293 results on '"Stawinski P"'
Search Results
252. Molecular and crystal structure of Sp-thymidin-3'-yl 4-thiothymidin-5'-yl methylphosphonate
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Szabò, Tomas, Norèus, Dag, Norrestam, Rolf, and Stawinski, Jacek
- Abstract
The molecular structure of one diastereomer of the dlnucleoslde methylphosphonate Tp{Me)sT (1) has been determined by X-ray diffraction methods. The crystal asymmetric unit contains one molecule of 1 and one methanol In an orthorhombic unit cell of dimensions a = 13.241(4), b = 13.844(3), c = 14.944(7) A, space group P2
1 21 21 . Both pyrimidlne bases In 1 are oriented antl relative to the 2′-deoxyribose rings, and the sugar conformations are 2E and 23 T In the 4-thlothymidlne and thymldine moieties, respectively. The deoxyribose-phosphonate backbone has an extended conformation with the bases completely unstacked and almost parallel. The absolute configuration at the phosphorus center In 1 is Sp .- Published
- 1993
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253. ChemInform Abstract: Nucleoside Phosphonates. Part 7. Oxidation of Nucleoside Phosphonate Esters.
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GAREGG, P. J., REGBERG, T., STAWINSKI, J., and STROEMBERG, R. +
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Among some methods for oxidation of phosphonates such as (I) the use of I2 proves to be the most efficient procedure.
- Published
- 1987
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254. Solid Support Synthesis of all-Rp-Oligo(ribonucleoside phosphorothioate)s
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Almer, Helena, Stawinski, Jacek, and Strömberg, Roger
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The first method for solid support synthesis of all-RP-oligo(ribonucleoside phosphorothioate)s is presented as well as attempts to increase the stereo-selectivity of the key step in this approach. The synthetic strategy consists of (i) a solid support synthesis procedure, using 5′-O-(4-methoxytriphenylmethyl)-2′-O-tert-butyldimethylsilyl-ribonucleoside 3-H-phosphonates, that due to stereoselectivity in the condensation step, gives oligomers with mostly SP-H-phosphonate diesters (72–89% under standard conditions), (ii) stereospecific sulfurization with S8 in pyridine to produce oligo(ribonucleoside phophoro-thioate)s enriched with internucleosidic linkages of RP configuration, (iii) treatment of the deprotected oligo-nucleotides with the enzyme Nuclease P1 from Penicillium citrinum, that specifically catalyses cleavage of SP-phosphorothioate diester linkages, which leaves a mixture of oligomers having all inter-nucleosidic linkages as RP-phosphorothioates, and finally (iv) isolation and HPLC purification of the full length all-RP oligomer. Mixed sequences containing the four common nucleosidic residues up to the chain length of a heptamer were synthesized. Change of N-4-protection on the cytidine building block from propionyl to N-methylpyrrolidin-2-ylidene gave a slightly improved diastereoselectivity in H-phospho-nate diester formation. Increased selectivity up to 99+ % was obtained with the guanosine building block when the amount of pyridine in the coupling step was reduced.
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- 1996
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255. ChemInform Abstract: Nucleoside H‐Phosphonates. Part 12. Synthesis of Nucleoside 3′‐(Hydrogen Phosphonothioate) Monoesters via Phosphinate Intermediates.
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STAWINSKI, J., THELIN, M., WESTMAN, E., and ZAIN, R.
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- 1990
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256. ChemInform Abstract: The H‐Phosphonate Method for Constructing Phosphodiester Linkages. A Progress Report
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STAWINSKI, J., STROMBERG, R., LINDH, I., REGBERG, T., SZABO, T., THELIN, M., WESTMAN, E., and GAREGG, P. J.
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- 1990
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257. ChemInform Abstract: Nucleoside Hydrogenphosphonates. Part 6. Reaction of Nucleoside Hydrogenphosphonates with Arenesulfonyl Chlorides.
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GAREGG, P. J., STAWINSKI, J., and STROEMBERG, R. +
- Abstract
The title reaction proceeds via the trimetaphosphite (V), the formation of which is facilitated by the presence of a base (pyridine).
- Published
- 1987
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258. Studies on the t-butyldimethylsilyl group as 2'-O-protection in oligoribonucleotide synthesis via the H-phosphonate approach
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Stawinski, Jacek, Strömberg, Roger, Thelin, Mats, and Westman, Erik
- Abstract
Two model compounds, 1 and 2, have been studied to test the stability of the t-butyldimethylsilyl (t-BDMSi) group towards conditions used during chemical synthesis of RNA fragments by the H-phosphonate approach. When 1 was treated with anhydrous acid for 16 h both the H-phosphonate diester and the t-BDMSi group remained intact. Removal of the t-BDMSi group from 2 with 1.0 M tetrabutylammonium fluoride (TBAF- 3H
2 O) in THF was complete within 4 h and neither concomitant cleavage nor migration of the phospho-diester linkage could be detected even after 24 h. The dimer 2 was not completely stable towards concentrated aqueous ammonia and both loss of the t-BDMSi group and concomitant cleavage of the phosphodiester linkage occurred upon prolonged treatment. These reactions were substantialy suppressed in ethanol containing ammonia solutions, however to alleviate this problem during oligoribonucleotide synthesis, more labile protecting groups for heterocyclic bases would be desired. In conclusion, these studies indicate that 2'-O-t-BDMSi can be considered as a convenient and safe protecting group, which should secure synthesis of oligoribonucleotides with exclusively 3'–5' internucleotidic linkages.- Published
- 1988
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259. ChemInform Abstract: Studies on Nucleoside Phosphonates and Their Derivatives. A Progress Report
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BOLLMARK, M., KERS, A., KERS, I., SZABO, T., ZAIN, R., STAWINSKI, J., CIESLAK, J., JANKOWSKA, J., and KRASZEWSKI, A.
- Abstract
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
- Published
- 1997
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260. The case of sulfonation in the chemical synthesis of oligonucleotides
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Kraszewski, A., Stawinski, J., and Wiewiórowski, M.
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The sulfonation of nucleosidic component, a side reaction during phosphotriester bond formation, as a function of the reactivity of the condensing agents and the kind of substituents in the starting phosphodiester is discussed. It was found that in the coupling reaction of nucleoside alkyl phosphodiesiers, the degree of sulfonation of the nucleosidic component was very high; while under the same conditions when the aryl group was present in the corresponding phosphodiester, this side reaction practically did not occur.
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- 1980
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261. ChemInform Abstract: Nucleoside H‐Phosphonates. Part 3. Chemical Synthesis of Oligodeoxyribonucleotides by the Hydrogenphosphonate Approach. Nucleoside H‐Phosphonates. Part 4. Automated Solid Phase Synthesis of Oligoribonucleotides by the Hydrogenphosphonate Approach.
- Author
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GAREGG, P. J., LINDH, I., REGBERG, T., STAWINSKI, J., STROEMBERG, R. +, and HENRICHSON, C.
- Abstract
The synthesis of oligodesoxy‐ribonucleotides such as (III) by the hydrogenphosphonate approach is described.
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- 1987
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262. ChemInform Abstract: Nucleotide Analogues Containing the P—F Bond. An Overview of the Synthetic Methods.
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BOLLMARK, M. and STAWINSKI, J.
- Abstract
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
- Published
- 1998
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263. The chemical synthesis of the anticodon loop of an eukaryotic initiator tRNA containing the hypermodified nucleoside N6-/N-threonylcarbonyl/-adenosine/t6A/1
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Adamiak, R.W., Biala, E., Grzéskowiak, K., Kierzek, R., Kraszewski, A., Markiewicz, W.T., Okupniak, J., Stawinski, J., and Wiewiórowski, M.
- Abstract
In this work, the first example of chemical synthesis of oligoribonucleotide containing the hypermodified nucleoside N6-/N-threonylcarbonyl/-adenosine/t6A/ is presented. Synthesis of the heptamer C-C-C-A-U-t6A-A
IX , the sequence of which is related to the anticodon loop of the initiator tRNA from yellow lupine, was achieved by: /i/ phosphotriester block synthesis of suitably protected heptamerVI containing an adenosine unit with a free exo-NH2 group, /ii/ highly effective “one-flask” procedure for the transformation of the free exo-NH2 group of adenosine unit of heptamerVI into a N,N′-disubstituted urea system of t6 A of heptamerVII /hypermodification/, and /iii/ final deprotection ofVIII /32% total yield/ with the use of a new approach for simultaneous hydrogenolysis /Pd0-hydrogen-pyridine/ of the p-nitrobenzyl group and 2,2,2-trichloroethyl groups from carboxyl function of t6A and internucleotide phosphates respectively.- Published
- 1978
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264. Inhibition of protein disulfide isomerase induces differentiation of acute myeloid leukemia cells
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Justyna Chlebowska-Tuz, Olga Sokolowska, Pawel Gaj, Michal Lazniewski, Malgorzata Firczuk, Karolina Borowiec, Hanna Sas-Nowosielska, Malgorzata Bajor, Agata Malinowska, Angelika Muchowicz, Kavita Ramji, Piotr Stawinski, Mateusz Sobczak, Zofia Pilch, Anna Rodziewicz-Lurzynska, Malgorzata Zajac, Krzysztof Giannopoulos, Przemyslaw Juszczynski, Grzegorz W. Basak, Dariusz Plewczynski, Rafal Ploski, Jakub Golab, and Dominika Nowis
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
A cute myeloid leukemia is a malignant disease of immature myeloid cells. Despite significant therapeutic effects of differentiation-inducing agents in some acute myeloid leukemia subtypes, the disease remains incurable in a large fraction of patients. Here we show that SK053, a thioredoxin inhibitor, induces differentiation and cell death of acute myeloid leukemia cells. Considering that thioredoxin knock-down with short hairpin RNA failed to exert antiproliferative effects in one of the acute myeloid leukemia cell lines, we used a biotin affinity probe-labeling approach to identify potential molecular targets for the effects of SK053. Mass spectrometry of proteins precipitated from acute myeloid leukemia cells incubated with biotinylated SK053 used as a bait revealed protein disulfide isomerase as a potential binding partner for the compound. Biochemical, enzymatic and functional assays using fluorescence lifetime imaging confirmed that SK053 binds to and inhibits the activity of protein disulfide isomerase. Protein disulfide isomerase knockdown with short hairpin RNA was associated with inhibition of cell growth, increased CCAAT enhancer-binding protein α levels, and induction of differentiation of HL-60 cells. Molecular dynamics simulation followed by the covalent docking indicated that SK053 binds to the fourth thioredoxin-like domain of protein disulfide isomerase. Differentiation of myeloid precursor cells requires the activity of CCAAT enhancer-binding protein α, the function of which is impaired in acute myeloid leukemia cells through various mechanisms, including translational block by protein disulfide isomerase. SK053 increased the levels of CCAAT enhancer-binding protein α and upregulated mRNA levels for differentiation-associated genes. Finally, SK053 decreased the survival of blasts and increased the percentage of cells expressing the maturation-associated CD11b marker in primary cells isolated from bone marrow or peripheral blood of patients with acute myeloid leukemia. Collectively, these results provide a proof-of-concept that protein disulfide isomerase inhibition has potential as a therapeutic strategy for the treatment of acute myeloid leukemia and for the development of small-molecule inhibitors of protein disulfide isomerase.
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- 2018
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265. Correction: Adenocarcinoma Arising From a Cervical Esophageal Inlet Patch: The Malignant Potential of a Small Lesion.
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Dziadkowiec KN, Sánchez-Luna SA, Stawinski P, Proenza J, and Delaflor-Weiss EP
- Abstract
[This corrects the article DOI: 10.7759/cureus.9284.]., Competing Interests: No competing interests declared., (Copyright © 2022, Dziadkowiec et al.)
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- 2022
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266. Prenatal Diagnosis of Jeune Syndrome Caused by Compound Heterozygous Variants in DYNC2H1 Gene-Case Report with Rapid WES Procedure and Differential Diagnosis of Lethal Skeletal Dysplasias.
- Author
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Stembalska A, Rydzanicz M, Klaniewska M, Dudarewicz L, Pollak A, Biela M, Stawinski P, Ploski R, and Smigiel R
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- Diagnosis, Differential, Ellis-Van Creveld Syndrome, Female, Humans, Mutation, Pregnancy, Exome Sequencing, Cytoplasmic Dyneins genetics, Prenatal Diagnosis
- Abstract
Skeletal dysplasias (SDs) are a large, heterogeneous group of mostly genetic disorders that affect the bones and cartilage, resulting in abnormal growth and development of skeletal structures. The high clinical and genetic diversity in SDs cause difficulties in prenatal diagnosis. To establish a correct prognosis and better management, it is very important to distinguish SDs with poor life-limiting prognosis or lethal SDs from other ones. Bad prognosis in foetuses is assessed on the basis of the size of the thorax, lung volumes, long bones’ length, bones’ echogenicity, bones’ angulation or presented fractures, and the concomitant presence of non-immune hydrops or visceral abnormalities. To confirm SD diagnosis and perform family genetic consultation, rapid molecular diagnostics are needed; therefore, the NGS method using a panel of genes corresponding to SD or whole-exome sequencing (WES) is commonly used. We report a case of a foetus showing long bones’ shortening and a narrow chest with short ribs, diagnosed prenatally with asphyxiating thoracic dystrophy, also known as Jeune syndrome (ATD; OMIM 208500), caused by compound heterozygous variants in the DYNC2H1 gene, identified by prenatally performed rapid-WES analysis. The missense variants in the DYNC2H1 gene were inherited from the mother (c.7289T>C; p.Ile2430Thr) and from the father (c.12716T>G; p.Leu4239Arg). The DYNC2H1 gene is one of at least 17 ATD-associated genes. This disorder belongs to the ninth group of SD, ciliopathies with major skeletal involvement. An extremely narrow, bell-shaped chest, and abnormalities of the kidneys, liver, and retinas were observed in most cases of ATD. Next to lethal and severe forms, clinically mild forms have also been reported. A diagnosis of ATD is important to establish the prognosis and management for the patient, as well as the recurrence risk for the family.
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- 2022
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267. Variants in the pancreatic CUB and zona pellucida-like domains 1 (CUZD1) gene in early-onset chronic pancreatitis - A possible new susceptibility gene.
- Author
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Rygiel AM, Unger LS, Sörgel FL, Masson E, Matsumoto R, Ewers M, Chen JM, Bugert P, Buscail L, Gambin T, Oracz G, Winiewska-Szajewska M, Mianowska A, Poznanski J, Kosińska J, Stawinski P, Płoski R, Koziel D, Gluszek S, Laumen H, Lindgren F, Löhr JM, Orekhova A, Rebours V, Rosendahl J, Párniczky A, Hegyi P, Sasaki A, Kataoka F, Tanaka Y, Hamada S, Sahin-Tóth M, Hegyi E, Férec C, Masamune A, and Witt H
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- Acinar Cells metabolism, Blotting, Western, Genetic Predisposition to Disease, Humans, Membrane Proteins genetics, Pancreatitis, Chronic genetics, Pancreatitis, Chronic pathology, Zona Pellucida metabolism, Zona Pellucida pathology
- Abstract
Objective: Non-alcoholic chronic pancreatitis (NACP) frequently develops in the setting of genetic susceptibility associated with alterations in genes that are highly expressed in the pancreas. However, the genetic basis of NACP remains unresolved in a significant number of patients warranting a search for further risk genes., Design: We analyzed CUZD1, which encodes the CUB and zona pellucida-like domains 1 protein that is found in high levels in pancreatic acinar cells. We sequenced the coding region in 1163 European patients and 2018 European controls. In addition, we analyzed 297 patients and 1070 controls from Japan. We analyzed secretion of wild-type and mutant CUZD1 from transfected cells using Western blotting., Results: In the European cohort, we detected 30 non-synonymous variants. Using different prediction tools (SIFT, CADD, PROVEAN, PredictSNP) or the combination of these tools, we found accumulation of predicted deleterious variants in patients (p-value range 0.002-0.013; OR range 3.1-5.2). No association was found in the Japanese cohort, in which 13 non-synonymous variants were detected. Functional studies revealed >50% reduced secretion of 7 variants, however, these variants were not significantly enriched in European CP patients., Conclusion: Our data indicate that CUZD1 might be a novel susceptibility gene for NACP. How these variants predispose to pancreatitis remains to be elucidated., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2022 IAP and EPC. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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268. Analysis of Mutational Profile of Hypopharyngeal and Laryngeal Head and Neck Squamous Cell Carcinomas Identifies KMT2C as a Potential Tumor Suppressor.
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Machnicki MM, Rzepakowska A, Janowska JI, Pepek M, Krop A, Pruszczyk K, Stawinski P, Rydzanicz M, Grzybowski J, Gornicka B, Wnuk M, Ploski R, Osuch-Wojcikiewicz E, and Stoklosa T
- Abstract
Hypopharyngeal cancer is a poorly characterized type of head and neck squamous cell carcinoma (HNSCC) with bleak prognosis and only few studies focusing specifically on the genomic profile of this type of cancer. We performed molecular profiling of 48 HPV (Human Papilloma Virus)-negative tumor samples including 23 originating from the hypopharynx and 25 from the larynx using a targeted next-generation sequencing approach. Among genes previously described as significantly mutated, TP53, FAT1, NOTCH1, KMT2C , and CDKN2A were found to be most frequently mutated. We also found that more than three-quarters of our patients harbored candidate actionable or prognostic alterations in genes belonging to RTK/ERK/PI3K, cell-cycle, and DNA-damage repair pathways. Using previously published data we compared 67 hypopharyngeal cancers to 595 HNSCC from other sites and found no prominent differences in mutational frequency except for CASP8 and HRAS genes. Since we observed relatively frequent mutations of KTM2C (MLL3) in our dataset, we analyzed their role, in vitro , by generating a KMT2C -mutant hypopharyngeal cancer cell line FaDu with CRISPR-Cas9. We demonstrated that KMT2C loss-of-function mutations resulted in increased colony formation and proliferation, in concordance with previously published results. In summary, our results show that the mutational profile of hypopharyngeal cancers might be similar to the one observed for other head and neck cancers with respect to minor differences and includes multiple candidate actionable and prognostic genetic alterations. We also demonstrated, for the first time, that the KMT2C gene may play a role of tumor suppressor in HNSCC, which opens new possibilities in the search for new targeted treatment approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Machnicki, Rzepakowska, Janowska, Pepek, Krop, Pruszczyk, Stawinski, Rydzanicz, Grzybowski, Gornicka, Wnuk, Ploski, Osuch-Wojcikiewicz and Stoklosa.)
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- 2022
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269. Haloperidol as a treatment option in cannabinoid hyperemesis syndrome.
- Author
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Stawinski P, Dziadkowiec K, Sah A, and Marcus A
- Abstract
Competing Interests: The authors declare no conflict of interest.
- Published
- 2022
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270. Prenatal Versus Postnatal Diagnosis of Meckel-Gruber and Joubert Syndrome in Patients with TMEM67 Mutations.
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Stembalska A, Rydzanicz M, Pollak A, Kostrzewa G, Stawinski P, Biela M, Ploski R, and Smigiel R
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- Abnormalities, Multiple genetics, Ciliary Motility Disorders genetics, Diagnosis, Differential, Encephalocele genetics, Eye Abnormalities genetics, Female, Humans, Kidney Diseases, Cystic genetics, Membrane Proteins metabolism, Mutation, Polycystic Kidney Diseases genetics, Pregnancy, Prenatal Diagnosis methods, Retinitis Pigmentosa genetics, Exome Sequencing methods, Abnormalities, Multiple diagnosis, Cerebellum abnormalities, Ciliary Motility Disorders diagnosis, Encephalocele diagnosis, Eye Abnormalities diagnosis, Kidney Diseases, Cystic diagnosis, Membrane Proteins genetics, Polycystic Kidney Diseases diagnosis, Retina abnormalities, Retinitis Pigmentosa diagnosis
- Abstract
Renal cystic diseases are characterized by genetic and phenotypic heterogeneity. Congenital renal cysts can be classified as developmental disorders and are commonly diagnosed prenatally using ultrasonography and magnetic resonance imaging. Progress in molecular diagnostics and availability of exome sequencing procedures allows diagnosis of single-gene disorders in the prenatal period. Two patients with a prenatal diagnosis of polycystic kidney disease are presented in this article. TMEM67 mutations were identified in both fetuses using a whole-exome sequencing (WES) study. In one of them, the phenotypic syndrome diagnosed prenatally was different from that diagnosed in the postnatal period.
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- 2021
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271. COVID-19-Induced Colitis: A Novel Relationship During Troubling Times.
- Author
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Stawinski P, Dziadkowiec KN, and Marcus A
- Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the resulting disease called coronavirus disease 2019 (COVID-19) has initiated a global health crisis declared by the World Health Organization (WHO). As the nature of this novel virus unfolds, there have been a variety of extra-pulmonary clinical presentations of COVID-19 affecting the gastrointestinal tract. We present a novel relationship between this disease and its clinical manifestation as COVID-19-induced colitis. Providing insight into this association will invariably facilitate earlier recognition and resultant treatment of COVID-19 along with reducing unintended exposure to healthcare workers., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Stawinski et al.)
- Published
- 2021
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272. Phenotypic expansion in Zhu-Tokita-Takenouchi-Kim syndrome caused by de novo variants in the SON gene.
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Slezak R, Smigiel R, Rydzanicz M, Pollak A, Kosinska J, Stawinski P, Malgorzata Sasiadek M, and Ploski R
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- Abnormalities, Multiple pathology, Child, Preschool, Developmental Disabilities pathology, Frameshift Mutation, Heterozygote, Humans, Intellectual Disability pathology, Male, Syndrome, Abnormalities, Multiple genetics, DNA-Binding Proteins genetics, Developmental Disabilities genetics, Intellectual Disability genetics, Minor Histocompatibility Antigens genetics, Phenotype
- Abstract
Background: The genetic etiology of intellectual and psychomotor disability without a defined spectrum of dysmorphic features is usually monogenic. As no diagnostic criteria for such diseases are established, the clinical diagnosis becomes to be a challenge. The object of our paper is to present two patients with non-specific clinical symptoms for whom whole-exome-sequencing identified the new SON mutations and thus allowed for establishing the diagnosis of Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome. In both patients, the same symptoms including hypotonia, developmental and speech delay, feeding difficulties as well as frequent infections of the respiratory tract and internal ear were observed. However, both cases presented also with exceptional symptoms such as in case 1 ventriculomegaly and asymmetry of ventricles, hypoplastic left heart syndrome (HLHS), intellectual disability, intestinal malrotation, gastroparesis, and duodenal atresia and in the case 2 febrile seizures and reduced IgA levels. We will be presenting the patients and comparing them to 30 previously described cases., Methods: Whole-exome sequencing (WES) was performed on the probands' DNA and paired-end sequenced (2x100 bp) on HiSeq 1500. Variants considered as disease-causing were validated in the proband and studied in all available family members by amplicon deep sequencing performed using Nextera XT Kit and sequenced on HiSeq 1500., Results: We have identified two new variants in SON gene. In case 1 it has been a heterozygous frameshift variant p.(Ala1340GlnfsTer26), while in case 2 it has been a heterozygous frameshift variant, p.(Asp1640GlyfsTer7). Both variants are described for the first time and up to now, are not mentioned in any database., Conclusion: As there are no precise criteria established for the clinical diagnosis of ZTTK, an identification of SON gene mutation by whole-exome-sequencing is the best method that allows for a diagnosis of this syndrome., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)
- Published
- 2020
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273. Gastrointestinal Stromal Tumor (GIST) Causing Obscure Gastrointestinal Bleeding: An Uncommon Way of Diagnosing An Uncommon Disease.
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Dziadkowiec KN, Stawinski P, Sánchez-Luna SA, and Katz A
- Abstract
Gastrointestinal stromal tumors (GISTs) are neoplasms that arise from the wall of the gastrointestinal tract or, rarely, from other intra-abdominal tissues. They are the most common mesenchymal tumors of the gastrointestinal tract and they should be considered in the differential diagnosis of obscure gastrointestinal bleeding. Computed tomography angiogram (CTA) can be utilized as an alternative imaging study when endoscopic and colonoscopy results are non-diagnostic. We report a case of a 59-year-old woman who presented with recurrent episodes of obscure overt gastrointestinal bleeding secondary to a gastrointestinal stromal tumor (GIST)., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Dziadkowiec et al.)
- Published
- 2020
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274. Is Multiple Sclerosis an Extra-Intestinal Manifestation of Inflammatory Bowel Disease? Food for Thought.
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Dziadkowiec KN, Stawinski P, Radadiya D, Al Abbasi B, and Isaac S
- Abstract
For many years there has been a suggested association between multiple sclerosis (MS) and inflammatory bowel disease (IBD). Aside from their common epidemiological and immunological similarities, there appears to be an association between the incidence of both diseases coexisting. We report a case of a 41-year-old man with chronic diarrhea and weakness, who was found to have concomitant MS and Crohn's Disease. Our report underscores the importance clinicians of maintaining a high degree of suspicion about the potential association of these conditions among these patient populations., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Dziadkowiec et al.)
- Published
- 2020
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275. Adenocarcinoma Arising From a Cervical Esophageal Inlet Patch: The Malignant Potential of a Small Lesion.
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Dziadkowiec KN, Sánchez-Luna SA, Stawinski P, and Proenza J
- Abstract
Inlet patches (IP) are heterotopic lesions consisting of gastric mucosa. Commonly located in the cervical esophagus, it is believed that they are remnants of fetal columnar epithelium arising from incomplete replacement during embryogenesis. A rare complication of IP is the development of proximal esophageal adenocarcinoma. We report a case of a 59-year-old male with intractable cough and dysphagia that was found to have a malignant transformation of an IP., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Dziadkowiec et al.)
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- 2020
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276. Analysis of De Novo Mutations in Sporadic Cardiomyopathies Emphasizes Their Clinical Relevance and Points to Novel Candidate Genes.
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Franaszczyk M, Truszkowska G, Chmielewski P, Rydzanicz M, Kosinska J, Rywik T, Biernacka A, Spiewak M, Kostrzewa G, Stepien-Wojno M, Stawinski P, Bilinska M, Krajewski P, Zielinski T, Lutynska A, Bilinska ZT, and Ploski R
- Abstract
The vast majority of cardiomyopathies have an autosomal dominant inheritance; hence, genetic testing is typically offered to patients with a positive family history. A de novo mutation is a new germline mutation not inherited from either parent. The purpose of our study was to search for de novo mutations in patients with cardiomyopathy and no evidence of the disease in the family. Using next-generation sequencing, we analyzed cardiomyopathy genes in 12 probands. In 8 (66.7%), we found de novo variants in known cardiomyopathy genes ( TTN , DSP , SCN5A , TNNC1 , TPM1 , CRYAB , MYH7 ). In the remaining probands, the analysis was extended to whole exome sequencing in a trio (proband and parents). We found de novo variants in genes that, so far, were not associated with any disease ( TRIB3 , SLC2A6 ), a possible disease-causing biallelic genotype ( APOBEC gene family), and a de novo mosaic variant without strong evidence of pathogenicity ( UNC45A ). The high prevalence of de novo mutations emphasizes that genetic screening is also indicated in cases of sporadic cardiomyopathy. Moreover, we have identified novel cardiomyopathy candidate genes that are likely to affect immunological function and/or reaction to stress that could be especially relevant in patients with disease onset associated with infection/infestation., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript or in the decision to publish the results.
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- 2020
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277. Changing facial features in a child with GAPO syndrome caused by novel mutation in the ANTXR1 gene and uniparental disomy of chromosome 2.
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Smigiel R, Rozensztrauch A, Walczak A, Rydzanicz M, Stawinski P, Berghausen-Mazur M, Kostrzewa G, Sasiadek M, and Ploski R
- Subjects
- Alleles, Child, Chromosomes, Human, Pair 2 genetics, Genetic Testing, Genotype, Humans, Exome Sequencing, Alopecia diagnosis, Alopecia genetics, Anodontia diagnosis, Anodontia genetics, Facies, Growth Disorders diagnosis, Growth Disorders genetics, Microfilament Proteins genetics, Mutation, Optic Atrophies, Hereditary diagnosis, Optic Atrophies, Hereditary genetics, Phenotype, Receptors, Cell Surface genetics, Uniparental Disomy genetics
- Published
- 2019
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278. A study in a Polish ataxia cohort indicates genetic heterogeneity and points to MTCL1 as a novel candidate gene.
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Krygier M, Kwarciany M, Wasilewska K, Pienkowski VM, Krawczyńska N, Zielonka D, Kosińska J, Stawinski P, Rudzińska-Bar M, Boczarska-Jedynak M, Karaszewski B, Limon J, Sławek J, Płoski R, and Rydzanicz M
- Subjects
- Age of Onset, Alleles, Child, Child, Preschool, Female, Gene Frequency, Genetic Testing, Genotype, Humans, Infant, Magnetic Resonance Imaging, Male, Poland, Ataxia diagnosis, Ataxia genetics, Genetic Heterogeneity, Microtubule-Associated Proteins genetics, Mutation, Phenotype
- Abstract
Inherited ataxias are a group of highly heterogeneous, complex neurological disorders representing a significant diagnostic challenge in clinical practice. We performed a next-generation sequencing (NGS) analysis in 10 index cases with unexplained progressive cerebellar ataxia of suspected autosomal recessive inheritance. A definite molecular diagnosis was obtained in 5/10 families and included the following diseases: autosomal recessive spastic ataxia of Charlevoix-Saguenay, POLR3B-related hypomyelinating leukodystrophy, primary coenzyme Q10 deficiency type 4, Niemann-Pick disease type C1 and SYNE1-related ataxia. In addition, we found a novel homozygous MTCL1 loss of function variant p.(Lys407fs) in a 23-year-old patient with slowly progressive cerebellar ataxia, mild intellectual disability, seizures in childhood and episodic pain in the lower limbs. The identified variant is predicted to truncate the protein after first 444 of 1586 amino acids. MTCL1 encodes a microtubule-associated protein highly expressed in cerebellar Purkinje cells; its knockout in a mouse model causes ataxia. We propose MTCL1 as a candidate gene for autosomal recessive cerebellar ataxia in humans. In addition, our study confirms the high diagnostic yield of NGS in early-onset cerebellar ataxias, with at least 50% detection rate in our ataxia cohort., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2019
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279. A Novel Monoallelic Nonsense Mutation in the NFKB2 Gene Does Not Cause a Clinical Manifestation.
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Kotlinowski J, Bukowska-Strakova K, Koppolu A, Kosińska J, Pydyn N, Stawinski P, Wilamowski M, Nowak W, Józkowicz A, Baran J, Płoski R, and Jura J
- Abstract
NF-κB signaling, acting through NFKB1 dependent canonical and NFKB2 dependent non-canonical pathways plays a critical role in inflammatory and immune responses. Recent studies have associated mutations in these two genes with a common variable immunodeficiency (CVID). While evaluating a female patient seeking a diagnosis explaining her recurrent infections, we found a novel heterozygous c.1831C > T (p.Arg611
∗ ) nonsense mutation in the NFKB2 gene which introduces a Stop codon in the ankyrin repeat domain of p100. Whole exome sequencing (WES) analysis, followed by Sanger sequencing, identified this previously unknown mutation in two other family members. Penetrance of the c.1831C > T variant was assessed by flow-cytometry and protein expression in peripheral blood mononuclear cells (PBMC); whereas, activation of the NF-κB2 signaling pathway was examined through immunoblotting and real-time PCR. Heterozygous c.1831C > T variant led to the expansion of lymphocyte B subpopulations with concomitant reduction of plasmablasts, low IgG levels, and accumulation of p52 in PBMC. On the other hand, tested subjects had normal levels of IgM, IgA, IgE and no impairment in lymphocytes proliferation. Although evaluated patients did not fulfill all clinical features of CVID, their health should be monitored in the future for possible late manifestation of the disease. In conclusion, we showed that NFKB2 haplodeficiency caused by c.1831C > T nonsense mutation is asymptomatic, possibly due to the compensatory mechanisms and allele redundancy.- Published
- 2019
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280. Homozygous mutation in the Neurofascin gene affecting the glial isoform of Neurofascin causes severe neurodevelopment disorder with hypotonia, amimia and areflexia.
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Smigiel R, Sherman DL, Rydzanicz M, Walczak A, Mikolajkow D, Krolak-Olejnik B, Kosinska J, Gasperowicz P, Biernacka A, Stawinski P, Marciniak M, Andrzejewski W, Boczar M, Krajewski P, Sasiadek MM, Brophy PJ, and Ploski R
- Subjects
- Animals, Conditioning, Psychological, DNA Mutational Analysis, Female, Homozygote, Humans, Infant, Intercellular Junctions genetics, Mice, Muscle Hypotonia metabolism, Nervous System Diseases metabolism, Poland, Protein Isoforms, Syndrome, Cell Adhesion Molecules genetics, Intercellular Junctions metabolism, Muscle Hypotonia genetics, Mutation, Nerve Growth Factors genetics, Nervous System Diseases genetics, Neuroglia metabolism
- Abstract
The Neurofascins (NFASCs) are a family of proteins encoded by alternative transcripts of NFASC that cooperate in the assembly of the node of Ranvier in myelinated nerves. Differential expression of NFASC in neurons and glia presents a remarkable example of cell-type specific expression of protein isoforms with a common overall function. In mice there are three NFASC isoforms: Nfasc186 and Nfasc140, located in the axonal membrane at the node of Ranvier, and Nfasc155, a glial component of the paranodal axoglial junction. Nfasc186 and Nfasc155 are the major isoforms at mature nodes and paranodes, respectively. Conditional deletion of the glial isoform Nfasc155 in mice causes severe motor coordination defects and death at 16-17 days after birth. We describe a proband with severe congenital hypotonia, contractures of fingers and toes, and no reaction to touch or pain. Whole exome sequencing revealed a homozygous NFASC variant chr1:204953187-C>T (rs755160624). The variant creates a premature stop codon in 3 out of four NFASC human transcripts and is predicted to specifically eliminate Nfasc155 leaving neuronal Neurofascin intact. The selective absence of Nfasc155 and disruption of the paranodal junction was confirmed by an immunofluorescent study of skin biopsies from the patient versus control. We propose that the disease in our proband is the first reported example of genetic deficiency of glial Neurofascin isoforms in humans and that the severity of the condition reflects the importance of the Nfasc155 in forming paranodal axoglial junctions and in determining the structure and function of the node of Ranvier.
- Published
- 2018
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281. Inhibition of protein disulfide isomerase induces differentiation of acute myeloid leukemia cells.
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Chlebowska-Tuz J, Sokolowska O, Gaj P, Lazniewski M, Firczuk M, Borowiec K, Sas-Nowosielska H, Bajor M, Malinowska A, Muchowicz A, Ramji K, Stawinski P, Sobczak M, Pilch Z, Rodziewicz-Lurzynska A, Zajac M, Giannopoulos K, Juszczynski P, Basak GW, Plewczynski D, Ploski R, Golab J, and Nowis D
- Subjects
- Female, HL-60 Cells, Humans, Leukemia, Myeloid, Acute enzymology, Leukemia, Myeloid, Acute pathology, Male, Neoplasm Proteins metabolism, Protein Disulfide-Isomerases metabolism, Cell Differentiation drug effects, Dipeptides pharmacology, Enzyme Inhibitors pharmacology, Leukemia, Myeloid, Acute drug therapy, Methacrylates pharmacology, Neoplasm Proteins antagonists & inhibitors, Protein Disulfide-Isomerases antagonists & inhibitors
- Abstract
A cute myeloid leukemia is a malignant disease of immature myeloid cells. Despite significant therapeutic effects of differentiation-inducing agents in some acute myeloid leukemia subtypes, the disease remains incurable in a large fraction of patients. Here we show that SK053, a thioredoxin inhibitor, induces differentiation and cell death of acute myeloid leukemia cells. Considering that thioredoxin knock-down with short hairpin RNA failed to exert antiproliferative effects in one of the acute myeloid leukemia cell lines, we used a biotin affinity probe-labeling approach to identify potential molecular targets for the effects of SK053. Mass spectrometry of proteins precipitated from acute myeloid leukemia cells incubated with biotinylated SK053 used as a bait revealed protein disulfide isomerase as a potential binding partner for the compound. Biochemical, enzymatic and functional assays using fluorescence lifetime imaging confirmed that SK053 binds to and inhibits the activity of protein disulfide isomerase. Protein disulfide isomerase knockdown with short hairpin RNA was associated with inhibition of cell growth, increased CCAAT enhancer-binding protein α levels, and induction of differentiation of HL-60 cells. Molecular dynamics simulation followed by the covalent docking indicated that SK053 binds to the fourth thioredoxin-like domain of protein disulfide isomerase. Differentiation of myeloid precursor cells requires the activity of CCAAT enhancer-binding protein α, the function of which is impaired in acute myeloid leukemia cells through various mechanisms, including translational block by protein disulfide isomerase. SK053 increased the levels of CCAAT enhancer-binding protein α and upregulated mRNA levels for differentiation-associated genes. Finally, SK053 decreased the survival of blasts and increased the percentage of cells expressing the maturation-associated CD11b marker in primary cells isolated from bone marrow or peripheral blood of patients with acute myeloid leukemia. Collectively, these results provide a proof-of-concept that protein disulfide isomerase inhibition has potential as a therapeutic strategy for the treatment of acute myeloid leukemia and for the development of small-molecule inhibitors of protein disulfide isomerase., (Copyright© 2018 Ferrata Storti Foundation.)
- Published
- 2018
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282. FRMPD4 mutations cause X-linked intellectual disability and disrupt dendritic spine morphogenesis.
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Piard J, Hu JH, Campeau PM, Rzonca S, Van Esch H, Vincent E, Han M, Rossignol E, Castaneda J, Chelly J, Skinner C, Kalscheuer VM, Wang R, Lemyre E, Kosinska J, Stawinski P, Bal J, Hoffman DA, Schwartz CE, Van Maldergem L, Wang T, and Worley PF
- Subjects
- Adolescent, Adult, Aged, Exons genetics, Female, Frameshift Mutation genetics, Humans, Male, Middle Aged, Morphogenesis genetics, Morphogenesis physiology, Mutation genetics, Neurogenesis genetics, Neurogenesis physiology, Pedigree, Young Adult, Dendritic Spines metabolism, Intellectual Disability genetics, Intracellular Signaling Peptides and Proteins genetics
- Abstract
FRMPD4 (FERM and PDZ Domain Containing 4) is a neural scaffolding protein that interacts with PSD-95 to positively regulate dendritic spine morphogenesis, and with mGluR1/5 and Homer to regulate mGluR1/5 signaling. We report the genetic and functional characterization of 4 FRMPD4 deleterious mutations that cause a new X-linked intellectual disability (ID) syndrome. These mutations were found to be associated with ID in ten affected male patients from four unrelated families, following an apparent X-linked mode of inheritance. Mutations include deletion of an entire coding exon, a nonsense mutation, a frame-shift mutation resulting in premature termination of translation, and a missense mutation involving a highly conserved amino acid residue neighboring FRMPD4-FERM domain. Clinical features of these patients consisted of moderate to severe ID, language delay and seizures alongside with behavioral and/or psychiatric disturbances. In-depth functional studies showed that a frame-shift mutation, FRMPD4p.Cys618ValfsX8, results in a disruption of FRMPD4 binding with PSD-95 and HOMER1, and a failure to increase spine density in transfected hippocampal neurons. Behavioral studies of frmpd4-KO mice identified hippocampus-dependent spatial learning and memory deficits in Morris Water Maze test. These findings point to an important role of FRMPD4 in normal cognitive development and function in humans and mice, and support the hypothesis that FRMPD4 mutations cause ID by disrupting dendritic spine morphogenesis in glutamatergic neurons., (© The Author(s) 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2018
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283. Coexistence of mutations in keratin 10 (KRT10) and the mitochondrial genome in a patient with ichthyosis with confetti and Leber's hereditary optic neuropathy.
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Kalinska-Bienias A, Pollak A, Kowalewski C, Lechowicz U, Stawinski P, Gergont A, Kosinska J, Pronicka E, Kowalski P, Wozniak K, and Ploski R
- Subjects
- Adolescent, Genetic Predisposition to Disease, Humans, Ichthyosis pathology, Infant, Newborn, Intellectual Disability genetics, Intellectual Disability pathology, Male, Mutation, Optic Atrophy, Hereditary, Leber pathology, Phenotype, Genome, Mitochondrial genetics, Ichthyosis genetics, Keratin-10 genetics, Optic Atrophy, Hereditary, Leber genetics
- Abstract
Ichthyosis with confetti (IWC) is a severe congenital genodermatosis characterized by ichthyosiform erythroderma since birth and confetti-like spots of normal skin appearing in childhood as a results of revertant mosaicism. This disorder is caused by mutations in KRT10 or KRT1 genes. We report a 16-year-old boy who presented ichthyosiform erythroderma with severe desquamation since birth and gradually worsening psycho-neurological symptoms (mental retardation, ataxia, dystonia, hypoacusis). The patient conspicuously lacked typical confetti-like spots at the age of 16. The molecular diagnostics by the whole exome sequencing showed a novel de novo (c.1374-2A>C) mutation in the KRT10 gene responsible for the development of IWC (KRT10 defect was confirmed by immunofluorescent study). Concurrently, the m.14484T>C mutation in mitochondrial MTND6 gene (characteristic for Leber's hereditary optic neuropathy or LHON) was detected in patient, his mother and brother. LHON causes frequent inherited blindness typically appearing during young adult life whose expression can be triggered by additional factors such as smoking or alcohol exposure. We speculate the effects of KRT10 and LHON mutations influence each other-skin inflammatory reaction due to severe ichthyosis might trigger the development of psychoneurological abnormalities whereas the mitochondrial mutation may reduce revertant mosaicism phenomenon resulting in the lack of confetti-like spots characteristic for IWC. However, based on a single case we should be cautious about attributing phenotypes to digenic mechanisms without functional data., (© 2017 Wiley Periodicals, Inc.)
- Published
- 2017
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284. Iterative Sequencing and Variant Screening (ISVS) as a novel pathogenic mutations search strategy - application for TMPRSS3 mutations screen.
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Lechowicz U, Gambin T, Pollak A, Podgorska A, Stawinski P, Franke A, Petersen BS, Firczuk M, Oldak M, Skarzynski H, and Ploski R
- Subjects
- Chromosome Disorders diagnosis, Chromosome Disorders pathology, Cohort Studies, Female, Gene Expression, Genes, Recessive, Genetic Testing methods, Hearing Loss, Sensorineural diagnosis, Hearing Loss, Sensorineural pathology, High-Throughput Nucleotide Sequencing, Humans, Male, Poland, Sequence Analysis, DNA, Chromosome Disorders genetics, Hearing Loss, Sensorineural genetics, Membrane Proteins genetics, Mutation, Neoplasm Proteins genetics, Serine Endopeptidases genetics, Software
- Abstract
Autosomal recessive diseases (ARD) are typically caused by a limited number of mutations whose identification is challenged by their low prevalence. Our purpose was to develop a novel approach allowing an efficient search for mutations causing ARD and evaluation of their pathogenicity without a control group. We developed Iterative Sequencing and Variant Screening (ISVS) approach based on iterative cycles of gene sequencing and mutation screening, and ISVS Simulator software ( http://zsibio.ii.pw.edu.pl/shiny/isvs/ ) for assessment of detected variants' significance. As shown by simulations, ISVS efficiently identifies and correctly classifies pathogenic mutations except for cases where the gene of interest has extremely high number of low frequency nonpathogenic variants. By applying ISVS, we found 4 known and 9 novel (p.C73Y, p.S124L, p.C194Mfs*17, c.782 + 2 T > A, c.953-5 A > G, p.L325Q, p.D334Mfs*24, p.R436G, p.M448T) TMPRSS3 variants among deaf patients. For 3 known and 5 novel variants the disease association was supported by ISVS Simulator odds >90:1. Pathogenicity of 6 novel mutations has been supported by in-silico predictions of variants' deleteriousness. By directly comparing variant prevalence in patients and controls, disease association was demonstrated only for two variants and it was relatively weak (P < 0.05). Summarizing, ISVS strategy and ISVS Simulator are useful for detection of genetic variants causing AR diseases.
- Published
- 2017
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285. Titin Truncating Variants in Dilated Cardiomyopathy - Prevalence and Genotype-Phenotype Correlations.
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Franaszczyk M, Chmielewski P, Truszkowska G, Stawinski P, Michalak E, Rydzanicz M, Sobieszczanska-Malek M, Pollak A, Szczygieł J, Kosinska J, Parulski A, Stoklosa T, Tarnowska A, Machnicki MM, Foss-Nieradko B, Szperl M, Sioma A, Kusmierczyk M, Grzybowski J, Zielinski T, Ploski R, and Bilinska ZT
- Subjects
- Adult, Cohort Studies, Female, Heterozygote, Humans, Kaplan-Meier Estimate, Male, Penetrance, Prevalence, RNA, Messenger genetics, RNA, Messenger metabolism, Cardiomyopathy, Dilated genetics, Connectin genetics, Genetic Association Studies, Mutation genetics
- Abstract
TTN gene truncating variants are common in dilated cardiomyopathy (DCM), although data on their clinical significance is still limited. We sought to examine the frequency of truncating variants in TTN in patients with DCM, including familial DCM (FDCM), and to look for genotype-phenotype correlations. Clinical cardiovascular data, family histories and blood samples were collected from 72 DCM probands, mean age of 34 years, 45.8% FDCM. DNA samples were examined by next generation sequencing (NGS) with a focus on the TTN gene. Truncating mutations were followed up by segregation study among family members. We identified 16 TTN truncating variants (TTN trunc) in 17 probands (23.6% of all cases, 30.3% of FDCM, 17.9% of sporadic DCM). During mean 63 months from diagnosis, there was no difference in adverse cardiac events between probands with and without TTN truncating mutations. Among relatives 29 mutation carriers were identified, nine were definitely affected (31%), eight probably affected (27.6%) one possibly affected (3.4%) and eleven were not affected (37.9%). When relatives with all affected statuses were combined, disease penetrance was still incomplete (62.1%) even after exclusion of unaffected relatives under 40 (82%) and was higher in males versus females. In all mutation carriers, during follow-up, 17.4% had major adverse cardiac events, and prognosis was significantly worse in men than in women. In conclusion, TTN truncating variants were observed in nearly one fourth of young DCM patient population, in vast majority without conduction system disease. Incomplete penetrance suggests possible influence of other genetic and/or environmental factors on the course of cardiotitinopathy. Counseling should take into account sex and incomplete penetrance., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2017
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286. Evidence for troponin C (TNNC1) as a gene for autosomal recessive restrictive cardiomyopathy with fatal outcome in infancy.
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Ploski R, Rydzanicz M, Ksiazczyk TM, Franaszczyk M, Pollak A, Kosinska J, Michalak E, Stawinski P, Ziolkowska L, Bilinska ZT, and Werner B
- Subjects
- Alleles, Electrocardiography, Fatal Outcome, Female, Genetic Association Studies, Genotype, Heart Function Tests, Humans, Infant, Magnetic Resonance Imaging, Phenotype, Radiography, Thoracic, Cardiomyopathy, Restrictive diagnosis, Cardiomyopathy, Restrictive genetics, Genes, Recessive, Mutation, Troponin C genetics
- Abstract
Restrictive cardiomyopathy is a rare form of pediatric cardiac disease, for which the known genes include MYH7, TNNT2, TNNI3, ACTC1, and DES. We describe a pediatric proband with fatal restrictive cardiomyopathy associated with septal hypertrophy and compound heterozygosity for TNNC1 mutations (NM_003280: p.A8V [c.C23T] and p.D145E [c.C435A]). This association between restrictive cardiomyopathy and TNNC1 mutations was strengthened by prospective observations on the second pregnancy in the family which revealed, in the presence of the same TNNC1 genotype, prenatally diagnosed hypertrophic cardiomyopathy which evolved into restrictive cardiomyopathy, heart failure and death at the age of 9 months. Contrary to previous reports, family and population analyses showed that each of the TNNC1 variants was not pathogenic when present alone. Our results (i) confirm that genetic backgrounds of hypertrophic cardiomyopathy and restrictive cardiomyopathy overlap and (ii) indicate that TNNC1 is a likely novel gene for autosomal recessive restrictive cardiomyopathy. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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287. Further evidence for GRIN2B mutation as the cause of severe epileptic encephalopathy.
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Smigiel R, Kostrzewa G, Kosinska J, Pollak A, Stawinski P, Szmida E, Bloch M, Szymanska K, Karpinski P, Sasiadek MM, and Ploski R
- Subjects
- Biomarkers, Child, Chromosome Deletion, Chromosomes, Human, Pair 4, Comparative Genomic Hybridization, DNA Mutational Analysis, Electroencephalography, Exome, High-Throughput Nucleotide Sequencing, Humans, Magnetic Resonance Imaging, Male, Neuroimaging, Physical Examination, RNA Splice Sites, Epilepsy diagnosis, Epilepsy genetics, Genetic Association Studies, Mutation, Phenotype, Receptors, N-Methyl-D-Aspartate genetics
- Abstract
Epileptic encephalopathies (EE) include a range of severe epilepsies in which intractable seizures or severe sub-clinical epileptiform activity are accompanied by impairment of motor and cognitive functions. Mutations in several genes including ion channels and other genes whose function is not completely understood have been associated to some EE. In this report, we provide a detailed clinical description of a sporadic male patient with early-onset epilepsy and epileptic encephalopathy in whom we performed complete exome sequencing (WES) and identified a GRIN2B mutation. The GRIN2B splicing mutation in intron 10 (c.2011-1G>A) was revealed in a WES study. The result was confirmed by Sanger sequencing. No mutation was found in both parents. Our finding confirms that early-onset EE may be caused not only by gain-of-function variants but also by splice site mutations-in particular those affecting the splice acceptor site of the 10th intron of the GRIN2B gene. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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288. Biallelic Mutations of VAC14 in Pediatric-Onset Neurological Disease.
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Lenk GM, Szymanska K, Debska-Vielhaber G, Rydzanicz M, Walczak A, Bekiesinska-Figatowska M, Vielhaber S, Hallmann K, Stawinski P, Buehring S, Hsu DA, Kunz WS, Meisler MH, and Ploski R
- Subjects
- Age of Onset, Amino Acid Sequence, Child, Child, Preschool, Exome genetics, Exons genetics, Female, Genes, Recessive, Heterozygote, Humans, Infant, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins chemistry, Mutation, Missense genetics, Pedigree, Alleles, Membrane Proteins genetics, Mutation, Nervous System Diseases genetics
- Abstract
In the PI(3,5)P2 biosynthetic complex, the lipid kinase PIKFYVE and the phosphatase FIG4 are bound to the dimeric scaffold protein VAC14, which is composed of multiple heat-repeat domains. Mutations of FIG4 result in the inherited disorders Charcot-Marie-Tooth disease type 4J, Yunis-Varón syndrome, and polymicrogyria with seizures. We here describe inherited variants of VAC14 in two unrelated children with sudden onset of a progressive neurological disorder and regression of developmental milestones. Both children developed impaired movement with dystonia, became nonambulatory and nonverbal, and exhibited striatal abnormalities on MRI. A diagnosis of Leigh syndrome was rejected due to normal lactate profiles. Exome sequencing identified biallelic variants of VAC14 that were inherited from unaffected heterozygous parents in both families. Proband 1 inherited a splice-site variant that results in skipping of exon 13, p.Ile459Profs(∗)4 (not reported in public databases), and the missense variant p.Trp424Leu (reported in the ExAC database in a single heterozygote). Proband 2 inherited two missense variants in the dimerization domain of VAC14, p.Ala582Ser and p.Ser583Leu, that have not been previously reported. Cultured skin fibroblasts exhibited the accumulation of vacuoles that is characteristic of PI(3,5)P2 deficiency. Vacuolization of fibroblasts was rescued by transfection of wild-type VAC14 cDNA. The similar age of onset and neurological decline in the two unrelated children define a recessive disorder resulting from compound heterozygosity for deleterious variants of VAC14., (Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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289. New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.
- Author
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Pronicka E, Piekutowska-Abramczuk D, Ciara E, Trubicka J, Rokicki D, Karkucińska-Więckowska A, Pajdowska M, Jurkiewicz E, Halat P, Kosińska J, Pollak A, Rydzanicz M, Stawinski P, Pronicki M, Krajewska-Walasek M, and Płoski R
- Subjects
- Biopsy, Child, Child, Preschool, DNA, Mitochondrial genetics, Female, Humans, Infant, Infant, Newborn, Male, Metabolism, Inborn Errors genetics, Muscles pathology, Mutation genetics, Pedigree, Exome genetics, Mitochondrial Diseases diagnosis, Mitochondrial Diseases genetics, Pediatrics, Sequence Analysis, DNA methods
- Abstract
Background: Whole-exome sequencing (WES) has led to an exponential increase in identification of causative variants in mitochondrial disorders (MD)., Methods: We performed WES in 113 MD suspected patients from Polish paediatric reference centre, in whom routine testing failed to identify a molecular defect. WES was performed using TruSeqExome enrichment, followed by variant prioritization, validation by Sanger sequencing, and segregation with the disease phenotype in the family., Results: Likely causative mutations were identified in 67 (59.3 %) patients; these included variants in mtDNA (6 patients) and nDNA: X-linked (9 patients), autosomal dominant (5 patients), and autosomal recessive (47 patients, 11 homozygotes). Novel variants accounted for 50.5 % (50/99) of all detected changes. In 47 patients, changes in 31 MD-related genes (ACAD9, ADCK3, AIFM1, CLPB, COX10, DLD, EARS2, FBXL4, MTATP6, MTFMT, MTND1, MTND3, MTND5, NAXE, NDUFS6, NDUFS7, NDUFV1, OPA1, PARS2, PC, PDHA1, POLG, RARS2, RRM2B, SCO2, SERAC1, SLC19A3, SLC25A12, TAZ, TMEM126B, VARS2) were identified. The ACAD9, CLPB, FBXL4, PDHA1 genes recurred more than twice suggesting higher general/ethnic prevalence. In 19 cases, variants in 18 non-MD related genes (ADAR, CACNA1A, CDKL5, CLN3, CPS1, DMD, DYSF, GBE1, GFAP, HSD17B4, MECP2, MYBPC3, PEX5, PGAP2, PIGN, PRF1, SBDS, SCN2A) were found. The percentage of positive WES results rose gradually with increasing probability of MD according to the Mitochondrial Disease Criteria (MDC) scale (from 36 to 90 % for low and high probability, respectively). The percentage of detected MD-related genes compared with non MD-related genes also grew with the increasing MD likelihood (from 20 to 97 %). Molecular diagnosis was established in 30/47 (63.8 %) neonates and in 17/28 (60.7 %) patients with basal ganglia involvement. Mutations in CLPB, SERAC1, TAZ genes were identified in neonates with 3-methylglutaconic aciduria (3-MGA) as a discriminative feature. New MD-related candidate gene (NDUFB8) is under verification., Conclusions: We suggest WES rather than targeted NGS as the method of choice in diagnostics of MD in children, including neonates with 3-MGA aciduria, who died without determination of disease cause and with limited availability of laboratory data. There is a strong correlation between the degree of MD diagnosis by WES and MD likelihood expressed by the MDC scale.
- Published
- 2016
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290. Exome sequencing reveals mutations in MFN2 and GDAP1 in severe Charcot-Marie-Tooth disease.
- Author
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Kostera-Pruszczyk A, Kosinska J, Pollak A, Stawinski P, Walczak A, Wasilewska K, Potulska-Chromik A, Szczudlik P, Kaminska A, and Ploski R
- Subjects
- Child, Preschool, Exome, Grandparents, Humans, Male, Mothers, Mutation, Severity of Illness Index, Charcot-Marie-Tooth Disease genetics, GTP Phosphohydrolases genetics, Mitochondrial Proteins genetics, Nerve Tissue Proteins genetics
- Abstract
The aim of our study was to characterize electrophysiologically and explain the genetic cause of severe Charcot-Marie-Tooth (CMT) in a 3.5-year-old with asymptomatic parents and a maternal grandfather with a history of mild adult-onset axonal neuropathy. Severity of neuropathy was assessed by Charcot-Marie-Tooth neuropathy score (CMTNS). Whole-exome sequencing was performed using an Illumina TruSeq Exome Enrichment Kit on the HiSeq 1500 with results followed up by Sanger sequencing on an ABI Prism 3500XL (Applied Biosystems, Foster City, CA, USA). Paternity was confirmed using a panel of 15 hypervariable markers. Electrophysiological studies demonstrated severe axonal sensory-motor neuropathy in the proband, mild motor neuropathy in his mother, and mild sensory-motor neuropathy in his grandfather. CMTNS in the proband, his mother, and grandfather was 21, 1, and 12, respectively. On genetic analysis, the boy was found to carry a heterozygous dominant MFN2 T236M mutation transmitted via the maternal line and a de novo GDAP1 H123R mutation. Our findings emphasize the need to search for more than one causative mutation when significant intrafamilial variability of CMT phenotype occurs and underline the role of whole-exome sequencing in the diagnosis of compound forms of CMT disease., (© 2014 Peripheral Nerve Society.)
- Published
- 2014
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291. Does p.Q247X in TRIM63 cause human hypertrophic cardiomyopathy?
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Ploski R, Pollak A, Müller S, Franaszczyk M, Michalak E, Kosinska J, Stawinski P, Spiewak M, Seggewiss H, and Bilinska ZT
- Subjects
- Animals, Female, Humans, Male, Cardiomyopathy, Hypertrophic genetics, Cardiomyopathy, Hypertrophic metabolism, Gene Deletion, Muscle Proteins genetics, Muscle Proteins metabolism, Mutation, Missense genetics, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism
- Abstract
Rationale: Variants in TRIM63, including a nonsense mutation (p.Q247X), have been suggested recently to cause hypertrophic cardiomyopathy., Objective: To verify pathogenicity of TRIM63 p.Q247X detected by whole-exome sequencing in a symptomless professional sports player seeking medical advice because of a prolonged QT interval found during a routine check-up., Methods and Results: Clinical studies were performed in the proband and his mother, who also carried TRIM63 p.Q247X. No evidence of hypertrophic cardiomyopathy was found in either person., Conclusions: The p.Q247X variant in TRIM63 is not likely to be a highly penetrant variant causing hypertrophic cardiomyopathy.
- Published
- 2014
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292. Insights into the transposable mobilome of Paracoccus spp. (Alphaproteobacteria).
- Author
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Dziewit L, Baj J, Szuplewska M, Maj A, Tabin M, Czyzkowska A, Skrzypczyk G, Adamczuk M, Sitarek T, Stawinski P, Tudek A, Wanasz K, Wardal E, Piechucka E, and Bartosik D
- Subjects
- Biological Evolution, Gene Transfer, Horizontal, Genes, Bacterial, Plasmids genetics, Promoter Regions, Genetic, Alphaproteobacteria genetics, DNA Transposable Elements physiology, Paracoccus genetics
- Abstract
Several trap plasmids (enabling positive selection of transposition events) were used to identify a pool of functional transposable elements (TEs) residing in bacteria of the genus Paracoccus (Alphaproteobacteria). Complex analysis of 25 strains representing 20 species of this genus led to the capture and characterization of (i) 37 insertion sequences (ISs) representing 9 IS families (IS3, IS5, IS6, IS21, IS66, IS256, IS1182, IS1380 and IS1634), (ii) a composite transposon Tn6097 generated by two copies of the ISPfe2 (IS1634 family) containing two predicted genetic modules, involved in the arginine deiminase pathway and daunorubicin/doxorubicin resistance, (iii) 3 non-composite transposons of the Tn3 family, including Tn5393 carrying streptomycin resistance and (iv) a transposable genomic island TnPpa1 (45 kb). Some of the elements (e.g. Tn5393, Tn6097 and ISs of the IS903 group of the IS5 family) were shown to contain strong promoters able to drive transcription of genes placed downstream of the target site of transposition. Through the application of trap plasmid pCM132TC, containing a promoterless tetracycline resistance reporter gene, we identified five ways in which transposition can supply promoters to transcriptionally silent genes. Besides highlighting the diversity and specific features of several TEs, the analyses performed in this study have provided novel and interesting information on (i) the dynamics of the process of transposition (e.g. the unusually high frequency of transposition of TnPpa1) and (ii) structural changes in DNA mediated by transposition (e.g. the generation of large deletions in the recipient molecule upon transposition of ISPve1 of the IS21 family). We also demonstrated the great potential of TEs and transposition in the generation of diverse phenotypes as well as in the natural amplification and dissemination of genetic information (of adaptative value) by horizontal gene transfer, which is considered the driving force of bacterial evolution.
- Published
- 2012
- Full Text
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293. Influence of experience on orientation maps in cat visual cortex.
- Author
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Sengpiel F, Stawinski P, and Bonhoeffer T
- Subjects
- Animals, Cats, Image Processing, Computer-Assisted, Neurons physiology, Visual Cortex cytology, Brain Mapping, Dominance, Cerebral physiology, Orientation physiology, Visual Cortex physiology
- Abstract
Experience is known to affect the development of ocular dominance maps in visual cortex, but it has remained controversial whether orientation preference maps are similarly affected by limiting visual experience to a single orientation early in life. Here we used optical imaging based on intrinsic signals to show that the visual cortex of kittens reared in a striped environment responded to all orientations, but devoted up to twice as much surface area to the experienced orientation as the orthogonal one. This effect is due to an instructive role of visual experience whereby some neurons shift their orientation preferences toward the experienced orientation. Thus, although cortical orientation maps are remarkably rigid in the sense that orientations that have never been seen by the animal occupy a large portion of the cortical territory, visual experience can nevertheless alter neuronal responses to oriented contours.
- Published
- 1999
- Full Text
- View/download PDF
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