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N Horn

Publications and source records attributed to N Horn.

At least 19 recordsLinked to original sources
PubMed1992

Mapping of the Menkes locus to Xq13.3 distal to the X-inactivation center by an intrachromosomal insertion of the segment Xq13.3-q21.2.

During a systematic chromosomal survey of 167 unrelated boys with the X-linked recessive Menkes disease (MIM 309400), a unique rearrangement of the X chromosome was detected, involving an insertion of the long arm segment Xq13.3-q21.2 into the short arm at band Xp11.4, giving the karyotype 46,XY,ins(X) (p11.4q13.3q21.2). The same rearranged X chromosome was present de novo in the subject's phenotypically normal mother, where it was preferentially inactivated. The restriction fragment length polymorphism and methylation patterns at DXS255 indicated that the rearrangement originated from the maternal grandfather. Together with a previously described X;autosomal translocation in a female Menkes patient, the present finding supports the localization of the Menkes locus (MNK) to Xq13, with a suggested fine mapping to sub-band Xq13.3. This localization is compatible with linkage data in both man and mouse. The chromosomal bend associated with the X-inactivation center (XIC) was present on the proximal long arm of the rearranged X chromosome, in line with a location of XIC proximal to MNK. Combined data suggest the following order: Xcen-XIST(XIC), DXS128-DXS171, DXS56-MNK-PGK1-Xqter.

Adult↗
PubMed1992

Characterization of a 1.0 Mb YAC contig spanning two chromosome breakpoints related to Menkes disease.

Menkes disease, an X-linked recessive disorder of copper metabolism, has recently been mapped to Xq13.3 by two Menkes patients carrying chromosome rearrangements within this region. The breakpoints have been investigated by nonisotopic in situ suppression hybridization using YACs isolated from this region with the flanking markers DXS56 and PGK1. Three YACs were extending over the breakpoints at Xq13.3 and were shown to be overlapping by partial digest restriction maps, IRS-PCR fingerprinting and by the presence of common cosmid clones. These cosmids were subcloned and one of the single copy probes detected both breakpoints using rare-cutting restriction enzyme digests of the patients. All the results together localize the breakpoints to about 100 kb within the overlapping region of the YACs. Mapping of both breakpoints in a 1 Mb YAC contig implies that these YACs contain at least partially, the gene responsible for Menkes disease.

Chromosome Aberrations↗
PubMed1992

Menkes disease: an X-linked neurological disorder of the copper metabolism.

Menkes disease is an X-linked, recessive disturbance of copper metabolism associated with a progressive clinical course and abnormal hair. The disease is dominated by neurological symptoms combined with connective tissue manifestations, most of which can be explained by the lack of important copper enzymes. Despite excessive accumulation of the metal in various tissues, a functional copper deficiency is evident, probably caused by a defective intracellular copper transport protein of unknown nature. The molecular basis of the copper disturbance has proven difficult to define and will most likely have to await cloning of the gene. The chromosomal region of interest has now been narrowed down to a sub-band on the long arm of the chromosome (Xq13.3), and positional cloning is in progress in a number of laboratories including our own. Identification of the Menkes gene will be of importance for our understanding of the cellular handling of copper and other trace elements.

Animals↗
PubMed1992

A lactococcal expression system for engineered nisins.

The nisin-producing Lactococcus lactis strain FI5876 has been modified and developed for use as an expression system for engineered nisin variants. Insertional inactivation of the resident nisA gene had a polar effect on downstream genes, including those involved in nisin immunity. However, subsequent chromosomal rearrangements in this region involving a newly discovered insertion element (IS905) generated a strain that was deficient in the nisA gene product but expressed those nisin determinants necessary for prenisin maturation, secretion, and immunity. Complementation of the lesion in the nisA gene by plasmid-encoded nisA genes containing site-specific mutations resulted in the exclusive production of altered nisins containing specific amino acid substitutions.

Amino Acid Sequence↗
PubMed1992

Multipoint linkage analysis in Menkes disease.

Linkage analyses were performed in 11 families with X-linked Menkes disease. In each family more than one affected patient had been diagnosed. Forty informative meioses were tested using 11 polymorphic DNA markers. From two-point linkage analyses high lod scores are seen for DXS146 (pTAK-8; maximal lod score 3.16 at recombination fraction [theta] = .0), for DXS1 (p-8; maximal lod score 3.44 at theta = .0), for PGK1 (maximal lod score 2.48 at theta = .0), and for DXS3 (p19-2; maximal lod score 2.90 at theta = .0). This indicates linkage to the pericentromeric region. Multilocus linkage analyses of the same data revealed a peak for the location score between DXS146(pTAK-8) and DXYS1X(pDP34). The most likely location is between DXS159 (cpX289) and DXYS1X(pDP34). Odds for this location relative to the second-best-supported region, between DXS146(pTAK-8) and DXS159 (cpX289), are better than 74:1. Visualization of individual recombinant X chromosomes in two of the Menkes families showed the Menkes locus to be situated between DXS159(cpX289) and DXS94(pXG-12). Combination of the present results with the reported absence of Menkes symptoms in male patients with deletions in Xq21 leads to the conclusion that the Menkes locus is proximal to DXSY1X(pDP34) and located in the region Xq12 to Xq13.3.

Female↗
PubMed1991

Incidence of Menkes disease.

We have calculated the incidence of Menkes disease for Denmark, France, The Netherlands, the United Kingdom and West Germany, based on known Menkes patients born during the time period 1976-87. Considering live-born Menkes patients, the combined incidence for these five countries is 1 Menkes patient per 298,000 live-born babies. If the number of affected aborted fetuses are taken into account, the incidence is 1 Menkes per 254,000 live-born babies. This incidence, which is 2-4 times lower than earlier published incidence figures, places Menkes disease as an extremely rare disease. The mutation rate for Menkes disease is estimated to be 1.96 x 10(-6), based on the number of isolated Menkes cases born during the time period 1976-87 and the total number of newborn males during this time.

Denmark↗
PubMed1991

Nisin biosynthesis genes are encoded by a novel conjugative transposon.

Genes for biosynthesis of the lactococcal peptide antibiotic nisin were shown to be encoded by a novel chromosomally located transposon Tn5301. The element is 70 kb in size and lacks inverted repeats at its termini. Although a copy of the insertion sequence IS904 is located near to one end, this did not appear to be involved in the transposition process. The integrated element is flanked by the directly repeated sequence 5'-TTTTTG-3'. Analysis of ten independent transconjugants revealed that Tn5301 integration is site-specific; two chromosomal targets were identified and shown to have some sequence homology. The element shares features with the Tn916 family of conjugative transposons and with Tn554 but is also exhibits some unique properties. Tn5301 is thus considered to be the prototype of a novel class of conjugative transposon.

Base Sequence↗
PubMed1990

Analysis of the genetic determinant for production of the peptide antibiotic nisin.

The structural gene for the precursor of the peptide antibiotic nisin was isolated and characterized. As with other lanthionine-containing antibiotics, nisin is synthesized as a pre-propeptide which undergoes post-translational modification to generate the mature antibiotic. The sequence data obtained agreed with those of precursor nisin genes isolated by other workers from different Lactococcus lactis strains. Analysis of regions flanking the precursor nisin gene revealed the presence of a downstream open reading frame that may be involved in maturation of the precursor molecule. Nucleotide sequences characteristic of an IS element were located upstream of the nisin determinant. This element, termed IS904, is present in multiple copies in the genome of L. lactis. The nisin determinant of L. lactis is a component of a large transmissible gene block that also encodes nisin resistance and sucrose-metabolizing genes. Gene probe experiments indicated that the nisin/sucrose gene block was located in the chromosome. Furthermore, the copy of IS904 identified adjacent to the precursor nisin gene lies at, or very close to, one end of this transmissible DNA segment and may play a role in mediating its transfer between strains.

Amino Acid Sequence↗
PubMed1990

Clinical expression of Menkes syndrome in females.

Three female patients with Menkes syndrome are described. Clinically, they have typical Menkes syndrome. Biochemically, they have significantly increased 64Cu-uptake in cultured fibroblasts. The chromosomal analysis was normal for two of the patients and abnormal for one patient (45X/46XX mosaicism).

Child, Preschool↗
PubMed1989

[Has Menckes' disease disappeared? Clinical picture and postnatal diagnosis].

Menkes disease is an X-linked recessive disease with an unknown disturbance in the copper-metabolism. We have been diagnosing patients for the last 15 years. Until 1978, six Danish families with Menkes disease were detected. Since 1978 we have only diagnosed one additional patient and one affected fetus in one of the already known families. As the incidence should be about 1 in 45,000 liveborn males, three additional patients should have been seen since 1978. To increase the chances of diagnosing all Danish Menkes patients the clinical symptoms are described. Until now, we have diagnosed 115 Menkes patients and have been in contact with more than 209 Menkes families from many different countries. If we compare the number of inhabitants per Menkes family in different countries, we obtain the following figures, 0.86 x 10(6) inhabitants per Menkes family in Denmark, increasing to 5.21 x 10(6) inhabitants per Menkes family in Italy. Finally some recent experience with copper therapy for treatment of Menkes patients is described.

Brain Diseases, Metabolic↗
PubMed1989

First-trimester diagnosis of Menkes disease: intermediate copper values in chorionic villi from three affected male fetuses.

Chorionic villus samples with copper contents of 1.91, 4.2, 5.6, and 6.3 ng/mg were observed in four cases with male karyotypes. These values were outside the range for unaffected males (0.30-0.85 ng/mg), and three of them were outside the control range (0.20-2.39 ng/mg). But these three values were below the values previously observed for affected Menkes fetuses (12.0-24.8 ng/mg). Follow-up by 64Cu uptake studies on the amniotic fluid cells was performed in three of these cases. A combination of 64Cu uptake and chase experiments on the amniotic fluid cells showed more convincingly than 64Cu uptake per se the direct copper values of 4.2 and 5.6 ng/mg to correspond to affected fetuses. Amniotic fluid cells from the male fetus with the CV copper value of 1.9 ng/mg showed normal results. The CV copper value of 6.3 ng/mg was considered pathognomonic for Menkes disease. The pregnancy was terminated, and the diagnosis was confirmed on fetal fibroblasts. Maternal deciduum prepared from the placentae showed in one of the cases with an affected fetus copper values ranging from 1.5 to 5.7 ng/mg. In six additional diagnostic cases, the copper content was determined in both CV samples and maternal deciduum. In three of these cases with normal CV sample copper, maternal decidua values of 4.85-7.8 ng/mg copper were observed. These results show that maternal deciduum contamination of a CV sample could cause a false-positive diagnosis.

Amniotic Fluid↗
PubMed1989

Prenatal and postnatal diagnosis of Menkes disease, an inherited disorder of copper metabolism.

105 patients with Menkes disease have been diagnosed from 64Cu-uptake studies in fibroblasts. These results are presented together with chase results following removal of 64Cu from the medium for 16 Menkes patients. Second-trimester prenatal diagnosis has been performed in 80 pregnancies with male karyotype. These 64Cu-uptake results show some overlap between the upper end of the normal range and the lower end of the Menkes range. Results are presented to show that a combination of 64Cu-uptake and chase results offers a better diagnostic potential than 64Cu-uptake per se. Chorionic villus copper values from 53 first-trimester prenatal diagnoses are presented. Maternal deciduum from some of these pregnancies contain similar high amounts of copper as found in the chorionic villus samples from affected fetuses. 64Cu-uptake in cultured chorionic villi from affected fetuses and unaffected fetuses is not discriminatory. Chase results seem however to offer a better diagnostic potential.

Brain Diseases, Metabolic↗
PubMed1988

The binding of mouse hybridoma and human IgE antibodies to the major fecal allergen, Der p I, of Dermatophagoides pteronyssinus. Relative binding site location and species specificity studied by solid-phase inhibition assays with radiolabeled antigen.

The relative binding site location and species specificity of 19 mouse hybridoma antibodies, produced in four laboratories, to Dermatophagoides pteronyssinus major fecal allergen, Der p I, was studied by using immobilized mAb and inhibitions of radiolabeled Ag binding. Four mAb groups were defined, within which 4, 6, 8, and 5 mAb, respectively, cross-inhibited each other. Five mAb were members of both group 2 and 3, demonstrating a considerable overlap of epitopes between the corresponding antibody-binding regions. The degree of mAb species specificity, as assessed by inhibition with cold Der p I and Ag Der m I and Der f I from the related species, Dermatophagoides microceras and Dermatophagoides farinae, was highly variable even for mAb binding to the same region on the Ag. Five cases of cross-reactivity between Der p I and Der m I and one case of cross-reactivity between Der p I and Der f I were found. The N-terminal 30 amino acids of the three species showed 7 substitutions between Der p I and Der m I/Der f I and 2 between Der f I and Der p I/Der m I. Single mAb inhibited up to 65% of labeled Der p I binding to immobilized human IgE from allergic patients' sera and up to 24% of labeled Der p I binding to immobilized rabbit antibodies. The spectrum of species specificities in human IgE sera, as assessed by inhibitions with cold Ag, was similar to that of the mAb. No evidence for the presence of strictly sequential epitopes, reactive with either mAb or human IgE was found, as judged from the weak inhibitory activity of acid-denatured Der p I.

Adult↗
PubMed1988

Variability in clinical expression of Menkes syndrome.

Six patients with Menkes syndrome are described, who differ from patients with the classical form of Menkes syndrome because of their longer survival; some of them also exhibited a milder manifestation of symptoms. Based on the present data and a summary of seven case reports describing Menkes patients with long survival, it may be possible to divide these patients into two subgroups: one group of severely affected patients with long survival and another group of very mildly affected patients with late onset of symptoms. Perhaps only the latter represents a true subgroup of Menkes syndrome. The possible benefits of copper therapy are discussed.

Brain Diseases, Metabolic↗
PubMed1988

Intestinal microflora and gastrointestinal adaptation in the rat in response to non-digestible dietary polysaccharides.

1. A comparison was made of the effect of a fibre-free diet and diets containing non-digestible polysaccharides on rat caecal and colonic physiology and microflora. 2. All polysaccharide-containing diets led to enlargement of the caecum and colon, associated with increased weight of contents, and of tissue. Carboxymethylcellulose (CMC) had the most marked effect and animals given this also had watery faeces. 3. The density of bacteria in the caecum and colon varied significantly with diet and the proportion of aerobic bacteria in the flora was increased by the CMC diet. 4. In vitro, CMC and hydroxypropylmethylcellulose were poorly fermented. 5. There was a high correlation (caecum r 0.93; colon r 0.94) between tissue weight and wet weight of organ contents but no correlation with bacterial density, number of bacteria per organ, moisture content or short-chain fatty acid content. 6. It is concluded that caecal and colonic enlargement is due to tissue hypertrophy in response to increased bulk of contents, irrespective of the nature of that bulk which varies with diet; it is unlikely that short-chain fatty acids or other microbial metabolites are the stimulus for the trophic response seen when non-digestible dietary polysaccharides are fed to rats.

Adaptation, Physiological↗
PubMed1987

Experience with first trimester prenatal diagnosis of Menkes disease.

We have performed 28 first trimester diagnoses for Menkes disease in 27 high risk pregnancies by direct copper measurement on chorionic villi (c.v.) Two male fetuses were found to be affected because of significantly increased copper content. In one male fetus a slightly increased copper content was observed indicating an exogenous copper contamination of the sample. This view was supported by normal results observed after abortion. Three out of 15 diagnostic c.v. samples with a female karyotype showed increased copper levels. In two of these cases, part of the copper content might have been released from the cannulae used for these particular biopsies. Histochemical visualization of copper accumulation in fixed chorionic villi of two affected fetuses and one female fetus was observed. [64Cu]-uptake studies have been performed on 11 diagnostic and 10 control c.v. samples. As the control samples in some cases were found to incorporate more [64Cu] than the corresponding diagnostic sample, this method cannot at present be used for diagnosis. Compiled results on newborn females gave evidence that two carriers expressed the paternal X-chromosome, and two carriers expressed the maternal X-chromosome in in chorionic villi.

Adult↗
PubMed1987

Postmortem Menkes diagnosis from carrier testing of female relatives.

A boy who died at 6 months of age was noted to have sparse, stubby and light hair, pili torti were observed microscopically, and his skin was dry and redundant. As a suspicion of Menkes disease was first raised after his death, serum copper and ceruloplasmin in serum were not measured. Unfortunately, no fibroblasts were available - only fixed and paraffin-embedded samples of brain, spleen and liver. The copper contents of the brain and the liver were lower than in an age-matched control. Fibroblast cultures from the mother, the maternal grandmother, and a maternal aunt of the index patient were analysed for 64Cu-uptake. All these females showed the uptake values expected for Menkes carriers, thus supporting the clinical suspicion of Menkes disease in the index patient. From the above-mentioned results it was highly likely that the index patient had suffered from Menkes disease. Adequate genetic counseling could thus be offered to the family, and in the next pregnancy a first trimester prenatal diagnosis was performed.

Brain Chemistry↗