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M H Breuning

Publications and source records attributed to M H Breuning.

At least 91 records · Page 5Linked to original sources
PubMed1997

Rapid detection of the major deletion in the Batten disease gene CLN3 by allele specific PCR.

The recent isolation of the CLN3 gene involved in Batten disease (juvenile neuronal ceroid lipofuscinosis) creates possibilities for direct detection of mutations which can confirm or indicate the clinical diagnosis of Batten disease. We have designed a rapid and reliable allele specific PCR test for the detection of the major deletion, which can be used in carrier diagnosis, presymptomatic diagnosis, and prenatal diagnosis.

Alleles↗
PubMed1996

PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.

A second gene for autosomal dominant polycystic kidney disease was identified by positional cloning. Nonsense mutations in this gene (PKD2) segregated with the disease in three PKD2 families. The predicted 968-amino acid sequence of the PKD2 gene product has six transmembrane spans with intracellular amino- and carboxyl-termini. The PKD2 protein has amino acid similarity with PKD1, the Caenorhabditis elegans homolog of PKD1, and the family of voltage-activated calcium (and sodium) channels, and it contains a potential calcium-binding domain.

Amino Acid Sequence↗
PubMed1996

Mutations in the gene-encoding SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, are associated with Brody disease.

Brody disease is a rare inherited disorder of skeletal muscle function. Symptoms include exercise-induced impairment of skeletal muscle relaxation, stiffness and cramps. Ca2+ uptake and Ca2+ ATPase activities are reduced in the sarcoplasmic reticulum, leading to the prediction that Brody disease results from defects in the ATP2A1 gene on chromosome 16p12.1-12.2, encoding SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase. A recent search, however, did not reveal any mutations in the ATP2A1 gene in three Brody patients. We have now associated Brody disease with the autosomal recessive inheritance of three ATP2A1 mutations in two families, suggesting that the disease is genetically heterogeneous. One mutation occurs at the splice donor site of intron 3, while the other two mutations lead to premature stop codons, truncating SERCA1, deleting essential functional domains and raising the intriguing question: how have these Brody patients partially compensated for the functional knockout of a gene product believed to be essential for fast-twitch skeletal muscle relaxation?

Calcium-Transporting ATPases↗
PubMed1996

Analysis of a large family with the second type of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder A mutation in at least three different genes can cause the disease. A mutation in the first gene, the PKD1 gene, which has been identified on chromosome 16p13.3, accounts for ADPKD in approximately 86% of the families with this disorder. In the majority of the other ADPKD families the disease is caused by a mutation in a second gene, the PKD2 gene. This gene has been mapped to chromosome 4q21-22, but has not yet been identified. In a few families ADPKD is not caused by a mutation in either the PKD1 or the PKD2 gene. The locus for a possible third gene has not yet been determined. Now that haplotype analysis with polymorphic markers at the ADPKD1 and ADPKD2 loci is possible, we can easily distinguish between both forms of ADPKD. We describe a large Dutch family in which ADPKD is linked to chromosome 4. Compared with ADPKD1 families, the disease in this family tends to run a milder course, as has been described previously for other ADPKD2 families.

Adult↗
PubMed1996

Detection of translation terminating mutations in the PKD1 gene.

Since the identification of the PKD1 gene in 1994, few mutations have been found. This is mainly due to the very strong homology between a large part of the PKD1 gene and another locus on the short arm of chromosome 16. It is expected that the majority of mutations at the PKD1 locus will be small deletions, insertions and point mutations. Amplification of a piece of DNA derived from the repeated area of the PKD1 gene will result in co-amplification of DNA fragments from the other locus. Detection of mutations is significantly hampered this way. We present a procedure, using the protein truncation test, which reduces the complexity caused by the homologous sequences. We have studied a group of 20 patients with ADPKD at the 3' end of the PKD1 transcript and have produced promising results.

Base Sequence↗
PubMed1996

Acute myelogenous leukemia: a disorder of gene splicing?

The two common rearrangements t(8;21) and inv(16) are found in approximately 20% of all acute myelogenous leukemias. Both aberrations result in the formation of a fusion gene, involving subunits of the core binding transcription factor (CBF). In this manuscript we hypothesize that the alternative splicing of the fusion genes, leading to truncated CBF subunits, contributes to the pathogenesis of t(8;21) and inv(16) leukemias.

Alternative Splicing↗
PubMed1996

Simple method for detection of MYH11 DNA rearrangements in patients with inv(16)(p13q22) and acute myeloid leukemia.

The pericentric inversion on chromosome 16 [inv(16)(p13q22)] and related t(16;16)(p13;q22) are recurrent aberrations associated with acute myeloid leukemia (AML) M4 Eo. Both abberations result in a fusion of the core binding factor beta (CBFB) and smooth muscle myosin heavy chain gene (MYH11). A selected genomic 6.9-kb BamHl probe detects MYH11 DNA rearrangements in 18 of 19 inv(16)/t(16;16) patients tested using HindIII digested DNA. The rearranged fragments were not detectable after remission in two cases tested, while they were present after relapse in one of these two cases tested.

Chromosome Inversion↗
PubMed1996

Adult, fetal, and polycystic kidney expression of polycystin, the polycystic kidney disease-1 gene product.

The polycystic kidney disease-1 gene, which is mutated in the majority of patients with autosomal dominant polycystic kidney disease, has been identified. The protein encoded by this gene, polycystin, has no homology with any gene known thus far. To gain more insight into the function of polycystin, we raised antibodies against synthetic peptides and a fusion protein corresponding to the sequence of two different fragments of polycystin. Two of the antibodies were capable of immunoprecipitating an in vitro transcription and translation product corresponding to a fragment of polycystin. In the cyst-lining epithelium of polycystic kidney disease-1 patients, a strong staining was observed. In normal adult and embryonic kidney tissues, expression was seen in the epithelium of all tubular structures and in the glomerular parietal and visceral epithelium (podocytes), although the podocytes were mainly recognized on cryosections and not on paraffin sections. A double-labeled immunofluorescence with one of the polycystin antibodies and the monoclonal antibody 8G8 ascertained that within the glomerular tuft podocytes were recognized.

Adult↗
PubMed1995

Carrier detection of Batten disease (juvenile neuronal ceroid-lipofuscinosis).

Batten disease, or the juvenile form of neuronal ceroid lipofuscinosis, is an autosomal recessive neurodegenerative disorder manifesting with progressive blindness, seizures, and dementia, leading to an early death. The CLN3 locus which is involved in Batten disease had been localized to chromosome 16p11.2. Linkage disequilibrium has been observed between CLN3 and polymorphic microsatellite markers D16S288, D16S299, and D16S298, making carrier detection and prenatal diagnosis by haplotype analysis possible. For the purpose of carrier detection, haplotypes from Dutch Batten patients and their families were constructed. Most patients share the same D16S298 allele, suggesting the presence of a founder effect in the Dutch population. In a large inbred Dutch family, in which Batten disease occurs with high frequency, haplotype analysis has been carried out with high accuracy for carrier detection.

Alleles↗
PubMed1995

Application of chromosome 16 markers in the differential diagnosis of neuronal ceroid-lipofuscinosis.

Accurate diagnosis of neuronal ceroid lipofuscinosis (NCL) is important for a correct prognosis of the disease and for genetic counseling. Up to now, no direct diagnostic test has been available for NCL. The clinical diagnosis is made on the basis of symptoms, neurophysiological, neuroradiological, and specific lipopigment pattern data. Recent advances in the genetics of NCL have enabled us to use polymorphic DNA markers linked to the CLN1 and CLN3 loci as a tool in the differential diagnosis of NCL. We have applied genetic analysis with polymorphic DNA markers flanking the CLN3 gene on chromosome 16 to two consanguineous families in which NCL occurs. In the first family, which is of Turkish extraction, two patients suffering from a protracted form of juvenile NCL previously had been diagnosed with juvenile NCL. Haplotypes from this family indicate that the patients and their healthy sibling are haplo-identical, suggesting that this protracted form of juvenile NCL is not linked to the CLN3 locus. In the second family, which is of Moroccan origin, one patient suffers from the early juvenile variant of NCL (Lake-Cavanagh). In this family, the patient and one of the healthy siblings have identical haplotypes, excluding linkage of early juvenile NCL to the CLN3 locus on 16p12.1-11.2. Therefore, these cases from different populations demonstrate that haplotype analysis can be used as an additional method to exclude the diagnosis of juvenile NCL.

Adult↗
PubMed1995

Mechanisms of MRP over-expression in four human lung-cancer cell lines and analysis of the MRP amplicon.

Some multidrug resistant cell lines over-express the gene encoding the multidrug-resistance-associated protein (MRP). In all cell lines reported thus far, over-expression is associated with gene amplification. We have studied the predominant mechanisms of MRP over-expression in 4 human lung-cancer cell lines that cover a range of drug-resistance levels, and we have analyzed the MRP amplicon. In the SW-1573-derived, weakly resistant cell line 30.3M, MRP mRNA is elevated 3-fold in the absence of gene amplification. Run-on analysis shows that the increased MRP gene expression in this cell line is due to transcriptional activation. In the highly resistant GLC4/ADR and COR-L23/R cells, MRP gene amplification predominates, whereas in the moderately resistant MOR/R cells, gene amplification is combined with a mechanism resulting in an additional increase in the level of MRP mRNA. Fluorescence in situ hybridization shows that, in the GLC4/ADR cells, amplified MRP sequences are present both in double minute chromosomes (DM) and in homogeneously staining regions (HSR). By pulsed-field gel electrophoresis we show that the MRP-containing DM are 1 Mb in length. Chromosome-16-specific repetitive sequences adjacent to the MRP gene are also present in the DM and HSR, compatible with the involvement of these sequences in recombination events underlying MRP gene amplification. Our results show that low levels of drug resistance may arise by transcriptional activation of the MRP gene, whereas at high levels of drug resistance amplification of the MRP gene predominates, possibly facilitated by the presence of recombination-prone sequences.

ATP-Binding Cassette Transporters↗
PubMed1995

Genetic heterogeneity in adult dominant polycystic kidney disease in Cypriot families.

Polycystic kidney disease is an inherited heterogeneous disorder that affects approximately 1:1000 Europeans. It is characterized mainly by the formation of cysts in the kidney that lead to end-stage renal failure with late age of onset. Three loci have been identified, PKD1 on the short arm of chromosome 16, which has recently been isolated and characterized, PKD2 on the long arm of chromosome 4, and a third locus of unknown location, that is apparently much rarer. In families that transmit the PKD2 gene there is a significantly later age of onset of symptoms, compared with families that transmit the PKD1 gene, and in general they present with milder progression of symptomatology. For the first time we attempted molecular genetic analysis in seven Cypriot families using highly polymorphic markers around the PKD1 and PKD2 genes. Our data showed that there is genetic and phenotypic heterogeneity among these families. For four of the families we obtained strong evidence for linkage to the PKD1 locus. In two of these families linkage to PKD1 was strengthened by excluding linkage to PKD2 with the use of marker D4S423. In three other families we showed linkage to the PKD2 locus. In the largest of these families one recombinant placed marker D4S1534 distal to D4S231, thereby rendering it the closest proximal marker known to us to date. The application of molecular methods allowed us to make presymptomatic diagnosis for a number of at-risk individuals.

Aged↗
PubMed1995

A century of mortality in five large families with polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) characteristically leads to end-stage renal failure in the fifth or sixth decade of life, which in the absence of therapeutic measures will lead to premature death. To determine excess mortality relative to the general population and chromosome 16-linked ADPKD patients, we studied 348 individuals who belonged to five large ADPKD families and who had at least a 50% probability of carrying the gene; the study data derive from a time span of approximately one century. Assessment of the diagnosis of ADPKD in the present generation was based on the characteristic roentgenographic appearance of polycystic kidneys and was confirmed by DNA analysis with flanking polymorphic markers around the polycystic gene. In the previous generation, we used Mendelian reasoning after pedigree analysis to identify persons with a 50% or 100% probability of carrying the polycystic gene. During the study period (1889 to 1992), 83 deaths occurred in 10,279 person-years. Mortality was increased 1.6-fold (95% confidence interval, 1.3 to 2.0) relative to the general population and was independent of the gender of the affected family member as well as the gender of the transmitting parent. The increased mortality was strongest in the 50 to 59 year age group (relative mortality, 3.2; 95% confidence interval, 2.0 to 4.8), but decreased after the 1970s, probably as a result of improvements in supportive care and, eventually, renal replacement therapy. In conclusion, the total life-span in ADPKD patients is improving, but remains low in comparison to the general population, and the gender of the transmitting parent or of the affected individual does not influence relative mortality.

Adolescent↗
PubMed1995

FISH in genome research and molecular diagnostics.

Fluorescence in situ hybridization (FISH) has profoundly altered the aspect of genome research and molecular diagnostics. Deletions of only a few kilobases can be detected by hybridizing probes to naked DNA fibers. Loss or gain of chromosomal material in tumor cells can be visualized using comparative genome hybridization. Further diversification of FISH application will result from new ultrasensitive detection techniques.

Chromosome Aberrations↗