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Biomedical subjects

H Kremer

Publications and source records attributed to H Kremer.

At least 37 records · Page 2Linked to original sources
PubMed2000

PTEN mutation analysis in two genetic subtypes of high-grade oligodendroglial tumors. PTEN is only occasionally mutated in one of the two genetic subtypes.

We recently identified two genetic subtypes of high-grade oligodendroglial tumors (HG-OT): 1p-/19q- HG-OT are characterized by a loss of chromosome 1p32-36 (del(1)(p32-p36) and/or a del(19)(q13. 3); whereas +7/-10 HG-OT harbor a gain of chromosome 7 (+7) and/or a -10 without a loss of 1p32-36 and 19q13.3. Because a -10 and a +7 are most frequently detected in glioblastomas (GBM), the genotype of +7/-10 HG-OT suggests that these tumors are GBM with a prominent oligodendroglial phenotype rather than anaplastic oligodendrogliomas. PTEN is a tumor suppressor gene, located at 10q23.3, which is involved in tumor progression of GBM and other neoplasms. In this study, we screened for PTEN mutations in six low-grade oligodendroglial tumors (LG-OT), five 1p-/19q- HG-OT, seven +7/-10 HG-OT, and nine xenografted GBM. PTEN mutations were detected in none of the LG-OT and 1p-/19q- HG-OT, once in +7/-10 HG-OT, and frequently in GBM. As one of the +7/-10 HG-OT harbored a PTEN mutation, this demonstrates that PTEN can be involved in the oncogenesis of this genetic subtype of HG-OT. The lower frequency of PTEN mutations in +7/-10 HG-OT compared to GBM suggests that these tumors are of a distinct tumor type rather than GBM. Published by Elsevier Science Inc.

Brain Neoplasms↗
PubMed2000

The natural history of hereditary neuralgic amyotrophy in the Dutch population: two distinct types?

On investigation of 101 attacks in 24 patients with hereditary neuralgic amyotrophy (HNA) from nine different families, we found that HNA can run two distinct courses: a 'classic' relapsing-remitting and a chronic undulating type with exacerbations. Only one type occurred per family, suggesting genetic heterogeneity. This is supported by the finding that only in a family with 'classic type' HNA are data of linkage analysis compatible with linkage to the 17q24-q25 interval which harbours a locus for the disease. The average number of attacks per patient during a follow-up of 26 years was four in the classic form of HNA and five in the chronic undulating type. All patients suffered from residual symptoms on follow-up, with a median Rankin score of 2 in both groups, showing that long-term prognosis is less favourable than previously reported.

Adolescent↗
PubMed1999

X-linked mental retardation: evidence for a recent mutation in a five-generation family (MRX65) linked to the pericentromeric region.

We report linkage analysis in a new family with nonspecific X-linked mental retardation, using 27 polymorphic markers covering the entire X-chromosome. We could assign the underlying disease gene, denoted MRX65, to the pericentromeric region, with flanking markers DXS573 in Xp11.3 and DXS990 in Xq21.33. A maximum LOD score of 3.64 was found at markers ALAS2 (Xp11.22) and DXS453 (Xq12) at straight theta = 0. Twenty-five of the 58 reported MRX families are linked to a region that is partially overlapping with the region reported here. Extension of the pedigree showed a number of unaffected distant relatives with haplotypes corresponding to the disease locus. Apparently, a new mutation in a female is causative for the disease in the family reported here. Furthermore, we show the importance of combining clinical, cytogenetic, and molecular studies since one of the family members, expected to be affected by the same genetic defect, has a 48,XXXY karyotype.

Adult↗
PubMed1999

X-linked mental retardation associated with cleft lip/palate maps to Xp11.3-q21.3.

A family is described in which X-linked mild to borderline mental retardation (MR) is associated with cleft lip/palate. Linkage analysis showed a maximum LOD score of Z=2.78 at straight theta=0.0 for the DXS441 locus with flanking markers DXS337 and DXS990, defining the region Xp11.3-q21.3 with a linkage interval of 25 cM.

Chromosome Mapping↗
PubMed1999

Four families (MRX43, MRX44, MRX45, MRX52) with nonspecific X-linked mental retardation: clinical and psychometric data and results of linkage analysis.

Four families are described in which mental retardation segregates in an X-linked fashion. Mental retardation was the only consistent clinical finding in all affected males. The degree of retardation varied from mild to profound both between and within families. Linkage analysis localized the genetic defect of MRX43 to Xp22. 31-p21.2, MRX44 to Xp11.3-p11.21, MRX45 to Xp11.3-p11.21, and MRX52 to Xp11.21-q21.33 with LOD scores of >2 at straight theta = 0.0 in all four families.

Adult↗
PubMed1999

Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations.

Cowden disease (CD) is characterised by multiple hamartomas in a variety of tissues. The pathological hallmark is the presence of a number of trichilemmomas. Several neurological symptoms are also part of CD with megalencephaly and Lhermitte-Duclos disease (LDD) as the most important features. Early recognition of CD patients is important because of the increased risk of developing malignancies. Breast cancer is the most frequent malignancy, but also urogenital, digestive tract, and thyroid cancers are found with higher frequencies. CD was localised to chromosome 10q23 and the PTEN gene (also known as MMAC1 or TEP1) was shown to be involved. Germline mutations were identified in both familial and sporadic CD patients. We identified eight PTEN mutations, of which seven were novel, in 13 CD patients. Combined with previous data we have identified 17 independent CD mutations. Gross DNA alterations in CD patients were not detected. Genotype-phenotype relations are discussed. The only correlation suggested to exist is that missense mutations are not detected in LDD patients. However, larger numbers are needed to confirm this. Association of PTEN mutations and the occurrence of malignant breast disease found in an earlier study cannot be confirmed. Clinical features of five CD patients without a PTEN mutation in the coding sequence do not differ from CD patients with a PTEN mutation. Furthermore, it is likely that we have identified the majority of CD patients in the Netherlands. From this we estimate that CD has a prevalence of about 1 in 250,000 in the Dutch population with a low mutation frequency.

Female↗
PubMed1999

Studies on a local effect of boar seminal plasma on ovulation time in gilts.

Previous studies showed that intrauterine infusion of seminal plasma at the onset of oestrus could advance ovulation in pigs, possibly to enhance the chances of fertilization by optimizing the chronological events of fertilization. This effect has been attributed to a local unilateral mechanism whereby infusion into a single uterine horn advances ovulation in the adjacent ovary. The present study was designed to elucidate possible mechanisms of local signal transduction. In a series of five experiments using 43 gilts, the ovarian response was investigated after infusion of seminal plasma at different sites of the female reproductive tract. The time of ovulation was detected sonographically at 4- or 2-h intervals. Single uterine horn infusion of 100 ml seminal plasma advanced ovulation on the ipsilateral ovary by 9.3 h (mean) compared with the contralateral ovary. Dissection of the ipsilateral isthmus abolished the unilateral seminal plasma effect. Unilateral infusion of 50 microliters or 1 ml seminal plasma or 50 microliters of the concentrated 1-10 kDa fraction in the lower isthmus was ineffective. Application of 5 ml seminal plasma into the tip of a ligated uterine horn lead to 3.6 h (mean) earlier ovulation on the adjacent ovary. In contrast, the infusion of 5 ml NaCl showed no effect. Application of 5 ml seminal plasma in the middle of the uterine horn between two ligatures was ineffective. It is concluded that, for the transduction of the local signal involved in the advancement of ovulation, contact of seminal plasma with the epithelium of the utero-tubal junction is essential.

Animals↗
PubMed1999

The gene for hypotrichosis of Marie Unna maps between D8S258 and D8S298: exclusion of the hr gene by cDNA and genomic sequencing.

Hypotrichosis of Marie Unna (MU) is an autosomal dominant hair-loss disorder with onset in childhood. A genomewide search for the gene was performed in a large Dutch family using 400 fluorescent microsatellite markers. Linkage was detected with marker D8S258, and analysis of this family and a further British kindred with additional markers in the region gave a combined maximum two-point LOD score of 13.42, with D8S560. Informative recombinants placed the MU gene in a 2.4-cM interval between markers D8S258 and D8S298. Recently, recessive mutations in the hr gene were reported in families with congenital atrichia, and this gene was previously mapped close to the MU interval. By radiation-hybrid mapping, we placed the hr gene close to D8S298 but were unable to exclude it from the MU interval. This, with the existence of the semidominant murine hr allele, prompted us to perform mutation analysis for this gene. Full-length sequencing of hr cDNA obtained from an affected individual showed no mutations. Similarly, screening of all exons of the hr gene amplified from the genomic DNA of an affected individual revealed no mutations. Analysis of expressed sequences and positional cloning of the MU locus is underway.

Alopecia↗
PubMed1999

A second gene for autosomal dominant Möbius syndrome is localized to chromosome 10q, in a Dutch family.

Möbius syndrome (MIM 157900) consists of a congenital paresis or paralysis of the VIIth (facial) cranial nerve, frequently accompanied by dysfunction of other cranial nerves. The abducens nerve is typically affected, and often, also, the hypoglossal nerve. In addition, orofacial and limb malformations, defects of the musculoskeletal system, and mental retardation are seen in patients with Möbius syndrome. Most cases are sporadic, but familial recurrence can occur. Different modes of inheritance are suggested by different pedigrees. Genetic heterogeneity of Möbius syndrome has been suggested by cytogenetic studies and linkage analysis. Previously, we identified a locus on chromosome 3q21-22, in a large Dutch family with Möbius syndrome consisting essentially of autosomal dominant asymmetric bilateral facial paresis. Here we report linkage analysis in a second large Dutch family with autosomal dominant inherited facial paresis. After exclusion of >90% of the genome, we identified the locus on the long arm of chromosome 10 in this family, demonstrating genetic heterogeneity of this condition. The reduced penetrance suggests that at least some of the sporadic cases might be familial.

Chromosome Mapping↗
PubMed1999

A limited repertoire of mutations of the luteinizing hormone (LH) receptor gene in familial and sporadic patients with male LH-independent precocious puberty.

Herein, we report mutation analysis of the LH receptor gene in 17 males with LH-independent precocious puberty, of which 8 were familial and 9 had a negative family history. A total of 7 different mutations (all previously reported) were detected in 12 patients. Among 10 European familial male-limited precocious puberty (FMPP) patients who had a LH receptor gene mutation, none had the Asp578Gly mutation, which is responsible for the vast majority of cases in the U.S. The restricted number of activating mutations of the LH receptor observed in this and other studies of FMPP strongly suggests that an activating phenotype is associated with very specific sites in the receptor protein. Clinical follow-up of the 5 patients who did not have LH receptor mutations shows that such cases most likely do not have true FMPP. LH receptor mutation analysis provides a sensitive tool for distinguishing true FMPP from other causes of early-onset LH-independent puberty in males.

Amino Acid Sequence↗
PubMed1999

A new X linked neurodegenerative syndrome with mental retardation, blindness, convulsions, spasticity, mild hypomyelination, and early death maps to the pericentromeric region.

We report on a family with an X linked neurodegenerative disorder consisting of mental retardation, blindness, convulsions, spasticity, and early death. Neuropathological examination showed mild hypomyelination. By linkage analysis, the underlying genetic defect could be assigned to the pericentromeric region of the X chromosome with a maximum lod score of 3.30 at theta=0.0 for the DXS1204 locus with DXS337 and PGK1P1 as flanking markers.

Blindness↗
PubMed1998

The role of the Th-1 to Th-2 shift of the cytokine profiles of CD4 helper cells in the pathogenesis of autoimmune and hypercatabolic diseases.

The task of the immune system is the continuous elimination of endogenous cellular debris and the elimination, when necessary, of exogenous structures. It therefore seems useful and practical to add to the paradigms 'self' and 'not self' the term 'altered self'. The concept of stress, introduced by W. B. Cannon and H. Selye in the 1930s, covers the wide range of aggressive environmental influences which for their part result in a uniform shift of the metabolism in the direction of catabolism. This results from the activation of the neuroendocrine stress axis, hypothalamus-pituitary-adrenals, and causes an increased release of catecholamines and glucocorticoids. These latter substances limit life-threatening acute-phase reactions by endogenous inflammation mediators. The purpose of the shift of the cytokine profiles of the CD4 lymphocytes from Th-1 to Th-2 is, with the return of a raised cortisol level to normal values, to temporarily take over the anti-inflammatory functions of the cortisol. A sustained Th-2 shift is an expression of a persistent hypercortisolism in autoimmune states. The suppression of the anti-inflammatory effects of cortisol as a result of states of excessive stress leads to hypercatabolic diseases such as AIDS, sepsis and toxic shock syndrome and protein calorie malnutrition (NAIDS). In the prevention and treatment of AIDS and NAIDS, besides the elimination of the causes of stress, the prophylactic and therapeutic efforts are based mainly on the activation of the mesenchymal production of anabolic matrix components, mainly glycosaminoglycans, and the neutralization of O2 and NO radicals and inflammation mediators from macrophages by polyanions and polyphenols. In our opinion, in sepsis and toxic shock syndromes, lasting reduction of the mortality rates for these diseases is best achieved through the early administration of high intravenous doses of gammaglobulins.

Animals↗
PubMed1998

An atypical form of bullous congenital ichthyosiform erythroderma is caused by a mutation in the L12 linker region of keratin 1.

Defective keratins are the cause of a number of hereditary disorders of the epidermis and other epithelia. The disease-causing mutations in keratins are clustered in the rod domain, and mutations in the helix boundary peptides cause the most severe forms of epidermal fragility syndromes. Siemens described a family with an atypical, mild form of bullous congenital ichthyosiform erythroderma. Linkage analysis in this family indicated that a defective type II keratin might be the underlying cause, keratins K1 and K2e being the best candidates. A substitution of valine for aspartic acid was detected at position 340 (D340V) in the L12 region of the K1 polypeptide. The mutation was found to cosegregate with the disorder in the family. Herewith, a genotype-phenotype correlation is shown for bullous congenital ichthyosiform erythroderma comparable with that described for epidermolysis bullosa simplex.

Genetic Linkage↗
PubMed1998

Localisation of a gene for non-specific X linked mental retardation (MRX46) to Xq25-q26.

We report linkage data on a new large family with non-specific X linked mental retardation (MRX), using 24 polymorphic markers covering the entire X chromosome. We could assign the underlying disease gene, denoted MRX46, to the Xq25-q26 region. MRX46 is tightly linked to the markers DXS8072, HPRT, and DXS294 with a maximum lod score of 5.12 at theta=0. Recombination events were observed with DXS425 in Xq25 and DXS984 at the Xq26-Xq27 boundary, which localises MRX46 to a 20.9 cM (12 Mb) interval. Several X linked mental retardation syndromes have been mapped to the same region of the X chromosome. In addition, the localisation of two MRX genes, MRX27 and MRX35, partially overlaps with the linkage interval obtained for MRX46. Although an extension of the linkage analysis for MRX35 showed only a minimal overlap with MRX46, it cannot be excluded that the same gene is involved in several of these MRX disorders. On the other hand, given the considerable genetic heterogeneity in MRX, one should be extremely cautious in using interfamilial linkage data to narrow down the localisation of MRX genes. Therefore, unless the underlying gene(s) is characterised by the analysis of candidate genes, MRX46 can be considered a new independent MRX locus.

Adult↗
PubMed1997

A Medical Mystery.

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Journal Article↗