nervous System Neoplasms pathology, Hemangioma, Cavernous, Central Nervous System pathology, Intracellular Signaling Peptides and Proteins genetics, Membrane Proteins genetics, Mutation, Proto-Oncogene Proteins genetics, rho-Associated Kinases metabolism
- Abstract
Purpose: The phenotypic manifestations of cerebral cavernous malformation disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase-mediated hyperpermeability, a potential therapeutic target, has not been established., Methods: We analyzed PDCD10 small interfering RNA-treated endothelial cells for stress fibers, Rho kinase activity, and permeability. Rho kinase activity was assessed in cerebral cavernous malformation lesions. Brain permeability and cerebral cavernous malformation lesion burden were quantified, and clinical manifestations were assessed in prospectively enrolled subjects with PDCD10 mutations., Results: We determined that PDCD10 protein suppresses endothelial stress fibers, Rho kinase activity, and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrated robust Rho kinase activity in murine and human cerebral cavernous malformation vasculature and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared with the more common KRIT1 and CCM2 familial and sporadic cerebral cavernous malformation, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features, including scoliosis, cognitive disability, and skin lesions, unrelated to lesion burden or bleeding., Conclusion: These findings define a unique cerebral cavernous malformation disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling, and the design of trials.Genet Med 17 3, 188-196.
- Published
- 2015
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4. NGLY1 mutation causes neuromotor impairment, intellectual disability, and neuropathy.
- Author
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Caglayan AO, Comu S, Baranoski JF, Parman Y, Kaymakçalan H, Akgumus GT, Caglar C, Dolen D, Erson-Omay EZ, Harmanci AS, Mishra-Gorur K, Freeze HH, Yasuno K, Bilguvar K, and Gunel M
- Subjects
- Abnormalities, Multiple genetics, Adolescent, Child, Corneal Opacity genetics, Female, Frameshift Mutation, Genotype, Humans, Male, Developmental Disabilities genetics, Intellectual Disability genetics, Movement Disorders genetics, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase genetics, Peripheral Nervous System Diseases genetics
- Abstract
N-glycanase 1 (NGLY1) is a conserved enzyme that is responsible for the deglycosylation of misfolded N-glycosylated proteins in the cytoplasm prior to their proteasome-mediated degradation. Disruption of this degradation process has been associated with various neurologic diseases including amyotrophic lateral sclerosis and Parkinson's disease. Here, we describe two siblings with neuromotor impairment, apparent intellectual disability, corneal opacities, and neuropathy who were found to possess a novel homozygous frame-shift mutation due to a 4 base pair deletion in NGLY1 (c.1533_1536delTCAA, p.Asn511LysfsX51). We hypothesize that this mutation likely limits the capability of neuronal cells to respond to stress due to accumulation of misfolded proteins, thereby impairing their survival and resulting in progressive loss of neurological function., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)
- Published
- 2015
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5. Ultrastructural analysis of vascular features in cerebral cavernous malformations.
- Author
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Tanriover G, Sozen B, Seker A, Kilic T, Gunel M, and Demir N
- Subjects
- Apoptosis Regulatory Proteins genetics, Apoptosis Regulatory Proteins immunology, Brain pathology, Carrier Proteins genetics, Carrier Proteins immunology, Cerebrovascular Circulation, Chromosome Mapping, Endothelium, Vascular pathology, Endothelium, Vascular ultrastructure, Gene Expression Regulation, Humans, Immunohistochemistry, Intracranial Arteriovenous Malformations genetics, Intracranial Arteriovenous Malformations physiopathology, Intracranial Arteriovenous Malformations surgery, KRIT1 Protein, Membrane Proteins genetics, Membrane Proteins immunology, Microscopy, Electron, Scanning, Microscopy, Electron, Transmission, Microtubule-Associated Proteins genetics, Microtubule-Associated Proteins immunology, Neuroglia pathology, Neuroglia ultrastructure, Pericytes pathology, Pericytes ultrastructure, Platelet Endothelial Cell Adhesion Molecule-1 genetics, Platelet Endothelial Cell Adhesion Molecule-1 immunology, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins immunology, Stromal Cells pathology, Stromal Cells ultrastructure, Blood Vessels pathology, Blood Vessels ultrastructure, Brain ultrastructure, Intracranial Arteriovenous Malformations pathology
- Abstract
Objective: Investigation of the structure of vascular malformations highlights the pathogenic mechanisms underlying their clinical behavior. One of the vascular malformations is called cerebral cavernous malformation (CCM). However, the ultrastructural features of the vascular malformations are not defined in detail., Methods: We aimed to investigate the ultrastructural features of CCMs using transmission (TEM), scanning (SEM) electron microscopy, and also immunohistochemistry methods with antibodies against CCM proteins such as CCM2 and CCM3. CCM tissues (n=6) microsurgically excised from patients for conventional indications., Results: CCM2 and CCM3 were strongly detected in the vascular endothelium. However, there was a very weak immunostaining in stroma. SEM observations revealed that there were ruptures and damages in the luminal endothelium, possibly due to the damage of intercellular junctions. TEM observations also showed a few ruptures and detachments between the endothelium and basal lamina as observed with partially damages and disconnections. The architecture of pericytes showed protrusions and shrinkages. Our results suggest that the thin vessel walls of CCMs were lacking of subendothelial support and intact basal lamina underlying the endothelial cells., Conclusion: This study is so far the first study attempting to show human CCM lesions with SEM. We believe that an understanding of the ultrastructural features of these lesions by light and electron microscopy techniques would help to understand the pathology of these diseases., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2013
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6. TESE-ICSI in patients with non-mosaic Klinefelter syndrome: a comparative study.
- Author
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Yarali H, Polat M, Bozdag G, Gunel M, Alpas I, Esinler I, Dogan U, and Tiras B
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- Adult, Biopsy, Female, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Klinefelter Syndrome genetics, Klinefelter Syndrome pathology, Male, Mosaicism, Klinefelter Syndrome physiopathology, Sperm Injections, Intracytoplasmic, Sperm Retrieval
- Abstract
There are limited data in the literature on the performance of testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) treatment in patients with Klinefelter syndrome. The current study compared TESE-ICSI treatment in patients with non-mosaic Klinefelter syndrome with controls having non-obstructive azoospermia and normal karyotype. Thirty-three consecutive patients (39 TESE-ICSI cycles) with Klinefelter syndrome (study group) and 113 consecutive patients (130 TESE-ICSI cycles) with non-obstructive azoospermia and normal karyotype (control group) were recruited in a private IVF setting. In the two groups, the mean ages of the men at the time of TESE were 32.0 +/- 6.4 and 34.3 +/- 5.8 years respectively (P < 0.05) and the successful sperm recovery rates per total TESE attempts were 56 (22/39) and 44% (57/130) respectively. Similarly, fertilization rates were comparable between the two groups. In the Klinefelter syndrome group, following biopsy and fluorescence in-situ hybridization, a normal karyotype was obtained in 42 of the 71 embryos (59%). The clinical pregnancy and implantation rates in the study and control groups were similar (39, 23 and 33, 26% respectively). In conclusion, patients with non-mosaic Klinefelter syndrome have sperm recovery and pregnancy rates comparable with patients having non-obstructive azoospermia and normal karyotype.
- Published
- 2009
- Full Text
- View/download PDF
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