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Biomedical subjects

M M Mannens

Publications and source records attributed to M M Mannens.

At least 19 recordsLinked to original sources
PubMed2001

Increased tumour risk for BWS patients correlates with aberrant H19 and not KCNQ1OT1 methylation: occurrence of KCNQ1OT1 hypomethylation in familial cases of BWS.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth malformation syndrome that maps to human chromosome 11p15.5, a region that harbours a number of imprinted genes. We studied the methylation status of H19 and KCNQ1OT1 (LIT1/KvDMR1) in a large series of BWS patients. Different patient groups were identified: group I patients (20%) with uniparental disomy and hence aberrant methylation of H19 and KCNQ1OT1; group II patients (7%) with a BWS imprinting centre 1 (BWSIC1) defect causing aberrant methylation of H19 only; group III patients (55%) with a BWS imprinting centre 2 (BWSIC2) defect causing aberrant methylation of KCNQ1OT1 only; and group IV patients (18%) with normal methylation patterns for both H19 and KCNQ1OT1. BWS patients have an increased risk of developing childhood tumours. In our patient group, out of 31 patients (group III) with KCNQ1OT1 demethylation only, none developed a tumour. However, tumours were found in 33% of patients with H19 hypermethylation (group I and II) and in 20% of patients with no detectable genetic defect (group IV). All four familial cases of BWS showed reduced methylation of KCNQ1OT1, suggesting that in these cases the imprinting switch mechanism is disturbed.

Alleles↗
PubMed2000

[Decoding of the human genome: a milestone, but not the end of the road].

The base sequence of the entire human DNA will be known within only a few years. So far, 16,000 of an expected total of 100,000 genes have been identified. Nowadays there are different stages of molecular unraveling: from fully sequenced genes, including mutations responsible for diseases, down to 'predicted' genes for which no corresponding protein is yet known. Moreover, the genes responsible for many monogenetic conditions have not yet been identified. The revolutionary approach of at random cloning and sequencing was shown to be successful in the recently published genome sequence of the fruit fly. The next landmark will be an overview of the characteristics and activity of every protein that this organism can synthesize. However, protein technology has developed less far than DNA-technology and will be subject of the next project.

Animals↗
PubMed2000

A case of methemoglobinemia type II due to NADH-cytochrome b5 reductase deficiency: determination of the molecular basis.

Clinical, biochemical and molecular findings in a patient with methemoglobinemia type II are described. Furthermore, a comparison between methemoglobinemia type I and type II, both caused by a deficiency of NADH-cytochrome b5 reductase (b5R), is made. Although the clinical pictures of type I and II are strikingly different, mutations in the diaphorase (DIA1) gene located on chromosome 22 have been described in both types. In the present patient, two newly identified mutations, both leading to a stop codon in exon 4 (Gln77Ter) and in exon 6 (Arg160Ter), were found. Identification of different mutations at different positions in the DIA1 gene might shed light on the clinical and biochemical differences between methemoglobinemia type I and type II.

Child↗
PubMed2000

Genomic organisation and chromosomal localisation of two members of the KCND ion channel family, KCND2 and KCND3.

To follow a candidate gene approach for the involvement of the KCND2 and KCND3 genes (Kv4.2 and Kv4.3) in the pathogenesis of the long QT syndrome (LQTS) and Brugada syndrome, it is necessary to determine the genomic organisation of KCND2 and KCND3. We therefore resolved the intron-exon boundaries and flanking intronic sequences and found that KCND2 consisted of six exons and KCND3 of seven exons. Subsequently, we designed the oligonucleotide primers needed for amplifying the coding exons of both KCND2 and KCND3 and established conditions for polymerase chain reaction amplification of each exon from genomic DNA. Furthermore, the chromosomal localisation of KCND2 and KCND3 was determined as 7q31 and 1p13.2, respectively. This information should facilitate the systematic screening of KCND2 and KCND3 exons for mutations in (inherited) arrhythmia syndromes, such as LQTS and Brugada.

Chromosome Walking↗
PubMed2000

Molecular genetic testing for familial hypercholesterolemia: spectrum of LDL receptor gene mutations in The Netherlands.

Mutations in the LDL receptor are responsible for familial hypercholesterolemia (FH). At present, more than 600 mutations of the LDL receptor gene are known to underlie FH. However, the array of mutations varies considerably in different populations. Therefore, the delineation of essentially all LDL receptor gene mutations in a population represents a prerequisite for the implementation of nation-wide genetic testing for FH. In this study, the frequency and geographical distribution of 13 known mutations were evaluated in a cohort of 1223 FH patients. We identified 358 mutation carriers, representing 29% of the FH cohort. Four mutations (N543H-2393de19, 1359--1G-->A, 313 + 1 G-->A and W23X) occurred with a relatively high frequency, accounting for 22.4% of the entire study cohort. Two of these common FH mutations (N543H-2393de19 and 1359 - 1G-->A) showed a preferential geographic distribution. Second, to further expand the array of LDL receptor gene mutations, we conducted mutation analysis by denaturing gradient gel electrophoresis (DGGE) in 141 children with definite FH. A mutation was identified in 111 patients, involving 16 new single base substitutions and four small deletions and insertions, which brings the number of different FH-causing mutations in our country up to 61. Our data indicate that an estimate of the prevalence of specific mutations, as well as the compilation of a database of all FH-causing mutations in a given country, can facilitate selection of the most appropriate molecular diagnostic approach.

Child↗
PubMed2000

Molecular characterisation of 10 Dutch properdin type I deficient families: mutation analysis and X-inactivation studies.

Properdin type I deficiency is characterised by complete absence of extracellular properdin, a positive regulator of the alternative pathway of complement activation. Properdin deficiency is associated with increased susceptibility to severe meningococcal disease. We have identified the genetic defect in 10 Dutch families. Six different mutations and one sequence polymorphism in the properdin gene were found. All amino acid substitutions were limited to conserved amino acids in exons 7 and 8 in contrast to the premature stops that were found in other exons. The missense mutations may alter the protein conformation in such a way that properdin will not be secreted and therefore catabolised intracellularly. The decreased properdin levels found in some healthy females carrying one mutated properdin gene were studied for X-inactivation. Most carriers with extreme low or high properdin levels showed preferential X-inactivation for the normal or mutated X chromosome, respectively. We observed some exceptions, suggesting additional regulation of properdin excretion apart from X-inactivation.

DNA↗
PubMed2000

Delineation and physical separation of novel translocation breakpoints on chromosome 1p in two genetically closely associated childhood tumors.

Sporadic childhood tumors associated with Beckwith-Wiedemann syndrome (BWS) all show abnormalities of the same region on chromosome 11. In addition to chromosome 11, other chromosome regions are affected in some of these tumor types. In this study we analyzed the region on chromosome 1p involved in the etiology of BWS-associated tumors, Wilms tumor, rhabdomyosarcoma, and hepatoblastoma. For this purpose we determined the location of two novel translocation breakpoints in this chromosome region in cells from a Wilms tumor and cells from a rhabdomyosarcoma. We constructed a map of the region and found that both breakpoints are separated by at least 875 kb. We identified a PAC clone which crosses the rhabdomyosarcoma breakpoint and found several exons within this clone. We established that this breakpoint is located proximal to the PAX7 gene and, therefore, identified a new region involved in the etiology of rhabdomyosarcomas.

Beckwith-Wiedemann Syndrome↗
PubMed1999

Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome.

BACKGROUND: Primary dysrhythmias other than those associated with the long QT syndrome, are increasingly recognized. One of these are represented by patients with a history of resuscitation from cardiac arrest but without any structural heart disease. These patients exhibit a distinct electrocardiographic (ECG) pattern consisting of a persistent ST-segment elevation in the right precordial leads often but not always accompanied by a right bundle branch block (Brugada syndrome). This syndrome is associated with a high mortality rate and has been shown to display familial occurrence. METHODS AND RESULTS: Pharmacological sodium channel blockade elicits or worsens the electrocardiographic features associated with this syndrome. Hence, a candidate gene approach directed towards SCN5A, the gene encoding the alpha-subunit of the cardiac sodium channel, was followed in six affected individuals. In two patients missense mutations were identified in the coding region of the gene: R1512W in the DIII-DIV cytoplasmic linker and A1924T in the C-terminal cytoplasmic domain. In two other patients mutations were detected near intron/exon junctions. To assess the functional consequences of the R1512W and A1924T mutations, wild-type and mutant sodium channel proteins were expressed in Xenopus oocytes. Both missense mutations affected channel function, most notably a 4-5 mV negative voltage shift of the steady-state activation and inactivation curves in R1512W and a 9 mV negative voltage shift of the steady-state activation curve in A1924T, measured at 22 degrees C. Recovery from inactivation was slightly prolonged for R1512W channels. The time dependent kinetics of activation and inactivation at -20 mV were not significantly affected by either mutation. CONCLUSIONS: Two SCN5A mutations associated with the Brugada syndrome, significantly affect cardiac sodium channel characteristics. The alterations seem to be associated with an increase in inward sodium current during the action potential upstroke.

Action Potentials↗
PubMed1998

The human chitotriosidase gene. Nature of inherited enzyme deficiency.

The human chitinase, named chitotriosidase, is a member of family 18 of glycosylhydrolases. Following the cloning of the chitotriosidase cDNA (Boot, R. G., Renkema, G. H., Strijland, A., van Zonneveld, A. J., and Aerts, J. M. F. G. (1995) J. Biol. Chem. 270, 26252-26256), the gene and mRNA have been investigated. The chitotriosidase gene is assigned to chromosome 1q31-q32. The gene consists of 12 exons and spans about 20 kilobases. The nature of the common deficiency in chitotriosidase activity is reported. A 24-base pair duplication in exon 10 results in activation of a cryptic 3' splice site, generating a mRNA with an in-frame deletion of 87 nucleotides. All chitotriosidase-deficient individuals tested were homozygous for the duplication. The observed carrier frequency of about 35% indicates that the duplication is the predominant cause of chitotriosidase deficiency. The presence of the duplication in individuals from various ethnic groups suggests that this mutation is relatively old.

Amino Acid Sequence↗
PubMed1997

Glucocerebrosidase genotype of Gaucher patients in The Netherlands: limitations in prognostic value.

Gaucher disease is a recessively inherited lysosomal storage disorder that is caused by a deficiency in glucocerebrosidase activity. The clinical expression is markedly heterogeneous with respect to age of onset, progression, severity, and neurological involvement. The relative incidence of glucocerebrosidase (GC) mutations has been studied extensively for Jewish but not for non-Jewish Caucasian patient populations. The present survey on mutant GC genotypes prevalent in Gaucher disease in The Netherlands was taken of 72 patients from different genetic backgrounds. This number is more than half the total number of affected Gaucher patients to be expected on the basis of the incidence of the disorder in this country. Analysis of nine GC mutations led to the identification of 74% of the mutant GC alleles in patients from 44 unrelated Dutch families (i.e., families that have lived in The Netherlands for at least several generations) and of 44% of the mutant GC alleles in patients from nine unrelated families that recently immigrated from both European and non-European countries. The N370S (cDNA 1226G) GC mutation proved to occur most frequently (41%) in the unrelated Dutch patients and less frequently (6%) in the unrelated immigrant patients and was always associated with the nonneuronopathic (Type 1) form of the disease. Apart from the association of the N370S mutation with Type 1 Gaucher disease, the prognostic value of GC genotyping was limited, since a particular GC genotype did not correlate closely to a specific clinical course, or to a specific relative responsiveness to enzyme-supplementation therapy.

Blotting, Southern↗
PubMed1995

Further delineation of the partial proximal trisomy 10q syndrome.

We report on a girl with a partial duplication of the proximal part of the long arm of chromosome 10, confirmed by chromosome painting. The phenotypic findings are compared to those found in six other published cases with the same karyotype. Recognition of a specific partial proximal trisomy 10q syndrome seems to be possible, consisting of mild to moderate developmental delay, postnatal growth retardation, microcephaly, prominent forehead, small and deep set eyes, epicanthus, upturned nose, bow shaped mouth, micrognathia, thick and flat helices of the ears, and long, slender limbs. Severe ocular malformations are possibly part of the syndrome. No major phenotypic differences were seen between patients with a duplication of segment 10q11-->10q22 and patients with a duplication of 10q21-->10q22.

Adenosine Kinase↗
PubMed1992

Cytogenetics and molecular genetics of Wilms' tumor of childhood.

We describe the way in which application of cytogenetic and molecular genetic techniques to the study of Wilms' tumor (WT) of the kidney and the associated congenital disorders, such as sporadic aniridia and the Beckwith-Wiedemann syndrome, has led to identification of two regions on the short arm of chromosome 11 (11p13 and 11p15) involved in tumor development. In addition, evidence shows that genomic imprinting may be an important factor in transformation. Such investigations have led to cloning of a candidate WT gene (WT1) from 11p13. Linkage studies in familial studies suggest that an additional locus is involved. Analysis of the cytogenetic data available on this tumor suggests that this may be situated on 1p, 16q, or 17p.

Aniridia↗
PubMedDate not supplied

The QM gene is X-linked and therefore not involved in suppression of tumorigenesis in Wilms' tumor.

Inactivation of one or more tumor-suppressor genes on the short arm of chromosome 11 is thought to play a role in the etiology of Wilms' tumor. A candidate gene, QM, was recently isolated by subtractive hybridization between a tumorigenic cell line (deleted for part of 11p) and a non-tumorigenic cell line (the tumorigenic cell line carrying an extra t(X;11)copy). We show here with an exon-specific polymerase chain reaction that the genomic homolog of the QM cDNA is located in the G6PD-color vision genes region in Xq28. No homologous sequences could be detected on 11p. Our experiments indicate that the QM gene is not involved in the suppression of Wilms' tumor.

Base Sequence↗