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Biomedical subjects

P Goodfellow

Publications and source records attributed to P Goodfellow.

At least 19 recordsLinked to original sources
PubMed2001

No evidence for BCL10 mutation in endometrial cancers with microsatellite instability.

Previous reports have suggested that the mononucleotide repeats in BCL10 frequently are mutated in both hematologic malignancies and solid tumors. We set out to determine whether these repeats, like simple repeat sequences in other genes, are a target for mutation in endometrial cancers with defective DNA mismatch repair. Primary endometrial cancers (n = 42) and endometrial cancer cell lines (n=5) with microsatellite instability (MSI) were investigated. BCL10 exons 2 and 3 were amplified by PCR and evaluated for mutation using denaturing high-performance liquid chromatography (DHPLC) and single stand conformational variant (SSCV) analysis. Variants were directly sequenced. No BCL10 mutations were detected in exons 2 or 3 by DHPLC or SSCV. A polymorphism in exon 3 (638G-->A) was seen in 4/42 (9.5%) MSI-positive endometrial cancers and 0/5 MSI-positive endometrial cancer cell lines. Thus, mutation in the mononucleotide repeat tracts of BCL10 is not a feature of endometrial cancers with defective DNA mismatch repair.

Adaptor Proteins, Signal Transducing↗
PubMed2001

The interleukin 1 receptor antagonist gene allele 2 as a predictor of pouchitis following colectomy and IPAA in ulcerative colitis.

BACKGROUND & AIMS: The interleukin 1 receptor antagonist gene allele 2 has been suggested as a determinant of both disease susceptibility and extent in ulcerative colitis. The aim of this study was to assess the allele as a predictor of both the indication for colectomy and the occurrence of pouchitis after ileal pouch-anal anastomosis formation. METHODS: Genotyping for the +2018 single nucleotide polymorphism in the interleukin 1 receptor antagonist gene was performed in 109 patients who had undergone colectomy, including 82 patients who had been followed prospectively after ileal pouch-anal anastomosis formation. RESULTS: Patients with pouchitis had a higher allele 2 carriage rate compared with those without pouchitis (72% vs. 45%) and Kaplan-Meier survival analysis showed that allele 2 carriers had a significantly increased incidence of pouchitis compared with noncarriers (log-rank test, 6.5). After adjustment for confounding covariates in a Cox proportional hazards model, the relative hazard was 3.1 (95% confidence interval [CI], 1.2-7.8; P = 0.02). Although there was a higher allele 2 carriage rate in patients with chronic refractory compared with acute severe ulcerative colitis (63% vs. 48%), this difference was not significant (odds ratio, 1.9; 95% CI, 0.9-4.1; P = 0.1). CONCLUSIONS: The interleukin 1 receptor antagonist gene allele 2 predicts pouchitis after ileal pouch-anal anastomosis in ulcerative colitis.

Adolescent↗
PubMed2001

Risk factors for epilepsy in a rural area in Tanzania. A community-based case-control study.

BACKGROUND AND METHODS: The high prevalence of epilepsy detected in rural Tanzania by Dr. Jilek-Aall since 1960, was verified by the World Health Organization (WHO) survey on neurological and seizure disorders. Neurologists and psychiatrists further interviewed both patients and controls using standard methods. The presence of possible risk factors was complemented by corroborative evidence through interviewing close relatives and scrutinizing medical records. Seizures were classified based on clinical symptoms and the use of EEG. RESULTS: A family history of epilepsy in first-degree relatives was found in 46.6% of patients, but in only 19.6% of controls. The odds ratio for family history with epilepsy was 3.52 (95% confidence interval, CI 2.4-5.74, p < 0.001). A past history of febrile convulsion was found in 44% of patients in comparison to 23% of the control group which was significant (odds ratio 2.4, 95% CI 1.5-3.8; p < 0.001). A history of intrapartum complications was found in 12.1% of patients and 1.8% of controls (odds ratio 7.3, 95% CI 2.5-25.2; p < 0.002). Head injury was not a significant risk factor for epilepsy in this rural community. CONCLUSION: The results indicated a strongly independent association between four factors and the risk of developing epilepsy. It would seem more likely that previous brain insults/diseases play a significant major role in the cause of epilepsy in the Mahenge area. However, a genetic predisposition to low threshold for convulsions cannot be excluded.

Adolescent↗
PubMed1998

A lust for science

Explore the source record for details and available documents.

Journal Article↗
PubMed1998

The genetics of multiple sclerosis: principles, background and updated results of the United Kingdom systematic genome screen.

Genetic susceptibility to multiple sclerosis is implicated on the basis of classical family studies and phenotype analyses. The only reproducible legacy from the candidate gene approach has been the discovery of population associations with alleles of the major histocompatibility complex. Systematic genome scanning has since been applied using a panel of anonymous markers to identify areas of linkage in co-affected siblings. Here, we describe the principles of genome screening and update the UK survey of multiple sclerosis. This identified 20 regions of potential interest, but in none was there unequivocal linkage. In theory, attempting to replicate these findings in a second set of sibling pair families is the most appropriate way to distinguish true from false positives, but unfortunately the number of families required to do this reliably is prohibitively large. We used three approaches to increase the definition achieved by the screen: (i) the number of sibling pairs typed in an identified region of potential linkage was extended; (ii) the information extraction was increased in an identified region; and (iii) a search was made for missed regions of potential linkage. Each of these approaches has considerable limitations. A chromosome-by-chromosome account is given to direct future searches. Although an additional marker placed distal to the 'hit' on chromosome 14q increased linkage in this area, and typing extra sibling pairs increased linkage on chromosomes 6p and 17q, evidence for linkage was more commonly reduced and no additional regions of interest were found. A further refinement of the genome screen was undertaken by conditioning for the presence of HLA-DR15. This produced a surprising degree of segregation among the regions of interest, which divided into two distinct groups depending on DR15 sharing: the DR15-sharing cohort comprised loci on chromosomal areas 1p, 17q and X; and the DR15-non-sharing cohort was made up of loci on 1cen, 3p, 7p, 14q and 22q. This result further highlights the genetic complexity of multiple sclerosis. What can now be inferred is that a gene of major effect is excluded from 95% of the genome and one with a moderate role from 65%, whereas genes which make a very small biological contribution cannot be discounted from any region. The available results suggest that multiple sclerosis depends on independent or epistatic effects of several genes each with small individual effects, rather than a very few genes of major biological importance.

Genetic Linkage↗
PubMed1997

Isolation of monochromosomal hybrids for mouse chromosomes 3, 6, 10, 12, 14, and 18.

Mouse/human somatic cell hybrids constitute a valuable resource for both genetic and physical mapping. In this report, we describe the production and characterization of a series of six monochromosomal hybrids generated by fusion of murine micro-cells with intact human recipient cells. The presence of each mouse chromosome was characterized by PCR analysis and the integrity of the mouse chromosome retained in the hybrids confirmed by fluorescence in situ hybridization (FISH) analysis.

Animals↗
PubMed1996

Physical mapping of the bloom syndrome region by the identification of YAC and P1 clones from human chromosome 15 band q26.1.

The gene for Bloom syndrome (BLM) has been mapped to human chromosome 15 band q26.1 by homozygosity mapping. Further refinement of the location of BLM has relied upon linkage-disequilibrium mapping and somatic intragenic recombination. In combination with these mapping approaches and to identify novel DNA markers and probes for the BLM candidate region, a contiguous representation of the 2-Mb region that contains the BLM gene was generated and is presented here. YAC and P1 clones from the region have been identified and ordered by using previously available genetic markers in the region along with newly developed sequence-tagged sites from radiation-reduced hybrids, polymorphic dinucleotide repeat loci, and end sequences of YACs and P1s. A long-range restriction map of the 2-Mb region that allowed estimation of the distance between polymorphic microsatellite loci is also reported. This map and the DNA markers derived from it were instrumental in the recent identification of the BLM gene.

Adenosine Triphosphatases↗
PubMed1996

Early steps in mammalian sex determination.

Since the cloning of the Y-located testis-determining factor, sex determining region Y (SRY), several other genes have been implicated in the process of mammalian sex determination. Mutations of an SRY-related gene, SRY-related high-mobility group box 9 (SOX9), result in autosomal sex reversal and campomelic dysplasia. The genes Steroidogenic factor 1 (SF1) and Wilms' tumour 1 (WT1) are required for early gonadal development as well as for the formation of adrenals and kidneys respectively. The gene responsible for adrenal hypoplasia congenita, DAX1, is a candidate for the X-linked dosage sensitive sex reversal gene (DSS).

Animals↗
PubMed1996

Sox9 expression during gonadal development implies a conserved role for the gene in testis differentiation in mammals and birds.

Heterozygous mutations in SOX9 lead to a human dwarfism syndrome, Campomelic dysplasia. Consistent with a role in sex determination, we find that Sox9 expression closely follows differentiation of Sertoli cells in the mouse testis, in experimental sex reversal when fetal ovaries are grafted to adult kidneys and in the chick where there is no evidence for a Sry gene. Our results imply that Sox9 plays an essential role in sex determination, possibly immediately downstream of Sry in mammals, and that it functions as a critical Sertoli cell differentiation factor, perhaps in all vertebrates.

Amino Acid Sequence↗
PubMed1995

Expression of Sry, the mouse sex determining gene.

In the mouse, Sry is expressed by germ cells in the adult testis and by somatic cells in the genital ridge. Transcripts in the former exist as circular RNA molecules of 1.23 kb, which are unlikely to be efficiently translated. We have used RNase protection to map the extent of the less abundant Sry transcript in the developing gonad. We demonstrate that it is a linear mRNA derived from a single exon. This begins in the unique region 5' of the protein coding region and extends several kilobases into the 3' arm of the large inverted repeat which bounds the Sry genomic locus. Knowledge of this transcript, which is very different from that of the human SRY gene, allows us to predict its protein product and reveals several features which may be involved in translational control. Our data is also consistent with there being two promoters for the Sry gene, a proximal one that gives functional transcripts in the genital ridge and a distal promoter used in germ cells in the adult testis. As RNase protection is a quantitative technique, a detailed timecourse of Sry expression was carried out using accurately staged samples. Sry transcripts are first detectable just after 10.5 days post coitum, they reach a peak at 11.5 days and then decline sharply so that none are detected 24 hours later. This was compared with anti-Müllerian hormone gene expression, an early marker of Sertoli cells and the first known downstream gene of Sry. Amh expression begins 20 hours after the onset of Sry expression at a time when Sry transcripts are at their peak. While this result does not prove a direct interaction between the two genes, it defines the critical period during which Sry must act to initiate Sertoli cell differentiation.

Amino Acid Sequence↗
PubMed1995

The SRY protein, like HMG 1, recognizes (CA)n sequences, an abundant repeat sequence in vertebrates.

The sex-determining region of the Y chromosome gene, sry is expressed in the foetal mouse for a brief period, just before testis differentiation, which could be consistent with negative autoregulation. SRY is a DNA binding protein which can bind to cruciform DNA and to linear DNA with a sequence specificity. We have examined if the Sry gene contain DNA binding sites for the SRY protein itself. We have found that in an in vitro assay, the SRY protein binds to several sites of the Sry gene and especially to a (CA)25 sequence and to a (CAG)30 repeat. These binding suggest that the function of SRY and in a general way HMG-box proteins may be mediated by an interaction with repeat sequences.

Animals↗
PubMed1993

Circular transcripts of the testis-determining gene Sry in adult mouse testis.

Sry is expressed at higher levels in the adult testis, where no function has been determined, than in the genital ridge, its critical site of action. cDNA and 5' RACE clones isolated from testis or from Sry-transfected cell lines have an unusual structure, with 3' sequences located in a 5' position. RNAase protection assays and reverse transcription polymerase chain reactions confirmed that these unusual RNA molecules represent the most abundant transcript in testis. Furthermore, oligonucleotide hybridization and RNAase H digestion proved that these Sry RNA molecules are circular. Similar transcripts were detected in the testes of mice with Mus musculus musculus, Mus musculus domesticus, and Mus spretus Sry genes. The circular RNA is found in the cytoplasm but is not substantially bound to polysomes. We suggest that the circles arise from normal splicing processes as a consequence of the unusual genomic structure surrounding the Sry locus in the mouse.

Animals↗
PubMed1993

Absent chondrodysplasia punctata in a male with an Xp terminal deletion involving the putative region for CDPX1 locus.

This is a follow-up report on a male patient with a 46,Y,r(X) karyotype. Although he had no clinico-radiological features of X-linked recessive chondrodysplasia punctata (CDPX1), molecular studies revealed an Xp terminal deletion involving the putative region for the CDPX1 locus (PABX-DXS31). We suspect that the absence of CDPX1 may be attributable to the nature of the disease and the extreme short stature of the patient (mean -5.6 S.D.).

Blotting, Southern↗
PubMed1993

Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.

Amino Acid Sequence↗
PubMed1992

Inverted repeat structure of the Sry locus in mice.

The testis-determining gene Sry is located on the short arm of the mouse Y chromosome in a region known to have undergone duplications and rearrangements in comparison with the equivalent portion of the human Y chromosome. Detailed analysis of the Sry genomic locus reveals a further difference in that the mouse Sry open reading frame lies within 2.8 kilobases of unique sequence at the center of a large inverted repeat. This repeat, which is found in both Mus musculus musculus and Mus musculus domesticus Y chromosomes, is not present at the human SRY locus. Recombination involving the repeat region may have led to an 11-kilobase deletion, precisely excising Sry in a line of XY female mice.

Animals↗