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Biomedical subjects

K Zerres

Publications and source records attributed to K Zerres.

At least 19 recordsLinked to original sources
PubMed2007

Robust association of the APOE epsilon4 allele with premature myocardial infarction especially in patients without hypercholesterolaemia: the Aachen study.

BACKGROUND: Genetic influence on the manifestation of coronary artery disease (CAD) and myocardial infarction (MI) has been shown previously. From many candidate genes the APOE (apolipoprotein E) with the major alleles epsilon2/epsilon3/epsilon4 is in the focus of interest. MATERIALS AND METHODS: In 1817 patients admitted for their first left heart catheterization at a premature age (males < 55 and females < 65) the association of APOE alleles with MI was analysed. Genotyping was done by 5' exonuclease assay (TaqMan). RESULTS APOE was significantly associated with hypercholesterolaemia (epsilon4 72% vs. epsilon3 66% vs. epsilon2 51%; P < 0.0001), and premature MI (epsilon4 57% vs. epsilon3 50% vs. epsilon2 41%; P < 0.0001; hazard ratio 1.41, 95%CI 1.14-1.75). In patients without hypercholesterolaemia, the APOE allele epsilon4 was highly predictive for the presence of premature MI (epsilon4 55% vs. epsilon3 45% vs. epsilon2 28%; P < 0.0001; hazard ratio 1.75, 95%CI 1.19-2.57). CONCLUSION: The APOEepsilon4 allele shows a robust association with premature MI independent of hypercholesterolaemia.

Adult↗
PubMed2006

Mutations in the gene encoding the Wnt-signaling component R-spondin 4 (RSPO4) cause autosomal recessive anonychia.

Anonychia is an autosomal recessive disorder characterized by the congenital absence of finger- and toenails. In a large German nonconsanguineous family with four affected and five unaffected siblings with isolated total congenital anonychia, we performed genomewide mapping and showed linkage to 20p13. Analysis of the RSPO4 gene within this interval revealed a frameshift and a nonconservative missense mutation in exon 2 affecting the highly conserved first furin-like cysteine-rich domain. Both mutations were not present among controls and were shown to segregate with the disease phenotype. RSPO4 is a member of the recently described R-spondin family of secreted proteins that play a major role in activating the Wnt/ beta -catenin signaling pathway. Wnt signaling is evolutionarily conserved and plays a pivotal role in embryonic development, growth regulation of multiple tissues, and cancer development. Our findings add to the increasing body of evidence indicating that mesenchymal-epithelial interactions are crucial in nail development and put anonychia on the growing list of congenital malformation syndromes caused by Wnt-signaling-pathway defects. To the best of our knowledge, this is the first gene known to be responsible for an isolated, nonsyndromic nail disorder.

Adult↗
PubMed2006

Submicroscopic unbalanced translocation resulting in del10p/dup13q detected by subtelomere FISH.

Chromosomal rearrangements involving the (sub)telomeres are an important cause of human genetic diseases: with the development of advanced molecular cytogenetic methods they have been identified as a major cause of mental retardation and/or congenital malformation syndromes. We identified a cryptic unbalanced de novo translocation 10p/13q by subtelomere FISH in a boy with mental and growth retardation (karyotype: 46,XY,der(10)t(10;13)(p15.1;q34)(D10S2488-,D13S296+)). Craniofacial dysmorphisms included frontal bossing, epicanthal folds, long philtrum, thin upper lip, short nose, mild retrognathy and a flat midface. In addition the patient had ASDII, a pyloric stenosis, bilateral inguinal hernias and cryptorchidism. His psychomotor development was significantly delayed. Microsatellite typing revealed the paternal origin of the two chromosomes involved in the rearrangement. By comparing our case with previously published patients with similar aberrations we conclude that the congenital malformations in our case are associated with the partial 10p deletion. The craniofacial features might be attributed to the 13q duplication. The identification of a 10p/13q translocation in our case highlights the importance of searching for cryptic subtelomeric imbalances in mentally retarded patients and helps to further delineate genotype-phenotype correlations in rare chromosomal disturbances.

Abnormalities, Multiple↗
PubMed2006

APOE alleles are not associated with calcific aortic stenosis.

OBJECTIVES: To analyse the association of APOE alleles with aortic stenosis (AS) in a large study population. METHODS: Patients with AS (n = 538) and a control group of the same age without heart disease (n = 536) were recruited. Left heart catheterisation was performed and mean gradient, aortic valve area, presence of stenotic coronary artery disease (CAD) and cardiovascular risk factors (hypercholesterolaemia, hypertension, smoking, diabetes mellitus and family history of CAD) were assessed. The frequency of the APOE major alleles e2, e3 and e4 was assessed by genotyping the polymorphisms APOE334 and APOE472 with a 5' exonuclease assay (TaqMan). RESULTS: Mean gradient across the aortic valve in cases was 50 (SD 20) mm Hg corresponding to a mean aortic valve area of 0.84 (SD 0.34) cm(2). 270 patients with AS had stenotic CAD. Among patients with AS, the prevalence of hypercholesterolaemia (64% v 40%, p < 0.001), smoking (43% v 27%, p < 0.001), diabetes (27% v 17%, p < 0.01), family history of CAD (30% v 21%, p </= 0.05), and male sex (65% v 44%, p < 0.001) was higher in those with than in those without CAD. The frequency of the major alleles was not different between cases and controls (APOE e2: 104 (19.3%) v 94 (17.5%); APOE e3: 319 (59.3%) v 332 (61.9%); APOE e4: 115 (21.3%) v 110 (20.5%); all p > 0.10). CONCLUSION: APOE e4 is not associated with AS, reflecting the different genetic backgrounds of CAD and AS.

Aged↗
PubMed2006

Outcome and effect of pregnancy in myotonic dystrophy type 2.

The authors reviewed the obstetric histories of 42 women of 37 families with myotonic dystrophy type 2 (DM2). Nine women (21%) had the first symptoms during pregnancy and worsening in subsequent pregnancies. Of 96 pregnancies, 13% ended as early and 4% as late miscarriages. Preterm labor occurred in 50% of pregnancies resulting in 27% preterm deliveries in women with overt DM2 in pregnancy. There was no evidence of a congenital DM2.

Adult↗
PubMed2006

Functional characterization of SLC7A9 polymorphisms assumed to influence the cystinuria phenotype.

Cystinuria is a hereditary disorder of cystine and dibasic amino acid transport across the luminal membrane of renal tubules and intestine, resulting in recurrent nephrolithiasis. While mutations in the SLC3-A1 gene cause type I cystinuria, patients with non-type I cystinuria mostly carry mutations in the SLC7A9 gene. However, there is evidence that further genetic factors cause and influence the cystinuria phenotype. We recently demonstrated that specific polymorphisms in Exons 3, 4, 5 and 6 of the SLC7A9 gene show a significant different allelic distribution between cystinuria patients and controls. To determine the role of the variants in these exons we transfected COS7 cells with expression constructs containing different haplotypes. Sequencing of cDNAs derived from the resulting SLC7A9 mRNAs did not reveal any differences in expression between the minigenes of the specific haplotypes. Our findings suggest that the variants in SLC7A9 do not influence splicing behavior. Thus, the reasons for the different allelic distribution between cystinuria patients and controls remain unclear. It is conceivable that this distribution is caused by the association of certain alleles with so far undetected mutations in the gene.

Amino Acid Transport Systems, Basic↗
PubMed2005

White-matter disease in 18q deletion (18q-) syndrome: magnetic resonance spectroscopy indicates demyelination or increased myelin turnover rather than dysmyelination.

Proton magnetic resonance spectroscopic data ((1)H-MR spectroscopy) of patients with 18q deletion syndrome have not yet been reported. (1)H-MR spectroscopy, performed in an affected 2-year-old girl with markedly delayed neuromotor development and typical supratentorial white-matter disease (WMD), showed an increase of choline and alpha-glutamate concentrations. Eight months later, simultaneously with clinical improvement, alpha-glutamate had normalised whereas choline remained slightly increased. Active demyelination or increased myelin turnover might contribute to the hitherto unexplained WMD of this rare disorder.

Aspartic Acid↗
PubMed2005

Search for mutations in SLC1A5 (19q13) in cystinuria patients.

To elucidate whether SLC1A5 is involved in the aetiology of cystinuria, we screened two non-type I cystinuria families without detectable mutations inSLC7A9 (and SLC3A1) but compatible with linkage to 19q13 for genomic variants in SLC1A5. Despite evidence for an involvement of SLC1A5 in the aetiology of cystinuria, we could not identify any mutation in this gene in the two families. With SLC1A5, a further candidate gene for cystinuria can be excluded as being involved in the pathogenesis of this disease in these two families. Of course, there remains the possibility that other genes are involved in cystinuria; further molecular studies will clarify the complex nature of this disorder.

Adolescent↗
PubMed2005

Mild Pelizaeus-Merzbacher disease caused by a point mutation affecting correct splicing of PLP1 mRNA.

We describe a 28-year-old male patient with a mild course of Pelizaeus-Merzbacher disease (PMD) who presented with developmental delay in his second year of life and was able to walk until 12 years of age. Several computed tomography scans in infancy and youth were normal, the diagnosis of PMD was eventually suggested by magnetic resonance imaging at the age of 24 years. Analysis of the proteolipid protein gene (PLP1) revealed a nucleotide exchange (c.762G>T) at the 3' border of exon 6, which did not entail an amino acid exchange but adversely affected splicing. PCR analysis of fibroblast cDNA showed that c.762G>T resulted in partial skipping of exon 6 in the PLP1 mRNA. Exclusion of exon 6 does not alter the reading frame but leads to absence of amino acids 232-253 that constitute a main part of the fourth transmembrane helix of the PLP protein. Remarkably, residual wild-type splicing was also detected in the patient's cultured fibroblasts. This might explain the mild phenotype in this case, as exon 6 skipping mutations resulted in a severe course of disease in other patients.

Adult↗
PubMed2005

Multi-exon deletions of the PKHD1 gene cause autosomal recessive polycystic kidney disease (ARPKD).

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 (polycystic kidney and hepatic disease 1) gene on chromosome 6p12, a large gene spanning 470 kb of genomic DNA. So far, only micromutations in the 66 exons encoding the longest open reading frame (ORF) have been described, and account for about 80% of mutations. OBJECTIVE: To test the hypothesis that gross genomic rearrangements and mutations in alternatively spliced exons contribute to a subset of the remaining disease alleles. METHODS: Using DHPLC for alternatively spliced exons and quantitative real time polymerase chain reaction to detect genomic imbalances, 58 ARPKD patients were screened, of whom 55 were known to harbour one PKHD1 point mutation in the longest ORF. RESULTS: Three different heterozygous PKHD1 deletions and several single nucleotide changes in alternatively spliced exons were identified. The detected partial gene deletions are most likely pathogenic, while a potential biological function of the alterations identified in alternatively spliced exons must await the definition of transcripts containing alternative exons and their predicted reading frames. CONCLUSIONS: Gross PKHD1 deletions account for a detectable proportion of ARPKD cases. Screening for major genomic PKHD1 rearrangements will further improve mutation analysis in ARPKD.

Base Sequence↗
PubMed2004

Long-term observations of patients with infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1).

We describe 6 unrelated patients affected by infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1) with prolonged survival upon mechanical ventilation (4.5-11 years), which has not been reported before. Biallelic mutations in the IGHMBP2 gene proved the diagnosis of SMARD1 in all patients. Disease onset was in the first 2 months in the described patients, starting with generalised hypotonia, failure to thrive, and early breathing difficulties. Diaphragmatic palsy was diagnosed and permanent ventilation was initiated 2-8 months after onset. Within months a more distal muscular atrophy became evident associated with joint contractures (talipes), hand drops, and fatty finger pads. Motor development remained minimal, loss of function was observed within the first year after which no further progression was recorded. Voiding dysfunction with reflux nephropathy was observed in 3 patients and has not been reported before. Further evidence of autonomic nerve dysfunction resulting in cardiac arrhythmia, hypertension, and excessive sweating was given in 2 patients. Investigative results were largely compatible with those obtained in classic SMA. However, neurogenic atrophy muscle was more pronounced in distal muscles, if examined, and there was evidence of peripheral nerve involvement at least in some patients.

Age Factors↗
PubMed2004

New options for prenatal diagnosis in autosomal recessive polycystic kidney disease by mutation analysis of the PKHD1 gene.

Due to the poor prognosis of severe autosomal recessive polycystic kidney disease (ARPKD), there is a strong demand for prenatal diagnosis (PD). Reliable PD testing is possible by molecular genetic analysis only. Although haplotype-based analysis is feasible in most cases, it is associated with a risk of misdiagnosis in families without pathoanatomically proven diagnosis. Linkage analysis is impossible in families where DNA of the index patient is not available. Direct mutation analysis of the recently identified polycystic kidney and hepatic disease 1 gene opens new options in families to whom a reliable PD cannot be offered on the basis of linkage analysis. We for the first time report two cases with PD based on mutation detection, illustrating the new options for PD in ARPKD.

Consanguinity↗
PubMed2004

Maternal uniparental disomy 16 and genetic counseling: new case and survey of published cases.

Uniparental disomy (UPD) is the occurrence of both homologous chromosomes from one parent. Maternal UPD(16) is the most often reported UPD other than UPD(15); almost all cases are associated with confined placental mosaicism (CPM). Most of maternal UPD(16) cases are characterised by intrauterine growth retardation (IUGR) and different congenital malformations. Maternal UPD(16) has therefore been suspected to have clinical effects: however, the lack of uniqueness and specificity of the birth defects observed suggests that the phenotype may be related in parts to placental insufficiency. We report on a new case of maternal UPD(16) associated with low level trisomy 16 mosaicism in placenta and fetus. IUGR was noticed at 19 gestational weeks and the fetus died intrauterine. Apart from different craniofacial dysmorphisms she showed anal atresia. While IUGR is probably associated with trisomy 16 mosaicism, anal atresia is more characteristic for maternal UPD( 16). Considering the features in our patient as well as those in maternal UPD (16) cases from the literature, indications for UPD (16) testing can be defined: They include trisomy 16 mosaicism, IUGR and congenital anomalies (anal atresia, congenital heart defects). However, there is an overlap of clinical signs in mosaic trisomy 16 cases mosaic for maternal UPD(16) as opposed to those mosaic for biparental disomy 16. The management of trisomy 16 pregnancies should not differ from those in which maternal UPD(16) is confirmed. Therefore, a prenatal testing for UPD(16) is not useful, but it should be offered postnatally. The molecular genetic proof of maternal UPD(16) excludes an increased recurrence risk for the family for further pregnancies.

Adult↗
PubMed2003

The interleukin-6 promoter polymorphism is associated with elevated leukocyte, lymphocyte, and monocyte counts and reduced physical fitness in young healthy smokers.

Smoking and interleukin-6 are important factors in driving inflammation. This study assessed the relationship between smoking, interleukin-6 genotype, physical fitness, and peripheral blood count in healthy young men. For this interleukin-6 promoter polymorphism -174 genotype-phenotype association study 1,929 healthy German male aviators recruited at the central German Air Force Institute of Aviation Medicine were stratified by smoking habits. Cardiovascular fitness was expressed as maximal physical working capacity (PWCmax) in watts per kilogram body weight as assessed by maximal exercise testing by cycle ergometry up to physical exhaustion. Smokers had higher leukocyte and lymphocyte counts than nonsmokers and lower PWCmax. In the overall study population the C allele of the interleukin-6 polymorphism was weakly associated with elevated leukocytes and lymphocytes; in nonsmokers the interleukin-6 polymorphism was not associated with altered phenotypes, but in smokers the interleukin-6 C allele was associated with higher leukocytes, lymphocytes, and monocytes and with lower PWCmax. Smoking is thus associated with elevated leukocytes and lymphocytes and with reduced physical fitness. Gene carriers with the interleukin-6 C allele may suffer particularly from cigarette smoking.

Adult↗