Dinucleotide repeat polymorphism at the D5S134 locus linked to the adenomatous polyposis coli (APC) gene.
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Base Sequence↗
Biomedical subjects
R J Trent
Publications and source records attributed to R J Trent.
Australian beta zero-thalassaemia: a high haemoglobin A2 beta zero-thalassaemia due to a 12 kb deletion commencing 5' to the beta-globin gene.
A large novel deletional beta zero-thalassaemia mutation associated with unusually high levels of haemoglobin A2 in heterozygotes is described in an Australian family. The deletion was characterized by restriction enzyme analysis followed by PCR amplification and sequencing of the breakpoint region. Australian beta zero-thalassaemia extends from 835 basepairs (bp) 5' to the cap site of the beta-globin gene downstream for 12.023 kb. This deletion, similar to previously described deletional beta zero-thalassaemias associated with high Hb A2, removes sequences 5' to the beta-globin gene promoter and emphasizes the functional importance of the 5' beta-globin region in eliciting the unusually high Hb A2 phenotype.
Base Sequence↗
HLA-DR,DQ nucleotide sequence polymorphisms in five Melanesian populations.
HLA-DRB1 nucleotide sequence polymorphisms have been examined in 304 Melanesians from the Papua New Guinean coast (Madang), islands (Rabaul) and highlands (Goroka), and from New Caledonia and Fiji. A total of 20 HLA-DRB1 alleles were detected by oligonucleotide hybridizations of exon 2 HLA-DRB1 polymerase chain reaction products, in a typing protocol designed to detect all 42 officially-designated HLA-DRB1 alleles. DRB1*1502 and 1101 alleles were the most common alleles in coastal and island Melanesians, while DRB1*1501, 1502 and 1408 predominated in Papua New Guinean highlanders. Undefined mixed lymphocyte reaction determinants in earlier studies of Melanesians could be accounted for in the present study as DRB1*0410, 1407 and 1408 in Papua New Guinean highlanders and as DRB1*1104 and 1602 in coastal people. Nucleotide sequence polymorphisms at HLA-DQA1, -DQB1, -DRB3 and -DRB5 were also determined for estimating HLA-DR,DQ allelic disequilibrium relationships; unusual haplotypes in Melanesians included DBR1*1502, DRB5*0101 and DRB1*0410, DQB1*0402. Previous claims of limited heterogeneity in the HLA-DR allele repertoire in Melanesians are now seen to reflect limitations of early typing reagents rather than any dramatic restriction in HLA-DR allelic diversity.
Alleles↗
Risk estimation in familial adenomatous polyposis using DNA probes linked to the familial adenomatous polyposis gene.
The familial adenomatous polyposis gene has recently been assigned to the long arm of chromosome five through linkage to several 5q DNA probes. These probes can now be used to trace inheritance of the disease gene in affected families. In this study, DNA samples from 152 members of 10 Australian familial adenomatous polyposis families have been examined for restriction fragment length polymorphisms detected by DNA probes C11P11, ECB27, and YN5.48. Linkage analysis confirmed linkage between the familial adenomatous polyposis gene and each probe with a maximum combined LOD score of 2.82 for C11P11, 2.90 for ECB27 and 5.49 for YN5.48 all at a recombination fraction of zero. Risk estimates were determined for the 51 at risk individuals in these families based on their restriction fragment length polymorphism data alone or in addition by including the effect of age dependent penetrance. Thirty two of those at risk (63%) could be assigned specific high (greater than or equal to 95%) or low (less than or equal to 5%) risks of developing familial adenomatous polyposis on the basis of their probe results. When the effect of age dependent penetrance was included, 26 (51%) fell at the extremes of risk (greater than or equal to 99% or less than or equal to 1%). Such estimates provide a sound basis for planning sigmoidoscopic screening of at risk family members and will thus facilitate surveillance in familial adenomatous polyposis families.
Adenomatous Polyposis Coli↗
Limited genetic diversity in polynesians reflected in the highly polymorphic 3'HVR alpha-globin gene marker.
Polynesians from five distinct island groups were studied with DNA probe alpha 3'HVR, a highly polymorphic VNTR (variable number of tandem repeats) minisatellite region associated with the alpha-globin gene cluster. Results showed a paucity of genetic heterozygosity together with clustering of alpha 3'HVR alleles with alpha-globin DNA haplotypes and alpha-globin gene rearrangements. This restricted diversity is consistent with population bottlenecks in the colonization of Polynesia.
Alleles↗
Implications of rDNA technology in the microbiology laboratory.
The present and potential future roles in service and research microbiological laboratories of recombinant DNA (rDNA) techniques (nucleic acid hybridization, nucleic acid amplification, in situ hybridization, pulsed field gel electrophoresis) are described. Applications rDNA technology include the detection of micro-organisms; an approach to the understanding of their role in disease pathogenesis and provision of alternative strategies for studying the epidemiology of infectious diseases.
DNA, Recombinant↗
Detection of beta and delta globin gene mutations by PCR and direct DNA sequencing in an individual with normal HbA2 beta thalassemia.
Normal HbA2 beta thalassemia in a Greek individual was shown to be due to co-inheritance of beta and delta thalassemias. The genetic defects were characterized by enzymatic amplification of the beta and delta globin genes and direct genomic sequencing. Two children with a typical high HbA2 beta thalassemia trait had inherited the beta thalassemia allele whilst a third child had low-normal HbA2 associated with delta+ thalassemia. Segregation patterns confirmed that the delta+/beta zero thalassemia defects were present in trans.
Adult↗
An A gamma globin promoter (four base-pair deletion) mutant shows linked polymorphic changes throughout the A gamma gene.
The A gamma fetal globin genes from a large Australian kindred with nondeletional A gamma hereditary persistence of fetal hemoglobin (HPFH) were cloned and sequenced. The -198 T----C mutation (British type HPFH) was demonstrated upstream of the A gamma gene on one allele. On the other allele, a 4-deletion was identified -222 to -225 bp upstream from the cap site. The 4-bp deletion allele was associated with a number of variations in the A gamma gene sequence: anA gamma T transition, in the second exon (T----C at +402 relative to the cap site); a HindIII polymorphism in the second intron; and a G gamma-like sequence in the 3' untranslated region (TCAC in place of CTCT, creating a SacI site). An association between the -222 to -225 deletion, the A gamma T polymorphism, and the second intron HindIII polymorphism has previously been reported. In addition, linkage of the HindIII polymorphism with the G gamma-like sequence in the 3' untranslated region of A gamma has also been described. The case described here is unique, with all four changes present in the one A gamma gene. It is also noteworthy because there is simultaneous occurrence of high (HPFH) and low (-222 to -225 deletion) expression mutants in the same patient. Despite the presence of the 4-bp deletion, the resulting hematological phenotype remained that of HPFH. When the 4-bp deletion promoter was studied in a K562-cell transient expression assay, there was found to be no statistically significant reduction in activity compared to the control A gamma promoter. The possible reasons for the observed differences between the in vivo and in vitro activity of this mutation are discussed.
Alleles↗
Outcome of 1500 consecutive chorionic villus samplings.
OBJECTIVE: To evaluate the clinical complications and diagnostic problems of chorionic villus sampling. DESIGN: A pragmatic retrospective analysis. SETTING: Tertiary obstetric referrals mostly to private practice; sampling carried out at Royal Prince Alfred Hospital; diagnostic analysis usually at Oliver Latham Laboratory, or the Clinical Immunology Research Centre, Royal Prince Alfred Hospital, New South Wales. PATIENTS: 1500 women in the first trimester of pregnancy requesting prenatal diagnosis because of a risk of chromosomal or inherited genetic disorder in the fetus. INTERVENTIONS: Ultrasound-guided passage of a catheter into the chorion through the cervix. MAIN OUTCOME MEASURES: Incidence of unintended abortion, preterm births, low weight infants and discrepant karyotypes. RESULTS: There were 42 unintended abortions (3.0%), about 0.4% higher than the background abortion rate in women of similar age. Abortion did not occur more frequently in women with vaginal bleeding earlier in that pregnancy. Rates of preterm births and birth of low birthweight infants did not differ from the general population. A second diagnostic test was required in 68 women (4.5%). Mosaicism and tetraploidy were usually confined to the chorion. CONCLUSION: Chorionic villus sampling is an acceptable diagnostic test. Amniocentesis should be offered to patients who show mosaicism or tetraploidy.
Abortion, Spontaneous↗
Dinucleotide repeat polymorphism of D15S10 in the Prader-Willi chromosome region (PWCR).
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Base Sequence↗
The single zeta globin gene rearrangement: hematologic phenotype and its frequent occurrence in Polynesian Niueans.
The single zeta globin gene rearrangement (-zeta/) is an unusual mutation associated with the alpha globin gene cluster on chromosome 16p13.3. It has been detected regularly among West Africans (gene frequency approximately 0.05) and sporadically among other populations. DNA samples from 186 Polynesian Niueans living in Auckland, New Zealand, were studied. Eighteen (gene frequency 0.05) were shown to have the -zeta/gene arrangement, which results from loss of the psi zeta 1 gene. Hematological phenotypes in six cord blood samples and 12 affected adults were normal. The high frequency for -zeta/in Niueans may represent another example of genetic drift and a founder effect in Polynesians or may reflect a different founding population.
Chromosomes, Human, Pair 16↗
A de novo unbalanced reciprocal translocation identified as paternal in origin in the Prader-Willi syndrome.
Interstitial cytogenetic deletions involving the paternally derived chromosome 15q11-13 have been described in patients with the Prader-Willi syndrome (PWS). We report a child with PWS and a de novo unbalanced karyotype -45,XY,-9,-15,+der(9)t(9;15)(q34;q13). Molecular studies with the DNA probe pML34 confirmed that only a single Prader Willi critical region (PWCR:15q11.2-q12) copy was present. Hybridisation of patient and parental DNA with the multi-allelic probe CMW1, which maps to pter-15q13, showed that the chromosome involved in the translocation was paternal in origin. This is the first example of a paternally-derived PWCR allele loss caused by an unbalanced translocation that has arisen de novo.
Blotting, Southern↗
Polymerase chain reaction (PCR) mutagenesis enabling rapid non-radioactive detection of common beta-thalassaemia mutations in Mediterraneans.
The IVS-1-110 (G----A) and IVS-1-1 (G----A) mutations occur in approximately 33% and 9% respectively of beta-thalassaemia alleles in Mediterraneans (Kazazian & Boehm, 1988). They are generally detected in polymerase chain reaction (PCR)-amplified material by allele-specific oligonucleotide (ASO) hybridization patterns. In this study, artificial base substitutions in amplified material have been created to distinguish normal from mutant alleles on the basis of restriction enzyme digestion patterns. Invariant target sites provide an internal control for restriction enzyme activity. Mutagenesis was achieved by 3' base mismatches in primers selected to anneal immediately adjacent to target sites. Digestion of PCR products from normal and thalassaemic alleles with the restriction enzymes MboI (IVS-1-110) and HinfI (IVS-1-1) produced different fragments on electrophoresis. The above strategy was validated by allele-specific oligonucleotide probing. Identification of the three commonest mutations in this population (IVS-1-110, codon 39 and IVS-1-1), which account for approximately 69% of thalassaemic alleles (Kazazian & Boehm, 1988), was subsequently undertaken in seven chorion villus biopsies.
Base Sequence↗
An unusual cutaneous lymphoma with B and T cell characteristics showing gallium-67 positive benign thymic hyperplasia following intensive chemotherapy.
This case illustrates two interesting features. Firstly it describes an unusual cutaneous lymphoma in an adolescent girl. This lymphoma showed features of B and T cell lineages with rearrangements of both immunoglobulin heavy chain and T cell beta chain genes. Secondly it describes the development of gallium-67 citrate (67Ga) scan positive benign thymic hyperplasia, 15 months after diagnosis and three months after cessation of intensive chemotherapy.
Adolescent↗
Molecular and cytogenetic studies of the Prader-Willi syndrome.
Twenty-seven subjects with the Prader-Willi syndrome (PWS) were studied. Sixteen (59%) had a cytogenetic deletion involving chromosome 15q11-13. Nine were non-deletional and two patients had structural rearrangements of chromosome 15: 47,XY, + del(15)(pter----q12), var(15)(p11) and 45,XX,t(14q15q). At the DNA level, a greater proportion of patients (74%) showed loss of one chromosome 15q11-13 allele using a combination of densitometry and RFLP analysis. Deletion sizes were variable with 13 of 20 detectable both cytogenetically and with probe pML34 (D15S9). The remaining seven had microdeletions at the pML34 locus. Heterogeneity was further seen in three subjects who had cytogenetic deletions but normal DNA studies. In one patient there was evidence of a duplication at the pML34 locus. A new molecular rearrangement was identified with probe p3.21 (D15S10) in two patients and their mothers. Fifteen family studies were performed. In all 10 families where there was a molecular deletion, this was shown to have arisen de novo. DNA mapping confirmed that the paternal 15q allele was lost in three patients with PWS.
Adolescent↗
Utility of the polymerase chain reaction (PCR) for prenatal diagnosis of genetic disease.
Gene amplification by the polymerase chain reaction (PCR) has been applied to prenatal diagnosis for alpha and beta thalassemias (1 and 5 cases respectively), Hemoglobin (Hb) Lepore/beta thalassemia (1 case) and cystic fibrosis (14 cases). Chorionic villus samples were obtained in the tenth week of pregnancy and DNA analysed in parallel with conventional gene mapping. Direct diagnosis of the common Mediterranean beta-thalassemia mutations (IVS-1-110 and codon 39), Hb Lepore, and the delta F508 mutation causing cystic fibrosis was achieved by hybridization of amplified material with pairs of allele-specific oligonucleotide (ASO) probes or by restriction enzyme digestion of PCR products. Results were confirmed by DNA mapping. Definitive diagnosis or exclusion of an affected fetus was possible in 17 of 21 cases thus examined. PCR reduces the time required for prenatal diagnosis. DNA contamination is a potential source of error.
Alleles↗
Molecular genetics and cytogenetics--a glossary and list of abbreviations.
A glossary of terms commonly used in molecular genetics and cytogenetics has been prepared to assist pathologists. The emphasis is on clinically relevant examples.
Abbreviations as Topic↗