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Biomedical subjects

A C Warren

Publications and source records attributed to A C Warren.

At least 37 records · Page 2Linked to original sources
PubMed1992

Comparative study of microsatellite and cytogenetic markers for detecting the origin of the nondisjoined chromosome 21 in Down syndrome.

Nondisjunction in trisomy 21 has traditionally been studied by cytogenetic heteromorphisms. Those studies assumed no crossing-over on the short arm of chromosome 21. Recently, increased accuracy of detection of the origin of nondisjunction has been demonstrated by DNA polymorphism analysis. We describe a comparative study of cytogenetic heteromorphisms and seven PCR-based DNA polymorphisms for detecting the origin of the additional chromosome 21 in 68 cases of Down syndrome. The polymorphisms studied were the highly informative microsatellites at loci D21S215, D21S120, D21S192, IFNAR, D21S156, HMG14, and D21S171. The meiotic stage of nondisjunction was assigned on the basis of the pericentromeric markers D21S215, D21S120, and D21S192. Only unequivocal cytogenetic results were compared with the results of the DNA analysis. The parental and meiotic division origin could be determined in 51% of the cases by using the cytogenetic markers and in 88% of the cases by using the DNA markers. Although there were no discrepancies between the two scoring systems regarding parental origin, there were eight discrepancies regarding meiotic stage of nondisjunction. Our results raise the possibility of recombination between the two marker systems, particularly on the short arm.

Base Sequence↗
PubMed1991

Alphoid DNA polymorphisms for chromosome 21 can be distinguished from those of chromosome 13 using probes homologous to both.

Although alphoid DNA sequences shared among acrocentric chromosomes have been identified, no human chromosome 21-specific sequence has been isolated from the centromeric region. To identify alphoid DNA restriction fragment length polymorphisms (RFLPs) specific for chromosome 21, we hybridized human genomic DNA with alphoid DNA probes [L1.26; aRI(680),21-208] shared by chromosomes 13 and 21. We detected RFLPs with restriction enzymes ECoRI, HaeIII, MboI,StuI, and TaqI. The segregation of these RFLPs was analyzed in the 40 CEPH families. Linkage analysis between these RFLPs and loci previously mapped to either chromosome 13 or 21 revealed RFLPs that appear to be specific to chromosome 21. These polymorphisms may be useful as genetic markers of the centromeric region of chromosome 21. Different alphoid loci within the centromeric region of chromosome 13 were identified.

Centromere↗
PubMed1991

A genetic linkage map of 27 markers on human chromosome 21.

We have constructed a genetic linkage map of the long arm of human chromosome 21 comprising 27 DNA markers. This map is an updated version of that reported earlier by group (1989, Genomics 4: 579-591), which contained 17 DNA markers. The current markers consist of 10 genes and 17 anonymous sequences. Traditional methods (restriction fragment length polymorphisms) were used to map 25 of these markers, whereas 2 markers were studied by polymerase chain reaction amplification of (GT)n dinucleotide repeats. Linkage analysis was performed on 40 CEPH families using the computer program packages LINKAGE, CRI-MAP, and MAPMAKER. Recombination rates were significantly different between the sexes, with the male map being 132 cM and the female map being 161 cM, assuming Kosambi interference and a variable ratio of sex difference in recombination. Approximately one-half of the crossovers in either sex occur distally, in terminal band 21q22.3, which also contains 16 of the markers studied. The average distance between adjacent markers was 6 cM.

Blotting, Southern↗
PubMed1990

Assignment of the Nance-Horan syndrome to the distal short arm of the X chromosome.

There are three types of X-linked cataracts recorded in Mendelian Inheritance in Man (McKusick 1988): congenital total, with posterior sutural opacities in heterozygotes; congenital, with microcornea or slight microphthalmia; and the cataract-dental syndrome or Nance-Horan (NH) syndrome. To identify a DNA marker close to the gene responsible for the NH syndrome, linkage analysis on 36 members in a three-generation pedigree including seven affected males and nine carrier females was performed using 31 DNA markers. A LOD score of 1.662 at theta = 0.16 was obtained with probe 782 from locus DXS85 on Xp22.2-p22.3. Negative LOD scores were found at six loci on the short arm, one distal to DXS85, five proximal, and six probes spanning the long arm were highly negative. These results make the assignment of the locus for NH to the distal end of the short arm of the X chromosome likely.

Abnormalities, Multiple↗
PubMed1990

Linkage mapping of the highly informative DNA marker D21S156 to human chromosome 21 using a polymorphic GT dinucleotide repeat.

A (GT)n repeat within the anonymous DNA sequence D21S156 was shown to be highly polymorphic in DNA from members of the 40 CEPH families. At least 12 alleles of this locus were recognized by electrophoresis on polyacrylamide gels of DNA amplified by the polymerase chain reaction (PCR) using primers flanking the (GT)n repeat. The polymorphism information content was 0.82. PCR amplification of DNA from somatic cell hybrid lines mapped D21S156 to human chromosome 21 and linkage analysis localized this marker close to the loci ETS2, D21S3, and HMG14 on chromosomal band 21q22.3. This polymorphism is highly informative and can serve as an anchor locus for human chromosome 21.

Alleles↗
PubMed1990

An alpha satellite DNA polymorphism specific for the centromeric region of chromosome 13.

Alpha satellite DNA is composed of variants of a short consensus sequence that are repeated in tandem arrays in the centromeric heterochromatin of each human chromosome. To define centromeric markers for linkage studies, we screened human genomic DNA for restriction fragment length polymorphisms using a probe detecting alphoid sequences on chromosomes 13 and 21. We describe one such DNA polymorphism. Analysis of linkage of this DNA marker to other polymorphic markers in the CEPH pedigrees demonstrates linkage to markers on the proximal long arm of chromosome 13 and defines the centromeric end of the linkage map of this chromosome.

Blotting, Southern↗
PubMed1990

The polydeoxyadenylate tract of Alu repetitive elements is polymorphic in the human genome.

To identify DNA polymorphisms that are abundant in the human genome and are detectable by polymerase chain reaction amplification of genomic DNA, we tested the hypothesis that the polydeoxyadenylate tract of the Alu family of repetitive elements is polymorphic among human chromosomes. We analyzed the 3' ends of three specific Alu sequences and found that two (in the adenosine deaminase gene and the beta-globin pseudogene) were polymorphic. This novel class of polymorphisms, termed AluVpA [Alu variable poly(A)] may represent one of the most useful and informative group of DNA markers in the human genome.

Alleles↗
PubMed1989

A genetic linkage map of 17 markers on human chromosome 21.

We have constructed a genetic linkage map of 17 markers on the long arm of human chromosome 21, including six genes and two anonymous loci with a variable number of tandem repeats. The estimated length of the map is 103 cM in males and 140 cM in females, assuming Kosambi interference. Recombination in females was approximately twice that in males between proximal markers. However, over half of the recombination events in either sex occur distally, in 21q22.3, although this region accounts for only about 15% of the physical length of chromosome 21.

Chromosome Mapping↗
PubMed1989

Major depression in Down's syndrome.

Five patients with trisomy 21 (Down's syndrome (DS], referred to us for evaluation of dementia, were instead found to have major depression. All had shown cognitive and behavioural deterioration and this had led to a mistaken diagnosis of Alzheimer's disease in two. We outline and contrast the features of major depression and Alzheimer's disease in DS, and suggest that electroconvulsive therapy is an effective treatment for major depression in DS.

Adolescent↗
PubMed1987

Evidence for reduced recombination on the nondisjoined chromosomes 21 in Down syndrome.

Trisomy 21 usually results from nondisjunction during meiosis I. In order to determine whether nondisjunction results from failure of normal chromosome pairing or premature unpairing, recombination frequencies were estimated between DNA polymorphic markers on the long arm of chromosome 21 in families containing one individual with trisomy 21. The recombination frequencies on chromosomes 21 that had undergone nondisjunction were then compared to those on chromosomes 21 that had disjoined normally. The data indicate that recombination is reduced between DNA markers on nondisjoined chromosomes 21. These results are consistent with the hypothesis that reduced chiasma formation predisposes to nondisjunction, resulting in trisomy 21 in humans.

Chromosome Mapping↗
PubMed1987

Gonadal function in patients with Down syndrome.

Gonadal function was evaluated in 100 home-reared persons with Down syndrome (DS) including 53 boys and men and 47 girls and women. In order to definitively evaluate gonadal function in our subjects, all patients with abnormal thyroid function were excluded from endocrine analysis. Among the men, the frequency of hypospadias and cryptorchidism was similar to that of the general population. In both men and women, the ages for the onset and completion of puberty were also normal. However, among adult men with DS, the mean stretched penile length and the mean testicular volume were significantly below the mean value of normal men. In the 23 men with DS, the mean serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were significantly elevated above the mean for normal men. By contrast, the mean plasma level of testosterone (T) was normal, suggesting a diagnosis of partial gonadal deficiency. Among the 14 women in the study, 6 had primary gonadal dysfunction. In prepubertal children, serum FSH levels in 3 boys and 5 girls were more than 2 SD above the mean for normal children, while serum levels of LH in 3 boys and 2 girls were abnormally elevated. When gonadal function was evaluated in male infants, serum levels of FSH were above the normal in 6 of 11 subjects. Serum LH was abnormally elevated in 3 of 8 female infants. Our data argue that primary gonadal deficiency is common in DS, that it is progressive from birth to adolescence, and that it is clearly manifest in adult patients.

Adolescent↗
PubMed1987

beta-Amyloid gene is not present in three copies in autopsy-validated Alzheimer's disease.

Recently, it has been suggested that Alzheimer's disease is associated with a duplication of the amyloid precursor protein gene localized to chromosome 21q21. In this study, a cloned DNA probe (B2.3), complementary to the sequence coding the beta-amyloid peptide, and DNA polymorphisms adjacent to this sequence were used to determine the number of copies of the beta-amyloid gene in DNA isolated from human blood and brain. Individuals with trisomy 21 (Down syndrome) who were heterozygous for the polymorphisms showed a gene-dosage effect, with one allele exhibiting twice the autoradiographic intensity as the other. Heterozygous individuals with Alzheimer's disease and controls showed equal intensities of the two allelic bands, suggesting that there are only two copies of the beta-amyloid gene in these individuals. In individuals with Alzheimer's disease and in controls who were homozygous for these polymorphisms, the number of copies of the beta-amyloid gene was determined by comparing the autoradiographic intensity of beta-amyloid alleles to that of DNA fragments detected by a reference probe. No difference was detected between these two groups.

Alzheimer Disease↗