WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects: HUMAN MUTATION

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation

Alterations in Lymphocyte Membrane Protein Content and Increased Lymphocyte Rigidity in Cats with Diabetes Mellitus

Objective: In a previous study we showed that red cell deformability was decreased in cats with non-insulin dependent diabetes mellitus (NIDDM) and it was associated with abnormalities in various theological parameters (blood and plasma viscosity, erythrocyte deformability, hemotological parameters) as well as alterations in red cell membrane proteins. On the other hand, there is limited data concerning the contribution of lymphocyte membrane protein abnormalities and increased lymphocyte rigidity to impaired blood rheology in diabetes. In the present study, we aimed to investigate lymphocyte deformability and alterations in lymphocyte membrane proteins in cats with NIDDM. Material and Methods: In this regard, we analyzed lymphocyte deformability in 10 cats with non-insulin dependent diabetes mellitus (male/female: 5/5, mean age: 3.08 +/- 1.39 years, mean weight: 3.26 +/- 1.25 kg.) and 10 healthy controls (male/female: 6/4, mean age 5.7 +/- 1.91 years, mean weight: 4.56 +/- 1.16 kg.) by using the microfilter technique. We also assessed membrane protein content by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). In addition, blood levels of glucose, total cholesterol, highdensity lipoprotein (HDL), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL) and trygliceride were determined. Results: We found that lymphocyte rigidity (-/+) was significantly increased in cats with NIDDM compared to controls (1.215 +/- 0.532 vs. 0.265 +/- 0.42; p<0.01). Blood (3.8 +/- 0.1 vs 4.4 +/- 0.2; p< 0.001) and plasma viscosity (1.2 +/- 0.1 vs. 1.4 +/- 0.1; p< 0.01) were significantly higher in the diabetic group. Blood levels of glucose (99.8 +/- 21 mg/dL vs. 177.9 +/- 53.2 mg/dL; p< 0.001), total cholesterol (106.4 +/- 15.6 mg/dL vs. 183.4 +/- 57.8 mg/dL; p< 0.001), LDL (12.1 +/- 5.3 mg/dL vs. 24.7 +/- 14.6 mg/dL; p< 0.02) and HDL (78.7 +/- 9.5 mg/dL vs. 133.4 +/- 44.9 mg/dL; p< 0.001) were significantly higher in the diabetic group. SDS-PAGE revealed that the band which corresponds to the protein with a weight of 37 kDA had disappeared in cats with NIDDM. Conclusion: We suggest that the observed abnormalities in membrane proteins may play a role in reduced lymphocyte deformability associated with diabetes mellitus and may have a role in increased blood viscosity

The Effects of Etodolac, Nimesulid and Naproxen Sodium on the Frequency of Sister Chromatid Exchange after Enclused Third Molars Surgery

Purpose: Non-steroidal anti-inflammatory drugs (NSAID) are frequently used in oral surgical procedures in dentistry. The evaluation of the frequency of sister chromatid exchange (SCE) is accepted as a reliable cytogenctic method to assess the genotoxic effects of environmental factors. Materials and Methods: In this study, the genotoxic effects of various NSAIDs were assessed in 30 patients to who they were administered following encluosed third molar surgery using SCE analysis before and after the operation. The frequency of SCE was evaluated before the operation and after 3 days of etodolac, nimesulid and naproxen use. Results: There was no statistically significant difference in the frequency of SCE between the preoperative and postoperative states in patients given etodolac, nimesulid or naproxen sodium. Conclusion: Short term use of selective and non-selective NSAIDs was not associated with a significant genotoxic effect that could be detected using the SCE method in peripheric lymphocytes

A POSSIBLE DELETERIOUS EFFECT OF INCREASED SERUM COPPER ON MYOCARDIAL FUNCTION IN PATIENTS WITH DILATED CARDIOMYOPATHY AWAITING TRANSPLANTATION

Objective: We aimed to evaluate the possible contribution of alterations in serum copper and zinc levels to cardiac dysfunction in patients with dilated cardiomyopathy

A 47,X,i(Xq),Y KARYOTYPE DETECTED KLINEFELTER SYNDROME PATIENT

Klinefelter syndrome, the first described chromosomal abnormality, is characterized with hypergonadotrophic hypogonadism and eunochoid body habitus. Its prevelance is one in 500-1000 live birth. Patients usually diagnosed while they are evaluated for infertility. The general abnormalities of Klinefelter syndrome are eunochoid body habitus, gynecomastia, decreased facial and pubic hair, personality and behaviourial problems. While 47, XXY chromosome structure is detected in 80% of the patients, it is thought that 20% of the patients have another numerical chromosomal abnormality. There is no clear data about the prevalence of structural chromosomal abnormalities, particularly isochromosome Xq, but its prevalence among Klinefelter syndrome patients is estimated to be 39%. In this case report we present clinical and laboratory findings of a Klinefelter syndrome patient who came to our clinics because of infertility and found to have 47,X,i(Xq),Y karyotype in conventional cytogenetic analyse

Clinical Characteristics and Mutation Spectrum of Neurofibromatosis Type 1 in 27 Turkish Families

Background: Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder that results in a predisposition to the growth of multiple tumors in the central nervous system, the peripheral nervous system, and the skin. The clinical manifestations of neurofibromatosis are associated with loss of neurofibromin expression which causes the upregulation of the RAS pathway. Although neurofibromatosis type 1 can be diagnosed based on the National Institutes of Health criteria, sometimes the diagnosis is difficult, in cases where the characteristic features do not develop. Moreover, other RAS-related disorders may present with significantly overlapping clinical features

ARTERIAL OBSTRUCTION IN A KLINEFELTER SYNDROME PATIENT WITH RARE KARYOTYPE (48, XXYY)

Introduction: Klinefelter syndrome, the first described chromosomal abnormality, is characterized with hypergonadotrophic hypogonadism and eunuchoid body habitus. Its prevalence is one in 500-1000 live births. The general abnormalities of Klinefelter syndrome are tall stature, eunuchoid body habitus, gynecomastia, decreased testis volume, sparse facial and pubic hair, personality and behaviourial problems. 47, XXY karyotype is detected in 80% of the patients, 20% of the patients have another numerical chromosomal abnormality among all patients. Classically, the number of extra X chromosomes correlates with more severe clinical findings. While classic Klinefelter syndrome patients (patients with 47, XXY karyotype) are diagnosed during the evaluation of infertility, while patients with karyotypes other than 47, XXY are diagnosed at an earlier period due to prominent clinical features. In this case report we present clinical and laboratory findings of a Klinefelter syndrome patient, who came to our clinic because of hypergonadotropic hypogonadism and tall stature, and was found to have 48, XXYY karyotype on conventional cytogenetic analyse

Genotoxicity of fixation devices analyzed by the frequencies of sister chromatid exchange

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