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Biomedical subjects

M Macek

Publications and source records attributed to M Macek.

At least 55 records · Page 3Linked to original sources
PubMed1995

Pancreatic insufficiency and pulmonary disease in German and Slavic cystic fibrosis patients with the R347P mutation.

Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) that codes for a cAMP-regulated chloride channel. The R347P is a missense mutation located within the first membrane spanning domain (MSD1) of the CFTR protein. This mutation occurs with an overall worldwide frequency of about 0.2%. The patients, originally described with this mutation were compound heterozygotes with the delta F508 mutation and had a very mild course of CF, suggesting that R347P, similar to other missense mutations affecting the MSD1 domain, causes a mild phenotype. We report here a group of 19 CF patients with the R347P mutation of German, Bulgarian, Czech, and Slovak origin, including two homozygotes. Most patients presented with early disease onset, pancreas insufficiency (PI), and early pulmonary involvement, suggesting that this mutation can lead to a severe course of CF. Most R347P alleles in the group studied share a common polymorphic haplotype. In addition, these analyses gave evidence for recurrence of the mutation in two CF patients of German and Czech origin.

Cystic Fibrosis↗
PubMed1995

Missense mutation (G480C) in the CFTR gene associated with protein mislocalization but normal chloride channel activity.

We have identified a novel CFTR missense mutation associated with a protein trafficking defect in mammalian cells but normal chloride channel properties in a Xenopus oocyte assay. The mutation, a cysteine for glycine substitution at residue 480 (G480C), was detected in a pancreatic insufficient, African-American, cystic fibrosis (CF) patient. G480C was found on one additional CF chromosome and on none of 220 normal chromosomes, including 160 chromosomes from normal African-American individuals. Western blot analysis and immunofluorescence studies revealed that, in 293T cells, the encoded mutant protein was not fully glycosylated and failed to reach the plasma membrane, suggesting that the G480C protein was subject to defective intracellular processing. However, in Xenopus oocytes, a system in which mutant CFTR proteins are less likely to experience an intracellular processing/trafficking deficit, expression of G480C CFTR was associated with a chloride conductance that exhibited a sensitivity to activation by forskolin and 3-isobutyl-1-methylxanthine (IBMX) that was similar to that of wild-type CFTR. This appears to be the first identification of a CFTR mutant with a single amino acid substitution in which the sole basis for disease is mislocalization of the protein.

Animals↗
PubMed1994

Swelling over the face: infantile cortical hyperostosis.

Swelling over the face in infancy may be caused by parotitis, abscess glandulae parotis, osteomyelitis, purulent lymph node, bone tumor or by infantile cortical hyperostosis (the Caffey-Silverman syndrome). The case report shows the typical clinical, laboratory and radiographic changes seen in infantile cortical hyperostosis. It is a benign condition, often disappearing spontaneously but also cases of recurrence are known. The knowledge of the typical signs and laboratory findings enables the determination of a quick and reliable diagnosis.

Face↗
PubMed1994

Amniotic fluid 17-hydroxyprogesterone in early pregnancy.

The results of measurement of 17-hydroxyprogesterone (17-OH-P) in 125 samples of amniotic fluid (AF) from early amniocenteses are presented. The fetuses from all pregnancies studied were unaffected by congenital adrenal hyperphasia caused by 21-hydroxylase deficiency. The AF 17-OH-P level increases slightly but significantly between the 11th and 15th week of gestation, with a maximum in the 14th week. There is no difference between the values measured in male and female fetuses. The AF 17-OH-P levels from the early gestation were compared with those from the 16th-22nd week of pregnancy (published previously). The overall differences of AF 17-OH-P concentrations when considered in all gestational age groups in the whole period 12-22 weeks were statistically insignificant. Thus, the biochemical prenatal diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency and control of its early fetal treatment could be carried out starting from the end of the first trimester in the same way as at the later period of gestation.

17-alpha-Hydroxyprogesterone↗
PubMed1994

The origin of the major cystic fibrosis mutation (delta F508) in European populations.

delta F508 is the most frequent cystic fibrosis (CF) mutation and accounts for approximately 70% of CF chromosomes worldwide. Three highly polymorphic microsatellite markers have been used to study the origin and evolution of delta F508 chromosomes in Europe. Haplotype data demonstrate that delta F508 occurred more than 52,000 years ago, in a population genetically distinct from any present European group, and spread throughout Europe in chronologically distinct expansions, which are responsible for the different frequencies of delta F508 in Europe.

Biological Evolution↗
PubMed1994

Independent origins of cystic fibrosis mutations R334W, R347P, R1162X, and 3849 + 10kbC-->T provide evidence of mutation recurrence in the CFTR gene.

Microsatellite analysis of chromosomes carrying particular cystic fibrosis mutations has shown different haplotypes in four cases: R334W, R347P, R1162X, and 3849 + 10kbC-->T. To investigate the possibility of recurrence of these mutations, analysis of intra- and extragenic markers flanking these mutations has been performed. Recurrence is the most plausible explanation, as it becomes necessary to postulate either double recombinations or single recombinations in conjunction with slippage at one or more microsatellite loci, to explain the combination of mutations and microsatellites if the mutations arose only once. Also in support of recurrence, mutations R334W, R347P, R1162X, and 3849 + 10kbC-->T involve CpG dinucleotides, which are known to have an increased mutation rate. Although only 15.7% of point mutations in the coding sequence of CFTR have occurred at CpG dinucleotides, approximately half of these CpG sites have mutated at least once. Specific nucleotide positions of the coding region of CFTR, distinct from CpG sequences, also seem to have a higher mutation rate, and so it is possible that the mutations observed are recurrent. G-->A transitions are the most common change found in those positions involved in more than one mutational event in CFTR.

Base Sequence↗
PubMed1994

[Is chorionic biopsy a dangerous and outdated method?].

The authors evaluated the risk of chorion biopsy used within the framework of prenatal diagnosis of the foetus. The incidence of abortions following transabdominal CVS (0.6%) did not differ from abortions after amniocentesis in the second trimester (0.5%). In a group of 1002 diagnostic biopsies of the chorion the authors did not record in the born infants reduction deformities of the extremities. Chorion biopsies were performed in 98% between the 10th and 12th week of gestation. The incidence of mosaicism--1.59%--was not significantly higher than reported in the literature. The authors recommend: to increase the size of the sample of chorion tissue by the use of a manual aspirator, the use of a 30 ml plastic syringe or the double needle method. They consider CVS a suitable method which serves the diagnosis of IUGR and the prenatal diagnosis of the foetus before the 20th week of gestation when cordocentesis involves risk.

Abortion, Spontaneous↗
PubMed1993

A mutation in CFTR produces different phenotypes depending on chromosomal background.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene but the association between mutation (genotype) and disease presentation (phenotype) is not straightforward. We have been investigating whether variants in the CFTR gene that alter splicing efficiency of exon 9 can affect the phenotype produced by a mutation. A missense mutation, R117H, which has been observed in three phenotypes, was found to occur on two chromosome backgrounds with intron 8 variants that have profoundly different effects upon splicing efficiency. A close association is shown between chromosome background of the R117H mutation and phenotype. These findings demonstrate that the genetic context in which a mutation occurs can play a significant role in determining the type of illness produced.

Base Sequence↗
PubMed1992

Incidence and expression of the N1303K mutation of the cystic fibrosis (CFTR) gene.

The N1303K mutation was identified in the second nucleotide binding fold of the cystic fibrosis (CF) gene last year. We have gathered data from laboratories throughout Europe and the United States of America in order to estimate its frequency and to attempt to characterise the clinical manifestations of this mutation. N1303K, identified on 216 of nearly 15,000 CF chromosomes tested, accounts for 1.5% of all CF chromosomes. The frequency of the N1303K allele varies significantly between countries and ethnic groups, being more common in Southern than in Northern Europe. This variation is independent of the delta F508 allele. It was not found on UK Asian, American Black or Australian chromosomes. N1303K is associated with four different linked marker haplotypes for the polymorphic markers XV-2c, KM.19 and pMP6d-9. Ten patients are homozygous for this mutation, whereas 106 of the remainder carry one of 12 known CF mutations in the other CF allele. We classify N1303K as a "severe" mutation with respect to the pancreas, but can find no correlation between this mutation, in either the homozygous or heterozygous state, and the severity of lung disease.

Base Sequence↗
PubMed1991

[Determination of steroid hormones in the amniotic fluid in prenatal genetic diagnosis].

In amniotic fluid from the second trimester of pregnancy levels of total and free testosterone, 17 alpha-hydroxyprogesterone and dehydroepiandrosterone were assessed. The median levels of total testosterone during the 15th to 24th week are 0.82 +/- 0.31 nmol/l in pregnancies with male foetuses and 0.32 +/- 0.11 nmol/l in pregnancies with female foetuses. The levels of free testosterone assessed by calculation from concentrations of SHBG and total testosterone are 0.15 +/- 0.04 for male and 0.05 +/- 0.04 nmol/l for female foetuses. The diagnostic reliability of sex determination of the foetus from the total testosterone concentration in amniotic fluid is 94% and estimation of free testosterone increases it further. The median normal 17 alpha-hydroxyprogesterone levels during the 15th to 23rd week of pregnancy are 8.7 +/- 3.5 nmol/l and do not depend on the sex of the foetus and week of pregnancy. The levels of dehydroepiandrosterone in amniotic fluid from the second trimester of pregnancy are in male foetuses 0.64 +/- 0.33 nmol/l and 0.61 +/- 0.32 nmol/l in female foetuses and do not differ. Assessment of testosterone levels serves as a supplementary method for determination of the sex of the foetus and may play an important part in the prenatal diagnosis of syndromes with agenesis of testicles. Estimation of 17 alpha-hydroxyprogesterone is used in prenatal diagnosis of congenital adrenal hyperplasia, estimation of dehydroepiandrosterone can be used in the prenatal diagnosis of hereditary forms of adrenal hypofunction.

17-alpha-Hydroxyprogesterone↗
PubMed1991

Stable isotope dilution analysis of N-acetylaspartic acid in CSF, blood, urine and amniotic fluid: accurate postnatal diagnosis and the potential for prenatal diagnosis of Canavan disease.

A sensitive and selective analytical technique is described for the determination of N-acetylaspartic acid in body fluids using stable isotope dilution in combination with positive chemical ionization mass spectrometry with selected ion monitoring. Control mean and ranges have been established: in urine 19.5 and 6.6-35.4 mumol/mmol creat.; in plasma 0.44 and 0.17-0.81 mumol/L; in cerebrospinal fluid 1.51 and 0.25-2.83 mumol/L; and in amniotic fluid 1.27 and 0.30-2.55 mumol/L. In a patient with Canavan disease, N-acetylaspartic acid concentration was elevated 80-fold in urine and 20-fold in plasma compared to the control means. A subsequent pregnancy of the mother was monitored and the N-acetylaspartic acid concentration in the amniotic fluid was within the control range and a healthy child was born.

Amidohydrolases↗
PubMed1991

The direct early diagnosis of cystic fibrosis by the detection of the delta F508 CFTR gene mutation in a prematurely delivered boy.

The suspicion of prenatal meconium ileus syndrome was raised in a pregnancy in a family with no history of cystic fibrosis because of significantly higher maternal serum alpha-fetoprotein in the 16th and 19th week of gestation, dispersed areas with increased echogenity in the fetal abdomen, slight fetal ascites in the 24th-25th weeks of gestation, decreased amniotic fluid gamma-glutamyltranspeptidase (GGT) activity and alpha-fetoprotein level in the 25th-26th weeks, and normal 46,XY karotype of the fetus. The detection of a homozygous deltaF508 cystic fibrosis transmembrane regulator (CFTR) gene mutation, by means of PCR from a small amount of white blood cells and urine sediment cells, substantiated the diagnosis of cystic fibrosis in a prematurely delivered boy in the 28th week of gestation. The repeated sweat test was unsuccessful. The autopsy examination confirmed the diagnosis of cystic fibrosis. Fetal meconium ileus syndrome was complicated by peritonitis and by formation of a meconium pseudocyst. Direct PCR typing improves postnatal diagnostic possibilities in the early neonatal period in prematurely delivered babies when the sweat test is difficult to perform.

Chromosome Deletion↗
PubMed1990

[Strategies in prenatal diagnosis of cystic fibrosis after the introduction of DNA analysis. Initial experience].

The authors describe their experience with the prenatal genetic diagnosis of cystic fibrosis (CF), using DNA analysis in the first trimester of pregnancy in three families with a 25% risk of CF. The authors examined polymorphisms of probes J3.11, met D, met H, KM-19 and XV-2c. All families were fully informative when one or two probes were used. In two families the development of unaffected children--carriers of the gene for CF was proved. In one of these foetuses in the 17th and 21st week false pathological values of microvilillous enzymes were assessed. With regard to this possibility the authors do not recommend to supplement the DNA analysis in the first trimester by biochemical examination of amniotic fluid. The results were confirmed by delivery of unaffected children. In one family DNA analysis revealed the development of an unaffected homozygote, the pregnancy was, however, terminated by a miscarriage. In women with an increased risk of abortion the authors recommend therefore to make the molecular genetic examination during the second trimester from amniotic fluid cells.

Chorionic Villi Sampling↗