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Biomedical subjects

A L Jørgensen

Publications and source records attributed to A L Jørgensen.

At least 19 recordsLinked to original sources
PubMed2001

Creutzfeldt-Jakob disease segregating in a three generation Danish family.

A three generation family is presented in which rapidly progressive, early-onset Creutzfeldt-Jakob disease without typical EEG changes segregates as an autosomal dominant disease. An aspartic acid to asparagine mutation at codon 178 of the prion gene, PRNP, co-segregates with the disease. As expected, the disease allele also carries the valine codon of the polymorphic valine/methionine codon 129 of the gene. In family members homozygous for this valine codon the disease was more rapidly progressive than in a heterozygous family member, who had a variant clinical phenotype. Definite neuropathological diagnosis required prion staining with specific antibodies.

Adult↗
PubMed1999

A presenilin-1 Thr116Asn substitution in a family with early-onset Alzheimer's disease.

Mutation in the presenilin-1 (PS-1) gene at chromosome 14q24.3 is the most common cause of autosomal dominant early-onset Alzheimer's disease. Here, we report a novel missense mutation in the presenilin-1 gene found in a three-generation Danish family with autopsy-verified early-onset Alzheimer's disease. Two affected first-degree relatives in two generations were found to be heterozygous for a cytosine to adenine transversion at the second position of codon 116, which changes the amino acid at that position from threonine to asparagine. This conservative amino acid substitution occurs in an evolutionary highly conserved region of the PS-1 protein and is associated with onset of the disease between age 35 and 41 years and 4-8 years' duration of the disease. Analysis of amyloid beta-protein (A beta) deposition in brain specimens from one affected family member showed predominance of A beta 42(43). Onset and progression of the disease were very similar in two sibs homozygous for the epsilon 3 allele and the epsilon 4 allele, respectively, of the polymorphic apolipoprotein E locus. The lack of effect of the high risk epsilon 4/epsilon 4 genotype on the disease in this family corroborates and extends previous observations that the presence of one copy of the epsilon 4 allele does not modulate PS-1 associated Alzheimer's disease.

Adult↗
PubMed1997

[Alzheimer's disease and genes].

Alzheimer's disease is genetically heterogeneous. The rare familial early-onset form of the disease is caused by dominant mutations in at least four different genes. Three of these genes have now been identified and the gene for presenilin 1 (PS1) on chromosome 14 is mutated in about 75% of the families. By contrast, the common form of Alzheimer's disease has late onset and may occur as sporadic cases in the families. This form is multifactorial and the most important genetic risk factor is the E4 allele of the polymorphic apolipoprotein E gene (APOE) on chromosome 19. The E4 allele is associated with moderately or strongly increased lifetime risk of Alzheimer's disease in persons with respectively one or two copies of the gene variant. Apolipoprotein E genotyping may serve as an adjunct in the diagnostic evaluation of Alzheimer's disease, but predictive genotyping of asymptomatic persons is premature and should not be done.

Alzheimer Disease↗
PubMed1997

[Apolipoprotein E genotypes in patients investigated for dementia].

Certain genotypes of apolipoprotein E (apoE, locus APOE) are associated with an increased risk for development of Alzheimer's disease. We present the distribution of the APOE alleles (E2, E3 and E4) in 50 Danish patients referred to a dementia clinic. The distribution of alleles in patients with dementia was E2: 2, E3: 36 and E4: 38; and in 12 patients without dementia E2: 1, E3: 18, and E4: 5. The frequency of E4 alleles was significantly increased (chi 2 = 42; df = 1; p < 10(-4)) among patients with Alzheimer's disease compared with a Danish control population. The study demonstrates a strong association between Alzheimer's disease and the E4 allele. No difference was found in the frequency of the E4 allele between Alzheimer and non-Alzheimer demented patients.

Alleles↗
PubMed1997

Alphoid repetitive DNA in human chromosomes.

The thesis describes the first extensive DNA sequence analysis that demonstrated that the tandemly repeated alphoid DNA in the centromere of the human chromosomes consists of distinct subfamilies and in a number equal to or exceeding the number of chromosomes. The expected presence of only one or a few distinct subfamily on individual chromosomes was supported by the characterization of an extremely well-defined subfamily specific for chromosome 7 and represented in the original collection of subfamilies. The pattern of chromosome-specificity breaks down among the acrocentric chromosomes where chromosomes 13 and 21 were found to share one and chromosomes 14 and 22 to share another specific subfamily. By in situ hybridization these subfamilies were shown not to be shared by other chromosomes. The remarkable pairwise pattern of sequence homogenization was present also in the chimpanzee genome raising the question of its biological role. However, the subfamilies on these human and chimpanzee chromosomes are not orthologous but were shown to originate from two evolutionarily different repeat families. It follows that dramatic sequence evolution has occurred in one or both species during or after separation. The sequence evolution might even occur at a higher rate in humans. This possibility was studied in orthologous alphoid sequences on the X chromosome of humans and the great apes. The analysis supports the general view that our closest relative is the chimpanzee and indicates that the rate of recombination is increased in the human repeat DNA. A "molecular clock" running faster in this DNA may have evolutionary implications. Finally, the usefulness of alphoid subfamilies as chromosome-specific markers is illustrated in a cytogenetic dissection of the centromeric region of Robertsonian translocations. The breakpoints were located to satellite III DNA leaving these chromosomes dicentric. The order of the different tandem DNAs on the p-arm of the acrocentric chromosomes could also be established.

Animals↗
PubMed1996

Extreme variant of the short arm of chromosome 15.

Using fluorescence in situ hybridization, primed in situ labelling, and conventional cytogenetic staining we have characterized an excessively enlarged short arm of chromosome 15. The likely mechanism explaining this variant chromosome involves amplification of rDNA sequences followed by inverted insertional translocation between the enlarged sister chromatids of the short arm of chromosome 15.

Chromatids↗
PubMed1996

A new mechanism in blue cone monochromatism.

Blue cone monochromatism (BCM) is a rare X-linked colour vision disorder characterized by the absence of both red and green cone sensitivity. Most mutations leading to BCM fall into two classes of alterations in the red and green pigment gene array at Xq28. In one class the red and green pigment genes are inactivated by deletion in the locus control region. In the second class genetic rearrangements have created an isolated pigment gene that carries an inactivating point mutation. Here we describe a clinical case of BCM caused by a new mutation where exon 4 of an isolated red pigment gene has been deleted. The finding represents the first intragenic deletion yet described among red and green pigment genes.

Base Sequence↗
PubMed1996

Familial Alzheimer's disease co-segregates with a Met146I1e substitution in presenilin-1.

The presenilin-1 (PS-1)/S 182 gene at chromosome 14q24.3 is, when mutated, the most common disease gene in autosomal dominant early-onset Alzheimer's disease. Substitution of methionine 146 of the gene product for either valine or leucine co-segregates with Alzheimer's disease with the age of onset in the late thirties or early forties. Here we describe a new substitution of methionine 146 for isoleucine that co-segregates with Alzheimer's disease with age of the onset in the early forties. All identified missense mutations in methionine codon 146 replace one hydrophobic amino acid (Met) with another (Val, Leu, Ile) and correspond to any nucleotide change at the first or third position of the codon. Second position mutations invariably lead to replacement of the hydrophobic methionine with a hydrophilic amino acid that may severely affect the function of the protein. The fact that no second position mutations have been identified so far may support the hypothesis that the protein product of PS-1 plays a crucial role during development.

Adult↗
PubMed1995

[Molecular genetics of red-green color blindness].

Normal colour vision is trichromatic and is mediated by the blue, green and red visual pigments present in the corresponding blue, green, and red cone cells of the retina. The red and green pigment genes have evolved from an ancestral pigment gene and reside in a head-to-tail tandem array on the long arm of the X chromosome. This arrangement and a high degree of homology predispose to illegitimate recombination between the red and green pigment genes explaining the various forms and the high frequency of red-green colour vision defects.

Color Vision Defects↗
PubMed1995

[Molecular genetic examination in sex-linked color blindness].

The molecular structure of the X-linked colour-vision locus was studied in a family where mild red-green colour-vision deficiency (deuteranomaly) segregated, and in a male with complete absence of red and green colour-vision (blue cone monochromasy). In individuals with normal colour-vision the red and green pigment genes had normal molecular structure whereas individuals with deuteranomaly, in addition to normal red and green genes, also had an abnormal hybrid gene consisting of parts of the green and red pigment genes. The individual with blue cone monocromasy had only a red-green hybrid gene inactivated by a critical mutation in codon 203. Thus, the phenotypes predicted from the individual genotypes were in complete accord with the observed phenotypes.

Adult↗
PubMed1994

Apolipoprotein E uptake and degradation via chloroquine-sensitive pathway in cultivated monkey cells overexpressing low density lipoprotein receptor.

Alzheimer's disease with late onset is associated with inheritance of isoform 4 of the polymorphic apolipoprotein E (ApoE). We describe an experimental model where intracellular interaction between ApoE isoforms and cellular proteins may be studied. Internalization and intracellular fate of ApoE from fresh normal cerebrospinal fluid is followed in COS cells (an SV40 transformed Simian kidney cell line) overexpressing the low density lipoprotein receptor. Chase and chloroquine experiments strongly suggest that internalized ApoE travels through the endosomal-lysosomal pathway after dissociation from the receptor in early endosome.

Alzheimer Disease↗
PubMed1993

X-inactivation pattern in carriers of X-linked retinitis pigmentosa: a valuable means of prognostic evaluation?

In a large family with X-linked retinitis pigmentosa 2 (XLRP2), we reexamined 7 obligate carrier females and 6 daughters of obligate carriers, whose linkage relationships suggested that they carried the XLRP2 gene. The phenotype varied from totally normal eyes through mild retinal changes to complete loss of vision. The X-inactivation analysis was carried out with the highly informative probe M27 beta on DNA from blood lymphocytes. This probe detects a locus DXS255 that is differentially methylated on the active and inactive X chromosomes. In 5 blind heterozygotes (aged 43 to 68 years), we found that the X chromosome carrying the RP2 gene was methylated and active in nearly all their cells. The opposite X inactivation pattern was found in a carrier female (aged 45 years) who gave normal findings on eye examination. Carriers with less skewed X inactivation had a less severe clinical outcome. However, we found little or no correlation between their phenotypes and the methylation status of their X chromosomes. Our results suggest that it may be possible to develop a predictive test that could identify cases with severe outcome and perhaps cases with normal outcome.

Adolescent↗
PubMed1992

Evolutionarily different alphoid repeat DNA on homologous chromosomes in human and chimpanzee.

Centromeric alphoid DNA in primates represents a class of evolving repeat DNA. In humans, chromosomes 13 and 21 share one subfamily of alphoid DNA while chromosomes 14 and 22 share another subfamily. We show that similar pairwise homogenizations occur in the chimpanzee (Pan troglodytes), where chromosomes 14 and 22, homologous to human chromosomes 13 and 21, share one partially homogenized alphoid DNA subfamily and chromosomes 15 and 23, homologous to human chromosomes 14 and 22, share another extensively homogenized subfamily. Such a pattern of homogenization presumably predates speciation 3-10 million years ago. However, the alphoid DNA on these human and chimpanzee chromosomes is not orthologous but originates from two evolutionarily different repeat families. It follows that dramatic sequence evolution has occurred in a concerted fashion among the chromosomes in one or both species during or after separation.

Animals↗
PubMed1992

Higher rate of evolution of X chromosome alpha-repeat DNA in human than in the great apes.

The rate of introduction of neutral mutations is lower in man than in other primates, including the chimpanzee. This species is generally regarded as our closest relative among the great apes. We present here an analysis of sequences of X chromosomal alphoid repetitive DNA from man and the great apes, which supports the closer relationship between man and chimpanzee and indicates a considerably increased rate of recombination in the human repeat DNA. These results indicate that the 'molecular clock' is running more quickly in man.

Animals↗
PubMed1992

Breakpoints in Robertsonian translocations are localized to satellite III DNA by fluorescence in situ hybridization.

We characterized 21 t(13;14) and 3 t(14;21) Robertsonian translocations for the presence of DNA derived from the short arms of the translocated acrocentric chromosomes and identified their centromeres. Nineteen of these 24 translocation carriers were unrelated. Using centromeric alpha-repeat DNA as chromosome-specific probe, we found by in situ hybridization that all 24 translocation chromosomes were dicentric. The chromatin between the two centomeres did not stain with silver, and no hybridization signal was detected with probes for rDNA or beta-satellite DNA that flank the distal and proximal ends of the rDNA region on the short arm of the acrocentrics. By contrast, all 24 translocation chromosomes gave a distinct hybridization signal when satellite III DNA was used as probe. This result strongly suggests that the chromosomal rearrangements leading to Robertsonian translocations occur preferentially in satellite III DNA. We hypothesize that guanine-rich satellite III repeats may promote chromosomal recombination by formation of tetraplex structures. The findings localize satellite III DNA to the short arm of the acrocentric chromosomes distal to centromeric alpha-repeat DNA and proximal to beta-satellite DNA.

Centromere↗
PubMed1992

Different patterns of X inactivation in MZ twins discordant for red-green color-vision deficiency.

Two female identical twins who were clinically normal were obligatory heterozygotes for X-linked deuteranomaly associated with a green-red fusion gene derived from their deuteranomalous father. On anomaloscopy, one of the twins was phenotypically deuteranomalous while the other had normal color vision. The color vision-defective twin had two sons with normal color vision and one deuteranomalous son. X-inactivation analysis was done with the highly informative probe M27 beta. This probe detects a locus (DXS255) which contains a VNTR and which is somewhat differentially methylated on the active and inactive X chromosomes. In skin cells of the color vision-defective twin, almost all paternal X chromosomes with the abnormal color-vision genes were active, thereby explaining her color-vision defect. In contrast, a different pattern was observed in skin cells from the woman with normal color vision; her maternal X chromosome was mostly active. However, in blood lymphocytes, both twins showed identical patterns with mixtures of inactivated maternal and paternal X chromosomes. Deuteranomaly in one of the twins is explained by extremely skewed X inactivation, as shown in skin cells. Failure to find this skewed pattern in blood cells is explained by the sharing of fetal circulation and exchange of hematopoietic precursor cells between twins. These data give evidence for X inactivation of the color-vision locus and add another MZ twin pair with markedly different X-inactivation patterns for X-linked traits.

Chromosome Mapping↗