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31.
Somatic mutation processes at a human minisatellite 总被引:6,自引:3,他引:6
Germline instability at human minisatellites frequently involves complex
inter-allelic transfers of repeat units usually restricted to one end of
the repeat array and apparently regulated by flanking DNA. In contrast,
nothing is known about the structural basis of somatic instability at
minisatellites. An electrophoretic size-enrichment strategy was therefore
developed at minisatellite MS32 (D1S8) to enable rare abnormal-length
mutants to be detected, validated and quantitated in blood DNA by single
molecule PCR. Structural analysis of rare mutant alleles in blood revealed
simple deletions/duplications of repeat unit blocks located at random along
the tandem repeat array, a mode of mutation completely different from that
seen in sperm. Furthermore, allele-specific suppression of sperm
instability at MS32 did not affect somatic instability. These data suggest
that conversion-based minisatellite mutation in sperm is completely
germline-specific and most likely meiotic in origin. Somatic instability
appears to occur by a separate pathway involving replication slippage or,
more likely, intra-allelic unequal crossing over.
相似文献
32.
Mutations in the TSC2 gene: analysis of the complete coding sequence using the protein truncation test (PTT) 总被引:4,自引:0,他引:4
Mutations in the TSC2 gene on chromosome 16p13.3 are responsible for
approximately 50% of familial tuberous sclerosis (TSC). The gene has 41
small exons spanning 45 kb of genomic DNA and encoding a 5.5 kb mRNA. Large
germline deletions of TSC2 occur in <5% of cases, and a number of small
intragenic mutations have been described. We analysed mRNA from 18
unrelated cases of TSC for TSC2 mutations using the protein truncation test
(PTT). Three cases were predicted to be TSC2 mutations on the basis of
linkage analysis or because a hamartoma from the patient showed loss of
heterozygosity for 16p13.3 markers. Three overlapping PCR products,
covering the complete coding sequence of mRNA, were generated from
lymphoblastoid cell lines, translated into 35S-methionine labelled protein,
and analysed by SDS-PAGE. PCR products showing PTT shifts were directly
sequenced, and mutations confirmed by restriction enzyme digestion where
possible. Six PTT shifts were identified. Five of these were caused by
mutations predicted to produce a truncated protein: (i) a sporadic case
showed a 32 bp deletion in exon 11, and a mutant mRNA without exon 11 was
produced; the normal exon 10 was also spliced out; (ii) a sporadic case had
a 1 bp deletion in exon 12 (1634delT); (iii) a TSC2-linked mother and
daughter pair had a G-->T transversion in exon 23 (G2715T) introducing a
cryptic splice site causing a 29 bp truncation of mRNA from exon 23; (iv) a
sporadic case showed a 2 bp deletion in exon 36; (v) a sporadic case showed
a 1 bp insertion disrupting the donor splice site of exon 37 (5007+2insA),
resulting in the use of an upstream exonic cryptic splice site to cause a
29 bp truncation of mRNA from exon 37. In one case, the PTT shift was
explained by in-frame splicing out of exon 10, in the presence of a normal
exon 10 genomic sequence. Alternative splicing of exon 10 of the TSC2 gene
may be a normal variant. Three 3rd base substitution polymorphisms were
also detected during direct sequencing of PCR products. Confirmed mutations
were identified in 28% of the families studied and on the assumption that
half of the sporadic cases should have TSC2 mutations, a crude estimate of
the detection rate would be 60%. This compares favourably with other
screening methods used for TSC2, notably SSCP, and since PTT involves much
less work it may be the method of choice.
相似文献
33.
Detecting pre-ovulatory luteinizing hormone surges in urine 总被引:2,自引:1,他引:2
Kesner JS; Knecht EA; Krieg EF Jr; Wilcox AJ; O'Connor JF 《Human reproduction (Oxford, England)》1998,13(1):15-21
The study objectives were to determine (i) if pre-ovulatory luteinizing
hormone (LH) surges, undetected in urine by two immunoradiometric assays
(IRMA), were detectable by an ultrasensitive immunofluorometric assay
(IFMA) and (ii) the influence of creatinine adjustment on the detection and
timing of the urinary LH surges. Daily urine specimens were contributed by
healthy 25-36 year old volunteers during 14 ovulatory menstrual cycles for
an epidemiological study conducted in 1983-1985. Specimens were selected as
having been previously assayed by two IRMA without consistently detecting
LH surges. These urine specimens were remeasured using an IFMA and adjusted
for creatinine concentration. IFMA measurements revealed unambiguous LH
surges in all cycles. Adjusting IRMA urinary LH values for creatinine
concentrations revealed previously undetected LH surges in four of eight
cycles. Creatinine adjustment also altered the timing of IRMA and IFMA LH
surges by 1-5 days. These results demonstrate an IFMA that detects pre-
ovulatory LH surges in unpreserved, frozen urine from cycles where such
surges were previously undetectable. Further, creatinine adjustment can
markedly affect detection and timing of the onset and peak of the urinary
LH surge. While our analysis suggests that this adjustment improves the
validity of the LH measure, this requires further investigation.
相似文献
34.
We performed a randomized doubled-blind study to evaluate whether there was a benefit in delay in tourniquet deflation with intra-articular administration of morphine and bupivacaine following operative arthroscopic surgery. In 34 patients the tourniquet was deflated immediately and in 38 patients the tourniquet remained inflated for 10 min following injection. The analgesic efficacy was assessed using pain scores and the amount of supplementary analgesia required. The results demonstrate no benefit in delay in tourniquet deflation. 相似文献
35.
36.
37.
38.
JC VANCE DC CHANT DI TUDEHOPE PH GRAY AJ HAYES 《Journal of paediatrics and child health》1997,33(6):504-508
Objectives: To describe the physical growth patterns of infants born to narcotic dependent mothers (INDM) over a 12 months period and, if possible, to relate the growth to drug taking patterns during pregnancy.
Methodology: The growth of a cohort of 43 INDM was measured during the first 12 months of life. Weight and length measurements were compared with percentile charts and converted to Z scores. Questionnaire data about drug taking practices, demographic variables and the neonatal period (including withdrawal scores) were obtained.
Results: Twenty-four (55.8%) of INDM had evidence of neonatal drug withdrawal requiring treatment with phenobarbitone. At birth, Z scores for weight and length indicated relative intrauterine growth retardation. By 12 months, there had been some catch up growth, but Z scores for weight and length were still below zero. Persistent weight retardation at 12 months was correlated with methadone dosage during pregnancy, but not the need for phenobarbitone therapy.
Conclusions: The growth patterns of INDM in the first 12 months of life indicated that at birth there was evidence of intrauterine growth retardation, but by 12 months the growth was little different from the rest of the community. There appears to be some influence of narcotic agents taken while pregnant on subsequent growth of INDM. 相似文献
Methodology: The growth of a cohort of 43 INDM was measured during the first 12 months of life. Weight and length measurements were compared with percentile charts and converted to Z scores. Questionnaire data about drug taking practices, demographic variables and the neonatal period (including withdrawal scores) were obtained.
Results: Twenty-four (55.8%) of INDM had evidence of neonatal drug withdrawal requiring treatment with phenobarbitone. At birth, Z scores for weight and length indicated relative intrauterine growth retardation. By 12 months, there had been some catch up growth, but Z scores for weight and length were still below zero. Persistent weight retardation at 12 months was correlated with methadone dosage during pregnancy, but not the need for phenobarbitone therapy.
Conclusions: The growth patterns of INDM in the first 12 months of life indicated that at birth there was evidence of intrauterine growth retardation, but by 12 months the growth was little different from the rest of the community. There appears to be some influence of narcotic agents taken while pregnant on subsequent growth of INDM. 相似文献
39.
Gonzales AJ; Christensen JG; Preston RJ; Goldsworthy TL; Tlsty TD; Fox TR 《Carcinogenesis》1998,19(7):1173-1183
40.
Identification of differentially expressed genes in aflatoxin B1- treated cultured primary rat hepatocytes and Fischer 344 rats 总被引:4,自引:1,他引:4
Harris AJ; Shaddock JG; Manjanatha MG; Lisenbey JA; Casciano DA 《Carcinogenesis》1998,19(8):1451-1458
Aflatoxin B1 (AFB1), a mutagen and hepatocarcinogen in rats and humans, is
a contaminant of the human food supply, particularly in parts of Africa and
Asia. AFB1-induced changes in gene expression may play a part in the
development of the toxic, immunosuppressive and carcinogenic properties of
this fungal metabolite. An understanding of the-role of AFB1 in modulating
gene regulation should provide insight regarding mechanisms of AFB1-induced
carcinogenesis. We used three PCR- based subtractive techniques to identify
AFB1-responsive genes in cultured primary rat hepatocyte RNA: differential
display PCR (DD-PCR), representational difference analysis (RDA) and
suppression subtractive hybridization (SSH). Each of the three techniques
identified AFB1- responsive genes, although no individual cDNA was isolated
by more than one technique. Nine cDNAs isolated using DD-PCR, RDA or SSH
were found to represent eight genes that are differentially expressed as a
result of AFB1 exposure. Genes whose mRNA levels were increased in cultured
primary rat hepatocytes after AFB1 treatment were corticosteroid binding
globulin (CBG), cytochrome P450 4F1 (CYP4F1), alpha-2 microglobulin,
C4b-binding protein (C4BP), serum amyloid A-2 and glutathione S-transferase
Yb2 (GST). Transferrin and a small CYP3A-like cDNA had reduced mRNA levels
after AFB1 exposure. Full-length CYP3A mRNA levels were increased. When
liver RNA from AFB1-treated male F344 rats was evaluated for transferrin,
CBG, GST, CYP3A and CYP4F1 expression, a decrease in transferrin mRNA and
an increase in CBG, GST, CYP3A and CYP4F1 mRNA levels was also seen.
Analysis of the potential function of these genes in maintaining cellular
homeostasis suggests that their differential expression could contribute to
the toxicity associated with AFB1 exposure.
相似文献