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J M Connor

Publications and source records attributed to J M Connor.

At least 73 records · Page 4Linked to original sources
PubMed1994

Identification of five novel mutations in the porphobilinogen deaminase gene.

We have studied the porphobilinogen deaminase gene transcripts from seven unrelated patients from the West of Scotland, all suffering from acute intermittent porphyria. This was achieved by reverse transcription and PCR amplification of mRNA followed by asymmetric amplification and direct sequencing. Five novel and two previously described mutations were identified and found to be single base substitutions. Of the five novel mutations, three were missense (R116Q, T2691, G274R) and two were nonsense (Q204 Stop, W283 Stop). Using Escherichia coli PBGD as a model, it is possible to predict and explain the deleterious effects that these mutations might have on the function and structure of the enzyme.

Bacterial Proteins↗
PubMed1994

Characterisation of inherited and sporadic mutations in neurofibromatosis type-1.

Neurofibromatosis type-1 (NF-1) is an autosomal dominant disorder, caused by mutations in the NF-1 gene. Mutation analysis in the NF-1 gene is complicated by the large size of the gene, the high mutation rate, and the presence of pseudogenes. By means of the polymerase chain reaction, we have amplified 70% of the NF-1 coding sequence using reverse transcribed mRNA and genomic DNA from 25 unrelated Scottish Caucasian patients. We have used chemical mismatch cleavage analysis and direct sequencing of asymmetrically amplifed PCR products to characterise mutations within the NF-1 gene. Using the above strategy, we detected 10 novel mutations and an intragenic polymorphism with a heterozygosity of approximately 47% in the Scottish population. Of the 10 mutations, 7 are potentially disease causing. They include splice site errors responsible for exon skipping (1721 + 3A to G) and (5749 + 2T to G), small insertions (7485insGG) and (6519insG), a nonsense mutation (R2496X), and missense and silent mutations (G1166D, K1419R, G1404G, S1311S, N1776N). A correlation of the phenotype with the genotype is presented. Thus, in this study we have identified a heterogeneous group of germline mutations, the majority of which are predicted to cause disruption of the protein product, neurofibromin. This approach has therefore proved to be useful for the detection of mutations in the gene for neurofibromatosis type-1, and can be applied to detection of molecular pathologies in general.

DNA Mutational Analysis↗
PubMed1994

Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene, second edition.

A large number of different mutations in the factor VIII (F8) gene have been identified as a cause of haemophilia A. This compilation lists known single base-pair substitutions, deletions and insertions in the F8 gene and reviews the status of the inversional events which account for a substantial proportion of mutations causing severe haemophilia A.

Base Sequence↗
PubMed1994

The chromosome constitution of human preimplantation embryos fertilized in vitro.

The chromosome constitution of five haploid, 178 diploid and 11 triploid embryos fertilized in vitro was determined after fixation on day 2 or day 3 of development. Karyotype analysis of 178 diploid embryos revealed abnormalities in 40 (22.5%) cases: 34 (19.1%) aneuploids, four (2.2%) mosaic embryos and two (1.1%) structural anomalies were identified. The majority of aneuploid karyotypes (28/34) involved a single chromosome but six embryos had aneuploidy of two or three chromosomes. The E group was most frequently involved in aneuploid karyotypes (10/23 hyperdiploid embryos) and trisomy 16, the most common single anomaly in diploid embryos, was detected in 2.2% (4/178) of cases. Only one case of sex chromosome monosomy was identified. An excess of female karyotypes was detected in abnormal cases (sex ratio 0.48); this ratio was significantly (P < 0.05) different from that observed in normal cases (74:64, XY:XX). The incidence of aneuploidy increased with maternal age but this did not reach statistical significance. Embryo morphology and growth rate, assessed by embryo development rating (EDR), did not distinguish between normal (mean score 7.9; mean EDR 96.1) and aneuploid (mean score 8.1; mean EDR, 92.1) embryos. Numbers of hyperploid (n = 17) and hypoploid (n = 11) embryos (non-mosaic cases involving single chromosomes) were not statistically different. The relative proportions of chromosomes involved in trisomic karyotypes showed a remarkable similarity to the pattern in spontaneous abortions. Pronuclear status was an unreliable predictor of ploidy. Small numbers of karyotyped triploid embryos revealed equal proportions of XXX, XXY and XYY embryos.

Abortion, Spontaneous↗
PubMed1994

Diagnosis in Prader-Willi syndrome.

Thirty one patients with the putative diagnosis of Prader-Willi syndrome were reassessed clinically and by DNA analysis. Eleven patients were judged not to have Prader-Willi syndrome and 20 to have the condition. This was confirmed by DNA analysis in all but one case. The diagnosis of Prader-Willi syndrome, especially in early infancy, should be made with caution unless confirmed by molecular genetic studies.

Adolescent↗
PubMed1994

Possible role of imprinting in the Turner phenotype.

We have attempted to investigate the role of imprinting in the phenotype of Turner's syndrome. Sixty-three patients were investigated for parental origin of the retained normal X chromosome; 43 were found to retain the maternal X (XM) and 20 the paternal (XP). The relationship between a child's pretreatment height centile and parental height centiles was examined in 36 patients. No significant correlation was found between child and parental height centiles for XP or child and paternal height centiles for XM (p > 0.05) but a strong correlation was found between child's height centile and maternal height centile (p < 0.01) for XM. Using pooled data from this and other studies there was no significant correlation with renal anomalies but a strong correlation between cardiovascular abnormalities and XM (0.01 > p > 0.001) and neck webbing and XM (p < 0.05). We conclude that imprinting may play a part in the Turner's syndrome phenotype, especially with respect to pretreatment height, cardiovascular anomalies, and neck webbing.

Female↗
PubMed1994

First trimester biochemical screening for trisomy 21: the role of free beta hCG, alpha fetoprotein and pregnancy associated plasma protein A.

The potential efficacy of screening for trisomy 21 in the first trimester, using maternal serum markers alpha fetoprotein, free beta human chorionic gonadotropin, unconjugated oestriol and pregnancy associated plasma protein A, was studied in an unselected population of women between the seventh and fourteenth week of gestation. Using a combination of alpha fetoprotein and free beta human chorionic gonadotropin, 53% of affected pregnancies could be identified at a false positive rate of 5%. Unconjugated oestriol and pregnancy associated plasma protein A levels were lower in cases of trisomy 21, but their inclusion with other markers did not significantly improve detection rate. Monitoring the same pregnancies also in the second trimester showed that screening in the first trimester identified the same cases as in the second. We conclude that first trimester screening using free beta human chorionic gonadotropin and alpha fetoprotein, is a viable possibility and will lead to detection rates in excess of 50%. Prospective studies are needed to confirm these observations.

Adolescent↗
PubMed1994

Impact of a regional screening programme using maternal serum alpha fetoprotein (AFP) and human chorionic gonadotrophin (hCG) on the birth incidence of Down's syndrome in the west of Scotland.

OBJECTIVES: To evaluate the impact of a large scale population screening programme on the birth incidence of Down's syndrome in the west of Scotland over a 12 month period. METHODS: Biochemical screening for Down's syndrome using maternal serum alpha fetoprotein, chorionic gonadotrophin, and maternal age was offered to a pregnant population of 37,226 women in the west of Scotland between 1991 and 1992. The combined risk of Down's syndrome pregnancy was reported for each of the 30,084 women who opted for screening. RESULTS: When a threshold risk of 1:220 was used 1523 women (5.1% of the screened population) were assigned to the high risk group, of whom 1070 (70%) proceeded to diagnostic amniocentesis or midtrimester chorionic villus sampling. When multiple sources of ascertainment were used 37 Down's syndrome pregnancies were identified within the screened population, 26 (70%) of which were within the high risk group and 21 (57%) of which were prenatally diagnosed. In addition, three Down's syndrome pregnancies were diagnosed by first trimester chorionic villus sampling before biochemical screening. A further 10 Down's syndrome pregnancies were identified at birth, eight to women who had not had a screening test and two to women who had moved into the area, making a total of 50 Down's syndrome pregnancies in the whole pregnant population of 37,226. Thus the potential prenatal detection rate in the screened population was 70% (26/37), the actual prenatal detection rate in the screened population was 57% (21/37), and the overall prenatal detection rate in the total (screened and unscreened) population was 48% (24/50). CONCLUSION: Biochemical screening for Down's syndrome is practical and effective in routine clinical practice, enabling women to make an informed choice about prenatal diagnosis and providing better use of scarce resources when a suitable protocol is applied to the whole pregnant population. Its maximum potential for the reduction of the birth incidence of Down's syndrome is limited by incomplete uptake of screening and compliance with diagnostic testing in the high risk group.

Adolescent↗
PubMed1993

Screening for molecular pathologies in Lesch-Nyhan syndrome.

Heteroduplex detection by hydrolink gel electrophoresis was performed to screen for small mutations in 12 Lesch-Nyhan syndrome families with characterised molecular pathology which included nine point mutations, two small deletions, and a 1-bp insertion. This modified protocol for heteroduplex detection by hydrolink gel electrophoresis detected all 12 of these mutations and was utilised to rapidly determine the carrier status of females from affected families. On the basis of these results this approach appears to be a rapid and reliable screening method for point mutations in addition to small length mutations and for carrier detection in Lesch-Nyhan syndrome.

DNA Mutational Analysis↗
PubMed1993

Second-trimester unconjugated oestriol levels in maternal serum from chromosomally abnormal pregnancies using an optimized assay.

Second-trimester unconjugated oestriol (UE3) levels were measured retrospectively in maternal serum from 78 chromosomally abnormal pregnancies and 390 matched controls using a radioimmunoassay kit (Amersham AMERLEX-M) optimized for use in the second trimester. Reduced levels of UE3 were found in a group of 49 Down's syndrome pregnancies with a median UE3 level of 0.79 multiples of the median (MOM) of the controls. Four trisomy 18 pregnancies had UE3 levels less than 0.7 MOM. There was a highly significant level of correlation between alpha-fetoprotein (AFP) and UE3 levels in the controls (r = 0.25, p < 0.01), the Down's syndrome pregnancies (r = 0.44, p < 0.01), and the other chromosome abnormalities (r = 0.61, p < 0.01). When used as an additional marker to AFP and human chorionic gonadotrophin in screening for Down's syndrome, UE3 does not appear to add to the sensitivity of such screening.

Chromosome Aberrations↗
PubMed1993

First-trimester biochemical screening for fetal chromosome abnormalities and neural tube defects.

Alpha-fetoprotein (AFP), unconjugated oestriol (UE3), intact human chorionic gonadotrophin (intHCG), and the free beta subunit of chorionic gonadotrophin (F beta HCG) were investigated in a series of 21 chromosomally abnormal and 14 open neural tube defect pregnancies ascertained from a series of 14,000 prospectively collected maternal serum samples at 6-14 weeks' gestation. In 16 cases of Down's syndrome, significant reductions were found for AFP (0.65 multiples of the normal median) and UE3 (0.67 MOM). IntHCG levels were unaltered (0.97 MOM) but a significant increase was found for F beta HCG (1.96 MOM). Significant correlations were found for AFP and UE3 in the controls and for intHCG and F beta HCG in both the control and the Down's syndrome pregnancies. In a group of five trisomy 18 pregnancies, median MOMs were for AFP 0.71, for UE3 0.34, for intHCG 0.27, and for F beta HCG 0.15. None of 13 pregnancies with open neural tube defects at 8-13 weeks gestation had elevated maternal serum AFP levels, whereas matched second-trimester samples from the same pregnancies at 16-18 weeks gestation all had significantly elevated AFP levels. Thus, biochemical screening for chromosome abnormalities may be practicable in the first trimester using free beta human chorionic gonadotrophin in combination with AFP and maternal age. However, a separate screening protocol using AFP at 15-18 weeks gestation would still be required for effective detection of neural tube defects.

Biomarkers↗
PubMed1993

Evidence for involvement of a second genetic locus on chromosome 11q in porphyrin metabolism.

Chester porphyria is a distinct type of acute porphyria, which shows a biochemical overlap with acute intermittent and variegate porphyrias and has a dual enzyme deficiency of porphobilinogen deaminase (PBGD) and protoporphyrinogen oxidase. Linkage analysis in an extensive family with Chester porphyria was undertaken using multiple polymorphic markers. A maximum two point Lod score of 5.25 at 0.07 recombination (confidence interval 0.01 to 0.14) was observed with D11S351, which has been localised to 11q23.1. Multipoint linkage analysis confirmed the two point results and gave a maximum Lod score of 7.33 at a distance less than 1 cM proximal to D11S351. PBGD also maps to 11q but four recombinants could be identified from ten informative meioses in this family using a PBGD DNA polymorphism. Thus, a separate locus on 11q appears to be the basis of Chester porphyria.

Chromosome Mapping↗
PubMed1993

Detection of a high mutation frequency in exon 12 of the porphobilinogen deaminase gene in patients with acute intermittent porphyria.

Direct cDNA sequencing was performed on asymmetrically amplified transcripts from the porphobilinogen deaminase (PBG-D) gene of thirteen unrelated individuals with acute intermittent porphyria. Four different mutations and a polymorphic site were detected in exon 12 of the gene, four being the result of single base substitutions and one being caused by dinucleotide deletion. All of these mutations are located in domain 3 of the PBG-D molecule, with the single base substitutions affecting the hydrophobic interfaces between domains 1 and 3. The dinucleotide deletion results in a frame-shift producing a premature stop codon.

Chromosome Deletion↗
PubMed1993

Scottish frequency of the common G985 mutation in the medium-chain acyl-CoA dehydrogenase (MCAD) gene and the role of MCAD deficiency in sudden infant death syndrome (SIDS).

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, is an autosomal recessive inborn error of metabolism associated with various clinical presentations, including sudden unexplained death in young children. We have determined the Scottish frequency of the common G985 mutation found in Caucasians and in samples from Scottish patients with sudden infant death syndrome (SIDS). The heterozygote frequency of the mutation was found to be 1 in 276 (95% confidence interval: 1/76-1/2279) in 552 healthy controls and 1 in 74 (95% confidence interval: 1/27-1/377) in 233 SIDS patients: a difference that was not statistically significant (Fisher's exact test; two-sided; p = 0.316). None of the SIDS samples was found to be homozygous for the G985 mutation.

Acyl-CoA Dehydrogenase↗
PubMed1993

Dyskeratosis congenita: three additional families show linkage to a locus in Xq28.

Dyskeratosis congenita (DC) is a rare inherited disorder with most families being of the X linked recessive type. We describe three families which show linkage to the marker DXS52 on Xq28. The combined maximum lod score was 2.00 at zero recombination. This is further evidence that the X linked DC gene is located at Xq28 and brings the reported maximum lod score for DC and DXS52 to 5.33 at zero recombination fraction, with a supporting recombination fraction interval of 0.00-0.10.

Adult↗
PubMed1993

A three generation family with fibrodysplasia ossificans progressiva.

A family with five persons affected with fibrodysplasia ossificans progressiva (myositis ossificans progressiva) in three generations is described. This is the first well documented three generation family with this condition and provides further evidence for autosomal dominant inheritance. A wide range of phenotypic severity is apparent, from disabling ectopic bone formation and premature death to an asymptomatic adult with characteristic big toe malformations.

Adolescent↗