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R Kruse

Publications and source records attributed to R Kruse.

At least 19 recordsLinked to original sources
PubMed1999

Peutz-Jeghers syndrome: four novel inactivating germline mutations in the STK11 gene. Mutations in brief no. 227. Online.

The diagnosis of Peutz-Jeghers syndrome is based on the occurrence of hamartomatous gastrointestinal polyps and perioral pigment spots. In view of the development of hamartomatous polyps in several syndromes and the variability of pigment spots in Peutz-Jeghers patients, identification of affected individuals is difficult. Recently, germline mutations in the STK11 gene have been reported as a molecular cause of Peutz-Jeghers syndrome. We present four novel inactivating mutations identified by direct sequencing of all 9 exons of the STK11 gene in 4 patients suggestive of Peutz-Jeghers syndrome: three frameshift mutations (125-137del; 474-480del; 516-517insT) and one nonsense mutation (Q220X). Our data obtained in these patients and in those reported previously emphasize the diagnostic value of histological discrimination between different types of hamartomatous polyps and of molecular analysis, particularly in cases with no family history of the disease.

AMP-Activated Protein Kinase Kinases↗
PubMed1999

Obtaining interpretable fuzzy classification rules from medical data.

For many application problems classifiers can be used to support a decision making process. In some domains-in areas like medicine especially-it is preferable not to use black box approaches. The user should be able to understand the classifier and to evaluate its results. Fuzzy rule based classifiers are especially suitable, because they consist of simple linguistically interpretable rules and do not have some of the drawbacks of symbolic or crisp rule based classifiers. Classifiers must often be created from data by a learning process, because there is not enough expert knowledge to determine their parameters completely. A simple and convenient way to learn fuzzy classifiers from data is provided by neuro-fuzzy approaches. In this paper we discuss extensions to the learning algorithms of neuro-fuzzy classification (NEFCLASS), a neuro-fuzzy approach for data analysis that we have presented before. We present interactive strategies for pruning rules and variables from a trained classifier to enhance its readability, and demonstrate our approach on a small example.

Algorithms↗
PubMed1999

Microsatellite instability-a useful diagnostic tool to select patients at high risk for hereditary non-polyposis colorectal cancer: a study in different groups of patients with colorectal cancer.

BACKGROUND: Clinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is based on a typical family history. As molecular genetic testing is predominantly restricted to these families, gene carriers not meeting the clinical criteria may be missed. AIMS: To examine the value of microsatellite instability (MSI) as a tool to increase the likelihood for uncovering a mismatch repair germline mutation in patients with colorectal cancer and to identify a genotype-phenotype relation in families with verified mutations. METHODS: Systematic search for germline mutations (hMSH2 and hMLH1 genes) was performed in 96 patients: 57 fulfilled the Amsterdam criteria (group 1) and 12 the looser HNPCC criteria (group 2). Seventeen patients showed familial clustering of cancers (group 3) and 10 patients under 50 years had sporadic cancer (group 4), the latter of whom all exhibited MSI+ tumours. RESULTS: A similar proportion of germline mutations was found in patients who fulfilled the clinical criteria of HNPCC and had MSI+ tumours (groups 1 and 2; 15/39) compared with patients who did not meet these clinical criteria but who had MSI+ tumours (groups 3 and 4; 8/27 patients). Affected relatives of patients with hMLH1 mutations showed a significantly higher frequency of colorectal cancer but a lower frequency of endometrium cancer than those with hMSH2 mutations. CONCLUSIONS: MSI in tumour tissue is a useful criterion for selecting patients who should be tested for germline mutations in the mismatch repair genes hMSH2 and hMLH1 irrespective of their family history. Among carriers of hMSH2 mutations the tumour spectrum was broader than among carriers of hMLH1 mutations.

Adult↗
PubMed1999

Frequent 4-bp deletion in exon 9 of the SMAD4/MADH4 gene in familial juvenile polyposis patients.

Familial juvenile polyposis (FJP) is a hamartomatous polyposis syndrome characterized by the appearance of juvenile polyps in the gastrointestinal tract. Patients with this syndrome are at an increased risk for cancer of the colon, stomach, and pancreas. Recently, germline mutations in the SMAD4/DPC4 gene (official symbol MADH4) have been found in the majority of patients suffering from FJP. We have examined 11 unrelated patients with FJP for MADH4 germline mutations by direct sequencing of genomic DNA encompassing all 11 exons of the gene. Besides a novel mutation (959-960delAC at codon 277, exon 6) in one patient, we observed a 4-bp deletion (1372-1375delACAG) in exon 9 in two unrelated patients. Examination with microsatellite markers flanking MADH4 supports an independent origin of the mutation in these two families. The same 4-bp deletion in exon 9 has previously been described in three out of nine patients examined for MADH4 mutations. Our results combined with these previous data demonstrate that a unique 4-bp deletion in exon 9 of MADH4 accounts for about 25% of all FJP cases and that other MADH4 mutations occur in an additional 15% of patients. Genes Chromosomes Cancer 25:403-406, 1999.

Adenomatous Polyposis Coli↗
PubMed1998

Genetic counseling in a patient with XXY/XXXY/XY mosaic Klinefelter's syndrome: estimate of sex chromosome aberrations in sperm before intracytoplasmic sperm injection.

OBJECTIVE: To report the sex chromosome aberrations in the sperm of a patient with mosaic Klinefelter's syndrome before ICSI. DESIGN: Case report. SETTING: Institute of Human Genetics, University Hospital PATIENT(S): A patient with an XXY/XXXY/XY mosaic Klinefelter's syndrome and extreme oligozoospermia. INTERVENTION(S): Skin biopsy, buccal smear, hair root sampling, and semen sampling. MAIN OUTCOME MEASURE(S): The karyotypes of three additional somatic cell systems and the ratio of sex chromosome aberrations in sperm. RESULT(S): After two-color fluorescence in situ hybridization of 202 interphase sperm nuclei, both the proportion of hyperhaploid 24, XY and 25, XXY sperm (5.0% and 0.5%, respectively) and of hyperhaploid 24, XX sperm (2.0%) were elevated. In contrast with peripheral lymphocytes, 93.9% of which showed sex chromosome aberrations, in the present patient only 7.5% of sperm proved to be hyperhaploid with an extra sex chromosome. CONCLUSION(S): The determination of sex chromosome aberrations in the sperm of a patient with mosaic Klinefelter's syndrome may provide additional information to estimate the transmission risk to his offspring.

Adult↗
PubMed1998

Panniculitis due to potassium bromide.

Potassium bromide again is well known to be surprisingly effective in patients with severe myoclonic epilepsy in infants (SME). Rare side effects on the skin reappeared, such as the febrile nodular panniculitis (Weber-Christian syndrome). In 1993 we described the first three cases of necrotizing panniculitis and introduced the term 'halogen panniculitis'. It is a systemic disease with crops of subcutaneous nodules, fever, elevated sedimentation rate, hepatosplenomegalia, and abdominal pain. Later severe necrosis of the skin and adipose tissue may happen with deep ulcerations. History and course of five cases, described in this paper, suggest either an allergy or toxic reason. Histologic picture shows inflammation of adipose tissues with infiltrating lymphocytes, but lymphocyte transformation test (LTT) was not reliable in diagnosing the disease. Possibly, bromides act as a chemokine and stimulate inflammatory processes. Bromide can be transformed into a bromine radical/free electron pair under UV irradiation at 228.8 nm in aqueous solution. The bromine radical may have detrimental effects on the tissue. However, despite some research, the origin of halogen panniculitis and similar diseases remains unclear.

Adolescent↗
PubMed1998

Concentrations of the atherogenic Lp(a) are elevated in FH.

Lipoprotein(a) (Lp(a)) is a complex in human plasma assembled from low-density lipoprotein (LDL) and apolipoprotein(a) (apo(a)). High plasma concentrations of Lp(a) are a risk factor for coronary heart disease (CHD) in particular in patients with concomitant elevation of LDL. We have analysed for elevated Lp(a) levels in patients with familial hypercholesterolaemia (FH), a condition caused by mutations in the LDL receptor (LDLR) gene and characterised by high LDL, xanthomatosis and premature CHD. To avoid possible confusion by the apo(a) gene which is the major quantitative trait locus controlling Lp(a) in the population at large, we used a sib pair approach based on genotype information for both the LDLR and the apo(a) gene. We analysed 367 family members of 30 South African and 30 French Canadian index patients with FH for LDLR mutations and for apo(a) genotype. Three lines of evidence showed a significant effect of FH on Lp(a) levels: (1) Lp(a) values were significantly higher in FH individuals compared to non-FH relatives (p < 0.001), although the distribution of apo(a) alleles was not different in the two groups; (2) comparison of Lp(a) concentrations in 28 sib pairs, identical by descent (i.b.d.) at the apo(a) locus but non-identical for LDLR status, extracted from this large sample demonstrated significantly elevated Lp(a) concentrations in sibs with FH (p < 0.001); (3) single i.b.d. apo(a) alleles were associated with significantly higher Lp(a) concentrations (p < 0.0001) in FH than non-FH family members. Variability in associated Lp(a) levels also depended on FH status and was highest when i.b.d. alleles were present in FH subjects and lowest when present in non-FH individuals. The study demonstrates that sib pair analysis makes it possible to detect the effect of a minor gene in the presence of the effect of a major gene. Given the interactive effect of elevated LDL and high Lp(a) on CHD risk our data suggest that elevated Lp(a) may add to the CHD risk in FH subjects.

Alleles↗
PubMed1998

A gene for universal congenital alopecia maps to chromosome 8p21-22.

Complete or partial congenital absence of hair (congenital alopecia) may occur either in isolation or with associated defects. The majority of families with isolated congenital alopecia has been reported to follow an autosomal-recessive mode of inheritance (MIM 203655). As yet, no gene has been linked to isolated congenital alopecia, nor has linkage been established to a specific region of the genome. In an attempt to map the gene for the autosomal recessive form of the disorder, we have performed genetic linkage analysis on a large inbred Pakistani family in which affected persons show complete absence of hair development (universal congenital alopecia). We have analyzed individuals of this family, using >175 microsatellite polymorphic markers of the human genome. A maximum LOD score of 7.90 at a recombination fraction of 0 has been obtained with locus D8S258. Haplotype analysis of recombination events localized the disease to a 15-cM region between marker loci D8S261 and D8S1771. We have thus mapped the gene for this hereditary form of isolated congenital alopecia to a locus on chromosome 8p21-22 (ALUNC [alopecia universalis congenitalis]). This will aid future identification of the responsible gene, which will be extremely useful for the understanding of the biochemistry of hair development.

Alopecia↗
PubMed1998

Muir-Torre phenotype has a frequency of DNA mismatch-repair-gene mutations similar to that in hereditary nonpolyposis colorectal cancer families defined by the Amsterdam criteria.

Muir-Torre syndrome (MTS) is an autosomal dominant disease defined by the coincidence of at least one sebaceous skin tumor and one internal malignancy. About half of MTS patients are affected by colorectal cancer. In a subgroup of MTS patients the disease has an underlying DNA mismatch-repair (MMR) defect and thus is allelic to hereditary nonpolyposis colorectal cancer (HNPCC). The purpose of this study was to examine to what extent germ-line mutations in DNA MMR genes are the underlying cause of the MTS phenotype. We ascertained 16 MTS patients with sebaceous skin tumors and colorectal cancer, and we examined their skin and visceral tumors for microsatellite instability. All the patients exhibited high genomic instability in at least one tumor. The search for germ-line mutations in the hMSH2 and hMLH1 genes in 13 of the MTS patients revealed truncating mutations in 9 (69%): eight mutations in the hMSH2 gene and one in the hMLH1 gene. This is the first systematic search for germ-line mutations in patients ascertained on the basis of sebaceous skin tumors. Our results indicate that (1) MTS patients exhibit significantly more mutations in the hMSH2 gene than in the hMLH1 gene; and (2) the subpopulation of MTS patients who are also affected by colorectal cancer, irrespective of family history and age at onset of tumors, may have a likelihood for an underlying DNA MMR defect similar to that for patients with a family history fulfilling the strict clinical criteria for HNPCC.

Adult↗
PubMed1998

Cloning, genomic organization, alternative transcripts and mutational analysis of the gene responsible for autosomal recessive universal congenital alopecia.

Complete or partial congenital absence of hair (congenital alopecia) may occur isolated or with associated defects. The majority of families with isolated congenital alopecia has been reported to follow an autosomal recessive mode of inheritance (MIM 203655). We have previously mapped the gene for autosomal recessive congenital alopecia in a large inbred Pakistani family in which affected persons show complete absence of hair development (universal congenital alopecia) to a 15 cM region on chromosome 8p21-22. Here we report the cloning and characterization of the human homologue of the mouse hairless gene and show that it is located in the critical region on chromosome 8p21-22. Determining the exon-intron structure allowed detailed mutational analysis of DNA samples of patients with universal congenital alopecia. We detected a homozygous missense mutation in the Pakistani family and a homozygous splice donor mutation in a family from Oman. In addition, we show that the human hairless gene undergoes alternative splicing and that at least two isoforms generated by alternative usage of exon 17 are found in human tissues. Interestingly, the isoform containing exon 17 is the predominantly expressed isoform in all tissues but skin, where exclusive expression of the shorter isoform was observed. We speculate that this tissue-specific difference in the proportion of hairless transcripts lacking exon 17 sequences could contribute to the tissue-specific disease phenotype observed in individuals with isolated congenital alopecia.

Adult↗
PubMed1997

The "possible triangle" test for extreme discordant sib pairs.

For the analysis of quantitative traits in nuclear families, extreme discordant sib pairs proved to be more powerful than unselected sib pairs. Here, we present a test that makes use of selected pairs and, in addition, restricts the parameters of the identical-by-descent distribution analogously to the "possible triangle" for affected sib pairs. In the Problem 2A data, extreme discordant sib pairs are selected. The analysis allowed the detection of most simulated major genes.

Chromosome Mapping↗
PubMed1997

Loss of the PLA2G2A gene in a sporadic colorectal tumor of a patient with a PLA2G2A germline mutation and absence of PLA2G2A germline alterations in patients with FAP.

The Min (multiple intestinal neoplasia) mouse with a germline mutation in the adenomatous polyposis coli gene serves as an animal model for familial adenomatous polyposis coli (FAP). The number and age at onset of colorectal adenomas varies in the offspring of Min mice crossed with other strains. The murine gene for the secretory phospholipase A2 (PLA2G2A) was found to be the main candidate for these variations. To test the hypothesis of a correlation between PLA2G2A gene alterations and human tumor development, we screened 14 patients with FAP and 20 patients with sporadic colorectal cancer for germline and somatic PLA2G2A gene mutations. None of the individuals with FAP showed PLA2G2A germline alterations. However, a germline mutation was observed in one patient with an apparently sporadic colorectal tumor; the wildtype allele was somatically lost in the tumor of this patient.

Adenomatous Polyposis Coli↗
PubMed1997

Hereditary nonpolyposis colorectal cancer: causative role of a germline missense mutation in the hMLH1 gene confirmed by the independent occurrence of the same somatic mutation in tumour tissue.

Evaluation of the causative role of germline mutations in DNA mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) families can be difficult. Whereas nonsense, frameshift or splice-site mutations are presumed to lead to dysfunctional gene products and thus are generally considered to be causative, the evaluation of missense mutations often remains uncertain. We observed a novel germline mutation in the hMLH1 gene (His-->Pro at codon 329) in an HNPCC family. The same missense mutation also occurred as a somatic event in the colonic tumours of two other HNPCC patients who had germline mutations at different sites of the hMLH1 gene. Thus, the H329P mutation present in the germline can be considered as having an aetiological role in this HNPCC family.

Adaptor Proteins, Signal Transducing↗
PubMed1997

High serum IgE concentrations: association with HLA-DR and markers on chromosome 5q31 and chromosome 11q13.

BACKGROUND: Linkage studies mapped a locus regulating total serum IgE concentrations in a noncognate fashion to chromosome 5q31 and a locus for atopy to chromosome 11q13. In contrast, antigen-driven IgE production seems to be largely controlled by major histocompatibility complex class II genes. OBJECTIVE: We therefore analyzed the association between the phenotype of high IgE serum levels and six microsatellite markers on chromosomes 5q31 and 11q13, as well as HLA-DRB1, in a random sample of the adult East German population. METHODS: One hundred twenty-nine persons identified as "cases" (serum IgE level > 200 kU/L) and 266 control subjects (serum IgE level < or = 200 kU/L) were genotyped for five 5q31 microsatellites (D5S436, D5S393, D5S210, IL-4, and IL-9) and an 11q13 microsatellite (FCERIB). Cases and controls were also typed for HLA-DRB1. Allele frequencies were compared between cases and controls by means of a two-sided Fisher's exact test. RESULTS: None of the markers was significantly associated although a weak association to the markers within the IL-9 gene and the FCER1B gene and to the HLA-DRB1*01 allele was found when specific IgE-positive cases were compared with negative controls. CONCLUSIONS: The weak associations observed after stratification for specific IgE might point to a contribution of genes in these regions to the development of allergy.

Adult↗