The GDAP1 p.Glu222Lys Variant-Weak Pathogenic Effect, Cumulative Effect of Weak Sequence Variants, or Synergy of Both Factors?

Charcot–Marie–Tooth disorders (CMT) represent a highly heterogeneous group of diseases of the peripheral nervous system in which more than 100 genes are involved. In some CMT patients, a few weak sequence variants toward other CMT genes are detected instead of one leading CMT mutation. Thus, the presence of a few variants in different CMT-associated genes raises the question concerning the pathogenic status of one of them. In this study, we aimed to analyze the pathogenic effect of c.664G>A, p.Glu222Lys variant in the GDAP1 gene, whose mutations are known to be causative for CMT type 4A (CMT4A). Due to low penetrance and a rare occurrence limited to five patients from two Polish families affected by the CMT phenotype, there is doubt as to whether we are dealing with real pathogenic mutation. Thus, we aimed to study the pathogenic effect of the c.664G>A, p.Glu222Lys variant in its natural environment, i.e., the neuronal SH-SY5Y cell line. Additionally, we have checked the pathogenic status of p.Glu222Lys in the broader context of the whole exome. We also have analyzed the impact of GDAP1 gene mutations on the morphology of the transfected cells. Despite the use of several tests to determine the pathogenicity of the p.Glu222Lys variant, we cannot point to one that would definitively solve the problem of pathogenici

The effect of bottom sediments on the content of heavy metals in meadow soils

The objects of the study were grasslands situated along the watercourse that collect matter directly from surface runoff from the surrounding fields and ditches. Therefore, the chemical composition of the bottom sediments can be varied. The aim of the study was to determine the content of anthropogenic fractions of selected heavy metals in meadow soils where the material from the watercourse maintenance was stored. Soil samples were collected along the banks of the Witonia “A” Channel (soil with sediment), and 30 meters from the watercourse (soil without sediment). The pH of soils without sediment was in the range 6.2–6.6, whereas the soil with sediment had a pH >7.0. The content of organic matter was 5.7–31.5%. The concentration of anthropogenic fractions of elements was determined by atomic absorption spectrometry after extraction with a (1 + 4) HCl solution. The anthropogenic enrichment coefficients (AEC) calculated in relation to the geochemical background level, were within the range: 0.9–2.8 for Zn, 1.2–3.5 for Cu, 0.7–3.1 for Pb, 1.0–2.8 for Ni and 0.3–0.9 for Cd. The AEC values for lead, copper, cadmium and nickel were usually higher in samples without sediment. A significant correlation between the metal and organic content (R2 =0.7–0.9) was found. On two sites, the level of heavy metals under investigation shows a significant local influence from anthropogenic pressure

Challenging iatrogenic menopause : oncofertility programme in Poland : a single-centre experience

Introduction: Menopause is defined as a 12-month period of time when menstruation permanently ceases. In some cases, menopause may be caused by external factors - for example gonadotoxic treatment that irreversibly damages ovarian tissue leading to loss of its hormonal and reproductive function. Oncofertility is a discipline that merges oncology and reproductive medicine, giving patients a chance to experience parenthood after gonadotoxic treatment is finished. Aim of the study: The purpose of the study is to present the implementation and first outcomes of the Oncofertility Programme in the University Clinic of Endocrinological Gynaecology and Gynaecology, University Hospital in Krakow, Poland. Material and methods: Patients interested in fertility preservation have been consulted in the University Clinic of Endocrinological Gynaecology and Gynaecology in Krakow since April 2016. Preliminary qualification to one of the available methods (embryo cryopreservation, oocyte cryopreservation, ovarian tissue cryopreservation) was conducted. Patients declaring a wish to join the programme were then referred to one of the three infertility treatment centres cooperating with the University Clinic, in order to undergo the chosen procedure. Results: During a period of 24 months, 18 patients were consulted. The youngest consulted patient was 20 years old, the oldest 39. Two years after the first consultation, a telephone survey among consulted patients was carried out to verify whether the patients finally underwent oncofertility procedures, and to ask about their reproductive status. Conclusions: The problem of fertility issues being inadequately addressed results in low referral rates to oncofertility programmes. Attempts to raise awareness of oncofertility possibilities among oncologists should be undertaken because critically few patients are being referred to oncofertility centres

A Yeast-Based Model for Hereditary Motor and Sensory Neuropathies: A Simple System for Complex, Heterogeneous Diseases

Charcot–Marie–Tooth (CMT) disease encompasses a group of rare disorders that are characterized by similar clinical manifestations and a high genetic heterogeneity. Such excessive diversity presents many problems. Firstly, it makes a proper genetic diagnosis much more difficult and, even when using the most advanced tools, does not guarantee that the cause of the disease will be revealed. Secondly, the molecular mechanisms underlying the observed symptoms are extremely diverse and are probably different for most of the disease subtypes. Finally, there is no possibility of finding one efficient cure for all, or even the majority of CMT diseases. Every subtype of CMT needs an individual approach backed up by its own research field. Thus, it is little surprise that our knowledge of CMT disease as a whole is selective and therapeutic approaches are limited. There is an urgent need to develop new CMT models to fill the gaps. In this review, we discuss the advantages and disadvantages of yeast as a model system in which to study CMT diseases. We show how this single-cell organism may be used to discriminate between pathogenic variants, to uncover the mechanism of pathogenesis, and to discover new therapies for CMT disease

Dysgerminoma and gonadoblastoma in the course of Swyer syndrome

We present a case of a woman with primary amenorrhea. Ultrasound imaging showed a uterus of normal size but bands of connective tissues at the site of ovaries. A genetic test was done which revealed the XY karyotype. Swyer syndrome was diagnosed. The patient did not report for the follow-up visits. Three years later, the woman reported back because of increasing abdominal circumference. The patient underwent an operation. Radical hysterectomy was performed. Histopathological examination showed dysgerminoma and gonadoblastoma on the left gonad and dysgerminoma on the right one. This case report presents the natural history of Swyer syndrome

Mutations in GDAP1 Influence Structure and Function of the Trans-Golgi Network

Charcot-Marie-Tooth disease (CMT) is a heritable neurodegenerative disease that displays great genetic heterogeneity. The genes and mutations that underlie this heterogeneity have been extensively characterized by molecular genetics. However, the molecular pathogenesis of the vast majority of CMT subtypes remains terra incognita. Any attempts to perform experimental therapy for CMT disease are limited by a lack of understanding of the pathogenesis at a molecular level. In this study, we aim to identify the molecular pathways that are disturbed by mutations in the gene encoding GDAP1 using both yeast and human cell, based models of CMT-GDAP1 disease. We found that some mutations in GDAP1 led to a reduced expression of the GDAP1 protein and resulted in a selective disruption of the Golgi apparatus. These structural alterations are accompanied by functional disturbances within the Golgi. We screened over 1500 drugs that are available on the market using our yeast-based CMT-GDAP1 model. Drugs were identified that had both positive and negative effects on cell phenotypes. To the best of our knowledge, this study is the first report of the Golgi apparatus playing a role in the pathology of CMT disorders. The drugs we identified, using our yeast-based CMT-GDAP1 model, may be further used in translational research

The effect of bottom sediments on the content of heavy metals in meadow soils

Tyt. z nagłówka.Bibliogr. s. 31-32.The objects of the study were grasslands situated along the watercourse that collect matter directly from surface runoff from the surrounding fields and ditches. Therefore, the chemical composition of the bottom sediments can be varied. The aim of the study was to determine the content of anthropogenic fractions of selected heavy metals in meadow soils where the material from the watercourse maintenance was stored. Soil samples were collected along the banks of the Witonia “A” Channel (soil with sediment), and 30 meters from the watercourse (soil without sediment). The pH of soils without sediment was in the range 6.2–6.6, whereas the soil with sediment had a pH  7.0. The content of organic matter was 5.7–31.5%. The concentration of anthropogenic fractions of elements was determined by atomic absorption spectrometry after extraction with a (1 + 4) HCl solution. The anthropogenic enrichment coefficients (AEC) calculated in relation to the geochemical background level, were within the range: 0.9–2.8 for Zn, 1.2–3.5 for Cu, 0.7–3.1 for Pb, 1.0–2.8 for Ni and 0.3–0.9 for Cd. The AEC values for lead, copper, cadmium and nickel were usually higher in samples without sediment. A significant correlation between the metal and organic content (R2 = 0.7–0.9) was found. On two sites, the level of heavy metals under investigation shows a significant local influence from anthropogenic pressure.Dostępny również w formie drukowanej.KEYWORDS: soil, bottom sediment, anthropogenic fractions of metals, AAS method

Two pathogenic mutations located within the 5'-regulatory sequence of the GJB1 gene affecting initiation of transcription and translation

In contrast to mutations in the coding sequences of a genes involved in the pathogenesis of Charcot-Marie-Tooth disease (CMT), little is known about CMT phenotypes resulting from a DNA variants located in regulatory sequences of a given " CMT gene". Charcot-Marie-Tooth type X1 disease (CMTX1) is caused by mutations in the GJB1 gene coding for an ion channel known as connexin, with a molecular mass of 32 kDa (Cx32). Only 0.01% of the GJB1 gene mutations have been reported in its 5' regulatory sequence. Pathogenic mutations occured in the internal ribosome entry site (IRES) are extremely rarely reported in human genetic disorders. To the best of our knowledge, in this study we report for the first time in an Eastern European population, two CMTX1 families in which two pathogenic mutations in the 5' regulatory sequence of the GJB1 gene (c.-529T>C and -459C>T) have been found. The two mutations identified in our study disturb the 5' UTR sequence in two different ways, by affecting the transcription factor SOX10 binding site (c.-529T>C) and by the disrupting IRES element of GJB1 gene (c.-459C>T). These regions are responsible for transcription (SOX10) and initiation of translation (IRES), respectively. On the basis of our findings that, in contrast to the most DNA sequence variants reported in untranslated regulatory regions of genes, the c.-459C>T and c.-529T>C mutations remain pathogenic in the context of different ethnic background