Prehled: Osteogenesis imperfecta je celosvetove rozšírené onemocnení pojivové tkáne vyznacující se rozsáhlou klinickou heterogenitou. Hlavním klinickým příznakem je zvýšená fragilita kostí zpusobená defektní produkcí kolagenu typu I, který je kódován geny COL1A1 a COL1A2. Z klinického, radiologického a genetického hlediska rozlišujeme 11 forem onemocnení, pricemž pouze první ctyri typy vznikají v dusledku mutací genu kolagenu typ I. Závažnost onemocnení se pohybuje od lehkých forem po letální typy onemocnení. Cíle a metody: Cílem studie je molekulárne-genetická analýza genu COL1A1 25 ceských pacientu postižených onemocnením osteogenesis imperfecta, konkrétne I-IV typem, a následné porovnání klinického obrazu jedincu se shodnými zmenami DNA. Výsledky: Mutace genu COL1A1 byly identifikovány u 3 z 25 ceských OI pacientu. Jedná se o nepríbuzné jedince s diagnózou osteogenesis imperfecta typ IA, III a IVB. Záver: Identifikace mutacního spektra prostrednictvím molekulárne genetických analýz dalších pacientu a jejich príbuzných je nezbytná nejen pro stanovení vztahu mezi genotypem a fenotypem postižených jedincu, ale zároven pro porovnání frekvence výskytu identifikovaných mutací ceské populace s dalšími populacemi.
Background: Osteogenesis imperfecta is a worldwide widespread disorder of connective tissue characterized by extensive clinical heterogeneity. The main clinical feature is increased bone fragility due to defective collagen type I production which is encoded by two genes – COL1A1 and COL1A2. Based on clinical, radiological and genetic features there is described 11 forms of the disease. Only the first four types result from the collagen type I mutations. Severity of the disorder ranges from mild to lethal forms. Objectives and Methods: The aim of this study is the molecular-genetic analysis of COL1A1 gene of 25 Czech patients suffering from the disease named osteogenesis imperfecta, specifically type I-IV, and comparison of clinical pictures of individuals with the same identified mutations. Results: COL1A1 gene mutations were identified in three of twenty-five Czech OI patients. These individuals come from unrelated families and are affected by osteogenesis imperfecta type IA, III and IVB. Conclusion: Further molecular-genetic analyses of other patients and their relatives are important for detection of the biggest mutational spectrum necessary for determination of possible genotype phenotype relationship of affected individuals and for comparison the Czech population with others countries.
- Keywords
- COL1A2,
- MeSH
- Diphosphonates MeSH
- Diagnostic Techniques and Procedures MeSH
- Research Support as Topic MeSH
- Fractures, Bone MeSH
- Genetic Predisposition to Disease MeSH
- Calcitonin MeSH
- Collagen Type I MeSH
- Bone and Bones physiopathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Molecular Biology MeSH
- Mutation MeSH
- DNA Mutational Analysis MeSH
- Osteogenesis Imperfecta * genetics classification MeSH
- Signs and Symptoms MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
- MeSH
- Point Mutation MeSH
- Dyneins genetics MeSH
- Mutagenesis, Insertional MeSH
- Humans MeSH
- Mutation, Missense MeSH
- RNA Splice Sites genetics MeSH
- Molecular Sequence Data MeSH
- Mutation * MeSH
- DNA Mutational Analysis MeSH
- Myosin VIIa MeSH
- Myosins genetics MeSH
- Codon, Nonsense MeSH
- Polymorphism, Single-Stranded Conformational MeSH
- Pedigree MeSH
- Amino Acid Sequence MeSH
- Sequence Deletion MeSH
- Sequence Homology, Amino Acid MeSH
- Sequence Alignment MeSH
- Tandem Repeat Sequences MeSH
- Usher Syndromes ethnology genetics MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
- Geographicals
- Czech Republic MeSH
- Italy MeSH
- Morocco MeSH
- Spain MeSH
- Turkey MeSH
Mutations in the early growth response 2 gene (EGR2) cause demyelinating neuropathies differing in severity and age of onset. We tested 46 unrelated Czech patients with dominant or sporadic demyelinating CMT neuropathy for mutations in the EGR2 gene. One novel de-novo mutation (Arg359Gln, R359Q) was identified in heterozygous state in a patient with a typical CMT1 phenotype, progressive moderate thoracolumbar scoliosis and without clinical signs of cranial nerve dysfunction. This patient is presently less affected compared to previously described Dejerine-Sottas neuropathy (DSN) patients carrying another substitution at codon 359 (Arg359Trp, R359W). This report shows that EGR2 mutations are rare in Czech patients with demyelinating type of CMT and suggests that different substitutions at codon 359 of EGR2 can cause significantly different phenotypes.
- MeSH
- Arginine genetics MeSH
- Charcot-Marie-Tooth Disease genetics complications physiopathology MeSH
- DNA-Binding Proteins genetics MeSH
- Financing, Organized MeSH
- Glutamine genetics MeSH
- Humans MeSH
- Adolescent MeSH
- Mutation MeSH
- DNA Mutational Analysis methods MeSH
- Neural Conduction physiology MeSH
- Neurologic Examination MeSH
- Peripheral Nerves physiopathology MeSH
- Scoliosis genetics complications physiopathology MeSH
- Trans-Activators genetics MeSH
- Check Tag
- Humans MeSH
- Adolescent MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
- Comparative Study MeSH
High rates of mutation in the TP53 tumor suppressor gene have been found in many human cancers, including breast tumors, making p53 one of the most studied proteins in oncology. However, the prognostic and predictive value of alterations in this gene remains ambiguous. To analyze the clinical value of somatic TP53 mutations, we collected clinical and molecular data on 210 women with primary breast cancer. We found significant associations of p53 mutations with tumor grade, metastasis, molecular subtype, Her2 status and inverse correlations with estrogen and progesterone receptor status. Cox proportional hazard analysis confirmed a strong prognostic value of p53 mutation for overall survival rate and highlighted significant interactions with lymph node involvement and tumor size. In relation to treatment options, TP53 mutations were associated with poor response to anthracyclines and radiotherapy. Categorization of TP53 mutations according to their type and location revealed that patients with nonsense mutation have the poorest prognosis in comparison with wild-type cases and other types of mutations in this gene. Classification of TP53 mutations with respect to the degree of disturbance of protein structure showed association of disruptive mutations with poorer patients' outcome in contrast to wild-type and non-disruptive mutations. In conclusion, the present study confirms p53 as a potential predictive and prognostic factor in oncology practice and highlights the growing evidence that distinct types of mutations have different clinical impacts.
- MeSH
- Carcinoma, Ductal, Breast genetics metabolism therapy MeSH
- Genes, p53 genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Carcinoma, Lobular genetics metabolism therapy MeSH
- Mastectomy MeSH
- Survival Rate MeSH
- Mutation, Missense MeSH
- Mutation genetics MeSH
- Breast Neoplasms genetics metabolism therapy MeSH
- Codon, Nonsense MeSH
- Prognosis MeSH
- Proportional Hazards Models MeSH
- Antineoplastic Agents therapeutic use MeSH
- Radiotherapy MeSH
- Receptor, ErbB-2 metabolism MeSH
- Receptors, Estrogen metabolism MeSH
- Receptors, Progesterone metabolism MeSH
- Aged MeSH
- Neoplasm Staging MeSH
- Neoplasm Grading MeSH
- Treatment Outcome MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Nádorový supresor p53 patří k „evergreenům“ molekulární onkologie. Byl objeven v roce 1979 a od té doby je intenzivně zkoumán. Protein p53 má „pouhých“ 393 aminokyselinových zbytků a funkce téměř každého jednoho z nich je pečlivě prozkoumaná a známá. Somatické mutace se vyskytují v téměř všech kodónech p53, jsou extrémně časté a vyskytují se téměř ve všech typech nádorů. Vrozené mutace p53 jsou vzácné, ale výrazně penetrantní a jsou typicky spojeny s rozvojem širokého spektra nádorů. V roce 2001 však v oblasti výzkumu p53 došlo k nečekanému objevu: v jižní Brazílii byla objevena alela R337H, která byla zcela netypicky spojena s jediným typem nádoru – dětským adrenokortikálním karcinomem – a vyznačovala se nízkou penetrancí. Nastala doslova honba za dalšími informacemi o fungování a důsledcích mutace R337H. Ta během několika málo let přinesla nejenom spoustu poznatků o vlastnostech této konkrétní varianty p53, ale i obecnějších principech fungování mutovaných variant p53. Také se ukázalo, že všechny alely R337H, které jsou v jižní Brazílii masivně rozšířené, pocházejí z jediného zdroje, tj. mají společného předka. Klíčová slova: Li‑Fraumeniho syndrom – adrenokortikální karcinomy – gen p53 – R337H Práce byla podpořena grantem IGA MZ ČR č. NT/13784-4/2012. Autoři deklarují, že v souvislosti s předmětem studie nemají žádné komerční zájmy. Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do biomedicínských časopisů. Obdrženo: 28. 4. 2014 Přijato: 19. 5. 2014
The p53 tumour suppressor is an evergreen of molecular oncology. Since its discovery in 1979 it has been subjected to intensive investigation. The p53 protein is composed of “only” 393 amino acid residues and the function of almost each of them has been addressed in detail. Somatic mutations are extremely frequent, they can be found almost in each of the p53 codons and in all types of tumours. Inherited p53 mutations are rare but very penetrant and they are typically associated with development of a broad spectrum of tumours. However, in 2001 the p53 research provided an unexpected discovery: the R337H allele was found in southern Brazil. This allele was atypically associated with only one type of tumour – childhood adrenocortical carcinoma – and it exhibited low penetrance. Therefore, new data on functioning and impact of the R337H mutation were highly desired. The results obtained during a few following years helped to elucidate not only this specific p53 variant but also provided insight in general principles of mutant p53 variants function. It also turned out that all R337H alleles that are very frequent in southern Brazil originate from one common ancestor.
- MeSH
- Adrenal Cortex Neoplasms * epidemiology genetics MeSH
- Genetic Predisposition to Disease MeSH
- Genes, p53 * genetics MeSH
- Humans MeSH
- Li-Fraumeni Syndrome * epidemiology genetics MeSH
- Mutation, Missense MeSH
- Tumor Suppressor Protein p53 * genetics MeSH
- Germ-Line Mutation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Geographicals
- Brazil MeSH
Závěrečná zpráva o řešení grantu Agentury pro zdravotnický výzkum MZ ČR
Nestr.
U ~50% rodin se syndromem dlouhého intervalu QT jsou nacházeny mutace v genech kódujících srdeční iontové kanály a související proteiny. Každá rodina má obvykle svou “vlastní” mutaci. Stejná mutace nacházená v nepříbuzných rodinách ze stejného regionu může představovat tzv. „founder mutation“. V naší databázi je stejná mutace c.926C>T; p.T309I-Kv7.1 genu KCNQ1přítomna v 5 nepříbuzných rodinách. Cílem projektu je potvrzení hypotézy, že mutace T309I-Kv7.1 představuje v našem regionu „founder mutation“. Rozšířením rodokmenů a genetickým screeningem v T309I-Kv7.1 rodinách budou identifikováni a klinicky vyšetření noví nosiči mutace. Funkční efekt mutace bude hodnocen biofyzikální analýzou u „wild type“ a mutovaného lidského IKs kanálu exprimovaného v CHO buňkách a matematickými simulacemi na lidskému modelu srdeční komorové buňky. Tato data umožní zavést genotypem a fenotypem řízená terapeutická opatření k prevenci maligních komorových arytmií a náhlé srdeční smrti i u asymptomatických nosičů mutace.; Mutations in genes encoding cardiac ionic channels and related proteins are identified in ~50% families with the long QT syndrome. Each family is usually characterized by its own mutation; the same mutation found in unrelated families living in the same region may represent the founder mutation. In our database, the same KCNQ1 mutation (c.926C>T; p.T309I-Kv7.1) was present in 5 putatively unrelated LQTS families. This project is aimed at verification of the hypothesis that T309I-Kv7.1 mutation is the founder mutation in our region. Using pedigree extension and genetic screening in T309I-Kv7.1 families, new mutation carriers will be identified and clinically investigated. The functional effect of the mutation will be revealed using biophysical analysis in wild type and mutant human IKs channels expressed in CHO cells, and mathematical simulations in a human ventricular cell model. These data will allow us to provide genotype and phenotype-guided therapeutic measures to prevent malignant arrhythmias and sudden cardiac death even in asymptomatic mutation carriers.
- MeSH
- Genetic Carrier Screening MeSH
- KCNQ1 Potassium Channel genetics MeSH
- Humans MeSH
- Patch-Clamp Techniques MeSH
- Models, Genetic MeSH
- Models, Cardiovascular MeSH
- Mutation genetics MeSH
- Models, Theoretical MeSH
- Intermediate-Conductance Calcium-Activated Potassium Channels genetics MeSH
- Check Tag
- Humans MeSH
- Conspectus
- Patologie. Klinická medicína
- NML Fields
- genetika, lékařská genetika
- kardiologie
- NML Publication type
- závěrečné zprávy o řešení grantu AZV MZ ČR
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder that is caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). Of the 21 Czech and Slovak patients who have been diagnosed with MPS I in the last 30 years, 16 have a severe clinical presentation (Hurler syndrome), 2 less severe manifestations (Scheie syndrome), and 3 an intermediate severity (Hurler/Scheie phenotype). Mutation analysis was performed in 20 MPS I patients and 39 mutant alleles were identified. There was a high prevalence of the null mutations p.W402X (12 alleles) and p.Q70X (7 alleles) in this cohort. Four of the 13 different mutations were novel: p.V620F (3 alleles), p.W626X (1 allele), c.1727 + 2T > G (1 allele) and c.1918_1927del (2 alleles). The pathogenicity of the novel mutations was verified by transient expression studies in Chinese hamster ovary cells. Seven haplotypes were observed in the patient alleles using 13 intragenic polymorphisms. One of the two haplotypes associated with the mutation p.Q70X was not found in any of the controls. Haplotype analysis showed, that mutations p.Q70X, p.V620F, and p.D315Y probably have more than one ancestor. Missense mutations localized predominantly in the hydrophobic core of the enzyme are associated with the severe phenotype, whereas missense mutations localized to the surface of the enzyme are usually associated with the attenuated phenotypes. Mutations in the 130 C-terminal amino acids lead to clinical manifestations, which indicates a functional importance of the C-terminus of the IDUA protein.
- MeSH
- Child MeSH
- Financing, Organized MeSH
- Iduronidase genetics MeSH
- Catalytic Domain genetics MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Molecular Sequence Data MeSH
- Mucopolysaccharidosis I genetics MeSH
- Mutation MeSH
- DNA Mutational Analysis MeSH
- Child, Preschool MeSH
- Amino Acid Sequence MeSH
- Protein Structure, Tertiary genetics MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
V práci jsme sledovali pozitivitu Leidenské mutace faktoru V u 49 žen hospitalizovaných na našem oddělení s žilní trombózou. Vyšetření na faktor V Leiden bylo provedeno u 19 pacientek, pozitivní nález byl u 7 nemocných (tj. u 36,8 %) s převážně proximálním typem trombózy žil DK a pánevních žil. Z uvedených 7 nemocných 6 užívalo hormonální antikoncepci.
The authors investigated the pozitivity ofthe Leiden mutation faktor V in 49 women hospitalized at their department with venous thrombosis. Examination for the presence of Leiden faktor V was made in 19 patients. A positive finding was recorded in 7 (i.e. 36.8%), predominantly with a proximal type of thrombosis of the veins of the lower extremities and pelvis. Of the mentioned seven patients six used hormonal contraception.
