Hemophilia A is an X-linked bleeding disorder caused by a quantitative or qualitative defect of coagulation factor VIII. Since factor VIII has been cloned and several intragenic and linked DNA polymorphisms discovered, DNA analysis is an accepted and commonly used method for carrier testing in hemophilia A. Both a direct method using detection of mutation and an indirect method based on linkage between the disease and DNA polymorphism are used for this purpose. In this study, DNA samples of 110 hemophilia A patients from 99 families were screened for factor VIII gene mutation using Southern blot analysis; in seven families, mutations were detected. In 13 females from six families with identified mutation, the direct diagnosis of carriers was performed. Four intragenic (BclI, XbaI, BglI and MspI in F8C locus) and two linked polymorphisms (TaqI in DXS52 locus and BglII in DXS15 locus) were studied in members of 47 hemophilia A families. BclI-XbaI-BglI haplotypes were analyzed in 90 unrelated X chromosomes. Eighteen out of 31 females (58%) were heterozygous for at least one intragenic polymorphism, and 29 out of 31 females (94%) were heterozygous for at least one intra- or extragenic polymorphism tested. Carrier diagnosis was made in 15 out of 25 possible carriers (60%) based on intragenic and in an additional 3 out of 25 (12%) only on linked polymorphism.

• MeSH
• detekce genetických nosičů MeSH
• faktor VIII genetika   MeSH
• haplotypy MeSH
• hemofilie A genetika   MeSH
• lidé MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• polymorfismus délky restrikčních fragmentů * MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• faktor VIII MeSH

Acute myeloid leukaemia (AML) is a complex haematological malignancy characterised by diverse genetic alterations leading to abnormal proliferation of myeloid precursor cells. One of the most significant genetic alterations in AML involves mutations in the FLT3 gene, which plays a critical role in haematopoiesis and haematopoietic homeostasis. This review explores the current understanding of FLT3 gene mutations and isoforms and the importance of the FLT3 protein in AML. FLT3 mutations, including internal tandem duplications (FLT3-ITD) and point mutations in the tyrosine kinase domain (FLT3-TKD), occur in 25-30% in AML and are associated with poor prognosis. FLT3-ITD mutations lead to constitutive activation of the FLT3 signalling pathway, promoting cell survival and proliferation. FLT3-TKD mutations affect the tyrosine kinase domain and affect AML prognosis in various ways. Furthermore, FLT3 isoforms, including shorter variants, contribute to the complexity of FLT3 biology. Additionally, nonpathological polymorphisms in FLT3 are being explored for their potential impact on AML prognosis and treatment response. This review also discusses the development of molecular treatments targeting FLT3, including first-generation and next-generation tyrosine kinase inhibitors, highlighting the challenges of resistance that often arise during therapy. The final chapter describes FLT3 protein domain rearrangements and their relevance to AML pathogenesis.

• Klíčová slova
• Acute myeloid leukaemia, FLT3, Gene isoforms, Mutations,
• MeSH
• akutní myeloidní leukemie * genetika   MeSH
• lidé MeSH
• mutace genetika   MeSH
• protein - isoformy genetika   MeSH
• tyrosinkinasa 3 podobná fms genetika   MeSH
• tyrosinkinasy MeSH
• viabilita buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• FLT3 protein, human MeSH Prohlížeč
• protein - isoformy MeSH
• tyrosinkinasa 3 podobná fms MeSH
• tyrosinkinasy MeSH

Paired box 9 (PAX9) is one of the best-known transcription factors involved in the development of human dentition. Mutations in PAX9 gene could, therefore, seriously influence the number, position and morphology of the teeth in an affected individual. To date, over 50 mutations in the gene have been reported as associated with various types of dental agenesis (congenitally missing teeth) and other inherited dental defects or variations. The most common consequence of PAX9 gene mutation is the autosomal-dominant isolated (non-syndromic) oligodontia or hypodontia. In the present review, we are summarizing all known PAX9 mutations as well as their nature and precise loci in the DNA sequence of the gene. Where necessary, we have revised the loci of the mutations in line with the reference sequence of the PAX9 gene as it appears in the current DNA databases.

• Klíčová slova
• PAX9, gene, hypodontia, mutation, oligodontia,
• MeSH
• anodoncie genetika   MeSH
• exony genetika   MeSH
• lidé MeSH
• mutace genetika   MeSH
• polymorfismus genetický MeSH
• transkripční faktor PAX9 genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• PAX9 protein, human MeSH Prohlížeč
• transkripční faktor PAX9 MeSH

The DNA methyl-transferase 3A gene (DNMT3A) is the third most frequently mutated gene in cytogenetically normal acute myeloid leukemia (CN-AML) patients (20-30 %), who belong to a group of patients with intermediate risk. About 60 % of mutations in this gene have been identified in the arginine codon R882. To date, there is no consensus on whether these mutations can be used as biomarkers for monitoring of minimal residual disease and management of preemptive AML therapy. We studied the occurrence of mutations in the DNMT3A gene in our cohort of patients and their persistence during AML treatment. Using next-generation sequencing, we identified four mutations in 11/25 of our analyzed patients--frequent R882C and R882H mutations, rare Y735S mutation, and a novel L347P mutation. Mutation R882C was detected in 5/11, R882H in 4/11 patients, and Y735S and L347P in one patient each. In 4/7 patients initially carrying mutations in the R882 codon, we found the persistence of mutations also during complete remission with, however, no correlation to AML kinetics. Our findings suggest that mutations in the DNMT3A gene can only be used as a biomarker for those AML patients in whom DNMT3A mutation is lost after therapy.

• Klíčová slova
• AML preleukemic stem cells, DNMT3A gene mutations, MRD, Next-generation sequencing,
• MeSH
• akutní myeloidní leukemie genetika   MeSH
• DNA methyltransferasa 3A MeSH
• DNA-(cytosin-5-)methyltransferasa genetika   MeSH
• dospělí MeSH
• kodon genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• missense mutace * MeSH
• monitorování fyziologických funkcí * MeSH
• nádorové biomarkery genetika   MeSH
• nádorové proteiny genetika   MeSH
• reziduální nádor MeSH
• senioři MeSH
• substituce aminokyselin MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA methyltransferasa 3A MeSH
• DNA-(cytosin-5-)methyltransferasa MeSH
• DNMT3A protein, human MeSH Prohlížeč
• kodon MeSH
• nádorové biomarkery MeSH
• nádorové proteiny MeSH

Germline mutations in two major susceptibility genes BRCA1 and BRCA2 contribute to the majority of inherited breast and ovarian cancers. Besides the germline mutation, tumor progression depends on the loss of a wild-type allele. Allelic losses in the BRCA1 and BRCA2 loci have also been detected in a high proportion of sporadic breast tumors, suggesting the role of these genes in the development of non-inherited breast cancer. Forty unselected breast tumors were analyzed for the loss of heterozygosity (LOH) at BRCA1 and BRCA2 regions and tumors with allelic deletions were screened for the presence of acquired genetic alterations in respective genes. 21.1% of 38 informative tumor samples carried LOH at the BRCA1 locus whereas 33.3% of 39 informative samples showed LOH at the BRCA2 locus. Pathogenic truncating mutations in the BRCA1 gene were found in two tumor samples with allelic losses, whereas no mutations were identified in the BRCA2 gene. Mutations were not detected in non-tumor samples from the same individuals, which indicated that the BRCA1 allele was inactivated by somatic mutations in tumor tissue. The c.1116G>A (1235G>A) nonsense mutation (p.W372X) belongs to the genetic abnormalities detected infrequently in hereditary tumors; the c.3862delG (3981delG) frameshift mutation (p.E1288fsX1306) is a novel gene alteration. The occurrence of inactivating somatic mutations in sporadic breast tumors suggested the role of the BRCA1 gene in tumorigenesis in at least a minor group of patients with non-familial breast cancer.

• MeSH
• DNA nádorová genetika   MeSH
• dospělí MeSH
• duktální karcinom prsu genetika   MeSH
• geny BRCA1 * MeSH
• geny BRCA2 MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikrosatelitní repetice MeSH
• mutační analýza DNA MeSH
• nádorová transformace buněk genetika   MeSH
• nádory prsu genetika   MeSH
• nesmyslný kodon MeSH
• posunová mutace * MeSH
• protein BRCA1 fyziologie   MeSH
• sekvenční analýza DNA MeSH
• senioři MeSH
• ztráta heterozygozity MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA nádorová MeSH
• nesmyslný kodon MeSH
• protein BRCA1 MeSH

Previous studies suggested that mutant beta-catenin gene cells in cutaneous adnexal tumors with matrical differentiation contribute to their tumorigenesis. Except for pilomatricoma and pilomatrical carcinoma, only a handful of other cutaneous adnexal tumor types have been studied. DNA was extracted from 86 lesions including 17 proliferating tricholemmal and trichilemmal tumors, 15 trichoblastomas, 7 trichoadenomas, 4 pilomatricomas, 1 pilomatrical carcinoma, 4 basal cell carcinomas (BCCs) with shadow cells, 2 trichofolliculomas, 3 BCCs with sebaceous differentiation, 9 sebaceous adenomas, 6 sebaceomas, 14 sebaceous carcinomas (both ocular and extraocular forms), 2 gigantic horns, and 2 apocrine mixed tumors with shadow cells and subjected to polymerase chain reaction with newly designed primers encompassing glycogen synthase kinase-3beta phosphorylation sites of the CTNNB1 gene. Also, 3 craniopharyngiomas were studied. Sequenced polymerase chain reaction products for possible beta-catenin gene mutations showed a total of 8 alterations. These included 5 different point mutations, 3 of them identified in 2 different tumors: S23N (cribriform trichoblastoma), D32Y (pilomatricoma and craniopharyngioma), G34R (pilomatrical carcinoma and craniopharyngioma), S37F (2 BCCs with shadow cell differentiation), and G34V (craniopharyngioma). This study broadens the list of cutaneous adnexal tumors harboring CTNNB1 mutations and extends the listing of the mutations occurring in these neoplasms.

• MeSH
• beta-katenin genetika   MeSH
• buněčná diferenciace MeSH
• dítě MeSH
• dospělí MeSH
• exony * MeSH
• kraniofaryngeom genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• molekulární sekvence - údaje MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• nádory hypofýzy genetika   MeSH
• nádory kožních adnex genetika   patologie   MeSH
• nádory kůže genetika   patologie   MeSH
• předškolní dítě MeSH
• regulace genové exprese u nádorů MeSH
• sekvence nukleotidů MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• beta-katenin MeSH
• CTNNB1 protein, human MeSH Prohlížeč

BACKGROUND: Hereditary mutations in the CHEK2 gene (which encodes CHK2 kinase) contribute to a moderately increased risk of breast cancer (BC) and other cancers. Large variations in the frequency of CHEK2 mutations and the occurrence of variants of unknown clinical significance (VUS) complicate estimation of cancer risk in carriers of germline CHEK2 mutations. PATIENTS AND METHODS: We performed mutation analysis of 1,526 high-risk Czech BC patients and 3,360 Czech controls. Functional analysis was performed for identified VUS using a model system based on a human RPE1-CHEK2-KO cell line harboring biallelic inactivation of endogenous CHEK2. RESULTS: The frequency of ten truncating CHEK2 variants differed markedly between BC patients (2.26%) and controls (0.11%; p = 4.1 × 1012). We also found 23 different missense variants in 4.5% patients and in 4.0% of controls. The most common was p.I157T, which was found in patients and controls with the same frequency. Functional analysis identified nine functionally deleterious VUS, another nine functionally neutral VUS, and four intermediate VUS (including p.I157T). We found that carriers of truncating CHEK2 mutations had a high BC risk (OR 8.19; 95% CI 4.11-17.75), and that carriers of functionally deleterious missense variants had a moderate risk (OR 4.06; 95% CI, 1.37-13.39). Carriers of these mutations developed BC at 44.4 and 50.7 years, respectively. Functionally neutral and functionally intermediate missense variants did not increase the BC risk. BC in CHEK2 mutation carriers was frequently ER-positive and of higher grade. Notably, carriers of CHEK2 mutations developed second cancers more frequently than BRCA1/BRCA2/PALB2/p53 or mutation non-carriers. CONCLUSION: Hereditary CHEK2 mutations contribute to the development of hereditary BC. The associated cancer risk in mutation carriers increases with the number of affected individuals in a family. Annual follow-up with breast ultrasound, mammography, or magnetic resonance imaging is recommended for asymptomatic mutation carriers from the age of 40. Surgical prevention and specific follow-up of other tumors should be considered based on family cancer history. The work was supported by grants from the Czech Health Research Council of the Ministry of Health of the Czech Republic NR 15-28830A, 16-29959A, NV19-03-00279, projects of the PROGRES Q28/LF1, GAUK 762216, SVV2019 / 260367, PRIMUS/17/MED/9, UNCE/MED/016, Progress Q26, LQ1604 NPU II and project AVČR Qualitas. The analysis of a set of unselected controls was made possible by the existence and support of the scientific infrastructure of the National Center for Medical Genomics (LM2015091) and its project aimed at creating a reference database of genetic variants of the Czech Republic (CZ.02.1.01/0.0/0.0/16_013/0001634). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 2. 4. 2019 Accepted: 14. 5. 2019.

• Klíčová slova
• CHEK2, breast cancer, functional analysis, hereditary mutations, variants of unknown significance,
• MeSH
• buněčné linie MeSH
• checkpoint kinasa 2 genetika   MeSH
• genetická predispozice k nemoci * MeSH
• lidé MeSH
• nádory prsu genetika   MeSH
• rizikové faktory MeSH
• zárodečné mutace MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• checkpoint kinasa 2 MeSH
• CHEK2 protein, human MeSH Prohlížeč

Forty Duchenne muscular dystrophy patients from the province of Moravia in the Czech Republic, who were previously found negative for large deletions in the dystrophin gene, were tested for the presence of point mutations in selected exons. Besides several intron and exon polymorphisms, two cases of nonsense mutations were detected in exon 70, thus causing the loss of the C-terminal domain of dystrophin. One of these, the mutation, S3365X, is newly reported here while the other, R3381X, has been described previously. These mutations, only 16 bp distant from each other, have a very different impact on the mental abilities of the corresponding patients.

• MeSH
• bodová mutace * MeSH
• dítě MeSH
• dystrofin genetika   MeSH
• elektroforéza v polyakrylamidovém gelu MeSH
• lidé MeSH
• mentální retardace komplikace   genetika   MeSH
• polymerázová řetězová reakce MeSH
• polymorfismus konformace jednovláknové DNA MeSH
• svalové dystrofie komplikace   genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dystrofin MeSH

Diamond-Blackfan anemia (DBA) is a rare genetic disorder affecting the bone marrow's ability to produce red blood cells, leading to severe anemia and various physical abnormalities. Approximately 75% of DBA cases involve heterozygous mutations in ribosomal protein (RP) genes, classifying it as a ribosomopathy, with RPS19 being the most frequently mutated gene. Non-RP mutations, such as in GATA1, have also been identified. Current treatments include glucocorticosteroids, blood transfusions, and hematopoietic stem cell transplantation (HSCT), with HSCT being the only curative option, albeit with challenges like donor availability and immunological complications. Gene therapy, particularly using lentiviral vectors and CRISPR/Cas9 technology, emerges as a promising alternative. This review explores the potential of gene therapy, focusing on lentiviral vectors and CRISPR/Cas9 technology in combination with non-integrating lentiviral vectors, as a curative solution for DBA. It highlights the transformative advancements in the treatment landscape of DBA, offering hope for individuals affected by this condition.

• Klíčová slova
• CRISPR/Cas9, Diamond–Blackfan anemia, gene therapy, hematopoietic stem cell transplantation, lentiviral vector, non-integrating lentiviral vector, rare genetic disorder, ribosomal protein genes, ribosomopathy,
• MeSH
• CRISPR-Cas systémy genetika   MeSH
• Diamondova-Blackfanova anemie * genetika   terapie   MeSH
• editace genu metody   MeSH
• genetická terapie * metody   MeSH
• genetické vektory MeSH
• Lentivirus genetika   MeSH
• lidé MeSH
• mutace genetika   MeSH
• ribozomální proteiny genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• ribozomální proteiny MeSH

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease. The disease is caused by mutations of the PKD1 (affecting roughly 85% of ADPKD patients) and PKD2 (affecting roughly 14% of ADPKD patients) genes, although in several ADPKD families, the PKD1 and/or PKD2 linkage was not found. Mutation analysis of the PKD1 gene is complicated by the presence of highly homologous genomic duplications of the first two thirds of the gene. METHODS: The direct detection of mutations in the non-duplicated region of the PKD1 gene was performed in 90 unrelated individuals, consisting of 58 patients with end-stage renal failure (manifesting before their 50th year of life) and 32 individuals from families where the disease was clearly linked to the PKD1 gene. Mutation screening was performed using denaturing gradient gel electrophoresis (DGGE). DNA fragments showing an aberrant electrophoretic banding pattern were sequenced. RESULTS: In the non-duplicated region of the PKD1 gene, 19 different likely pathogenic germline sequence changes were identified in 19 unrelated families/individuals. Fifteen likely pathogenic sequence changes are unique for the Czech population. The following probable mutations were identified: 9 nonsense mutations, 6 likely pathogenic missense mutations, 2 frameshifting mutations, one in-frame deletion and probable splice site mutation. In the non-duplicated region of the PKD1 gene, 16 different polymorphisms or unclassified variants were detected. CONCLUSION: Twenty probable mutations of the PKD1 gene in 90 Czech individuals (fifteen new probable mutations) were detected. The establishment of localization and the type of causal mutations and their genotype phenotype correlation in ADPKD families will improve DNA diagnosis and could help in the assessment of the clinical prognosis of ADPKD patients.

• MeSH
• dospělí MeSH
• duplikace genu MeSH
• kationtové kanály TRPP genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• missense mutace MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• polycystické ledviny autozomálně dominantní genetika   MeSH
• polymorfismus genetický MeSH
• sekvenční analýza DNA MeSH
• zárodečné mutace MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• kationtové kanály TRPP MeSH
• polycystic kidney disease 1 protein MeSH Prohlížeč