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ABSTRACT: Some of the APC negative FAP and AFAP cases have recently been found to be attributable to MYH associated polyposis (MAP). MAP is an autosomal recessive syndrome associated with 5-100 colorectal adenomas and caused by mutation in the MYH gene. Here, we screened for germline MYH mutations in 82 APC-mutation-negative probands with classical and attenuated familial adenomatous polyposis using the denaturing high performance liquid chromatography (DHPLC) method in combination with sequencing. Altogether 12 previously reported changes and four novel genetic alterations, mostly in intronic sequences, were identified. The results revealed the presence of biallelic germline MYH mutations in two patients. These patients were compound heterozygotes for two of the most common germline mutations c.494 A>G (p.Y165C); c.1,145 G>A (p.G382D). These variants are established to be associated with adenomatous polyposis and colorectal cancer. No novel pathogenic mutation has been identified in our study.
European Journal of Cancer 08/2007; 43(10):1617-21. · 5.54 Impact Factor
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ABSTRACT: ADPKD is the most common hereditary renal disease. IGAN is a mesangial proliferative glomerulonephritis characterized by diffuse mesangial deposition of immunoglobulin A. ET-1 has been suggested to be a major disease-promoting factor in renal diseases. The vasoconstrictor effect of ET-1 is mediated by the ET-A receptor. We have investigated the influence of C/T polymorphism in exon 8 of the EDNRA gene. A total number of 193 patients (87 males, 106 females) with ADPKD entered into this study. Patients were divided into three groups: 1. 47 pts with ESRD later than in 63 years (slow progressors), 2. 49 pts with ESRD before 45 (rapid progressors) and 3. 97 pts with ESRD between 45-63 years. Moreover, we examined a group of 153 pts with histologically proven IGAN (116 males, 37 females). Pts were divided into two groups: 1. 79 pts with ERSD during 5 years of the study (IGAN rapid progressors) and 2. 74 patients with normal renal function (IGAN slow progressors). As a control group we used 100 genetically unrelated healthy subjects. The distribution of C/T polymorphism did not significantly differ between rapid and slow progressors of ADPKD and IGAN. The comparison of ESRD ages showed that CC females with ADPKD failed significantly later than CT heterozygotes: CC (57.4 +/- 8.1 years), CT (53.0 +/- 9.1 years) and TT (54.5 +/- 6.4years) (t-test, P = 0.018). To conclude, the CC genotype could be protective in ADPKD females. This genotype was described to be associated with lower pulse pressure.
Folia biologica 02/2007; 53(4):134-7. · 1.15 Impact Factor
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ABSTRACT: Hereditary colorectal adenomatous polyposis syndromes are a predisposition to colorectal carcinoma development. The familial adenomatous polyposis is the most common analyzed syndrome that results from germline mutations in the APC gene. In addition to, the autosomal recessive form of polyposis has been recently reported. This disease is caused by germ-line mutations in the base excision repair MYH gene. The goal of this study is the identification of genetic causes of the colorectal polyposis, the determination of the frequency and type of the APC and MYH germ-line mutations in the set of families with colorectal polyposis in Czech population.
The set of 103 probands with FAP was screened for germ-line APC mutations using the Protein Truncation Test and Denaturing Gradient Gel Electrophoresis. The MYH mutational screening was performed on 60 unrelated patients without detected APC mutations using the Denaturing High Performance Liquid Chromatography. Automated sequencing was carried out to identify found mutations. Totally, the 51 germ-line APC mutations (69,9%) are reported in the set of 72 probands including 31 novel mutations unique for Czech population. Molecular genetic analysis of the MYH gene revealed 15 DNA variations (25 %) including two patients identified as p.Y 165C/p.G382D compound heterozygotes (3,3%) and 13 polymorphisms or intronic changes (21,7%). The novel variants were detected in the 5 patients.
Present study reflects the extremely heterogenous spectrum of the APC mutations in Czech population and confirms the previously reported data. However, the changes found in the MYH gene still need more extensive studies. Our results are important for genetic counselling and further clinical management among at-risk family members. It also enables distinction among different types of the colorectal polyposis.
Casopís lékar̆ů c̆eských 02/2006; 145(6):475-9.
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R Brdicka,
M Beránek,
M Cimburová,
J Dvorácková,
D Dvoráková,
J Hájková,
C Haskovec, V Kebrdlová,
M Karas,
A Kratochvílová, [......],
F Musil,
M Putzová,
S Rozmanová,
P Riedlová,
M Safrová,
O Scheinost,
P Stolba,
J Trka,
T Vanecek,
R Vrtel
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ABSTRACT: Laboratories dealing with human genome, both inherited and acquired changes, dispose with similar methods and technology. The spectrum of genetic tests is relatively broad and the number of mutations or variants tested differs substantially. Also the number of examinations carried out in individual laboratories varies. Data presented in the tables come from the year 2004 and indicate the number of examinations requested and number of positive results. Many laboratories mentioned in the registry CZDDNAL (http://www.uhkt.cz/lab_a_vysetreni/nr lab_dna_diag/dna_lab_db) perform the same tests but there is also a great number of tests carried out by only one laboratory. Reasons of the request, cost-effectiveness and clinical utility of genetic testing is being discussed.
Casopís lékar̆ů c̆eských 02/2006; 145(2):98-103.
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ABSTRACT: Familial adenomatous polyposis (FAP) is an autosomal dominant predisposition to colorectal cancer and is caused by germline mutations in the adenomatous polyposis coli gene. The most prominent clinical manifestation is the presence of hundreds to thousands of colorectal polyps. A milder phenotype is found in patients affected with AFAP/ multiple adenomas. We screened the entire APC coding region using the combination of DGGE, PTT and direct sequencing and identified causative mutations in 52 of 77 patients. Thirteen of the mutations found were novel. In addition, we also tested 21 APC mutation/negative probands for the two most common mutations in the MYH gene. Four patients showed neither dominant transmission of the disease nor evidence of APC mutations. In one of them the most common biallelic germline mutation in the MYH gene was detected. Correlations between the localization of germline mutations and clinical manifestations of the diseases are discussed.
Human Mutation 05/2004; 23(4):397. · 5.69 Impact Factor
