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D E Barton

Publications and source records attributed to D E Barton.

At least 37 records · Page 2Linked to original sources
PubMed1996

Molecular genetic investigation of the neurofibromatosis type 2 tumor suppressor gene in sporadic meningioma.

The authors investigated the role of somatic mutations of the neurofibromatosis type 2 (NF2) gene in sporadic meningioma. Neurofibromatosis 2 is a dominantly inherited familial tumor syndrome predisposing affected patients to a variety of central nervous system tumors including vestibular schwannoma and meningioma. Neurofibromatosis type 2 is caused by germline mutations in the NF2 tumor suppressor gene. In addition, the authors and others have reported that somatic NF2 gene mutations occur frequently in nonfamilial vestibular schwannoma. In this study, molecular genetic analysis was performed on 23 nonfamilial meningiomas. Paired DNA samples extracted from the blood and tumors of the patients were analyzed for loss of heterozygosity (LOH) in the region of the NF2 gene on chromosome 22 using closely linked DNA markers. The NF2 gene mutations were sought by single-stranded conformation polymorphism analysis and DNA sequencing. Fourteen (61%) of 23 meningiomas showed LOH in the region of the NF2 gene on chromosome 22. Somatic NF2 gene mutations were detected in eight meningiomas (35%) after screening all 17 exons. All tumors with NF2 gene mutations showed simultaneous chromosome 22 LOH. Review of the histopathological findings of the cases studied did not demonstrate any predominance of genetic abnormalities in a particular histological type of meningioma. These results are compatible with the hypothesis that the NF2 gene acts as a tumor suppressor and that its inactivation is important in the pathogenesis of sporadic meningioma.

Chromosomes, Human, Pair 22↗
PubMed1995

Normal CAG and CCG repeats in the Huntington's disease genes of Parkinson's disease patients.

The clinical features of Parkinson's disease, particularly rigidity and bradykinesia and occasionally tremor, are seen in juvenile-onset Huntington's disease. Therefore, the CAG and CCG repeats in the Huntington's disease gene were investigated in 45 Parkinson's disease patients and compared to 40 control individuals. All of the Parkinson's disease chromosomes fell within the normal size ranges. In addition, the distributions of the two repeats in the Parkinson's disease patients did not differ significantly from those of the control population. Therefore, abnormalities of these trinucleotide repeats in the Huntington's disease gene are not likely to contribute to the pathogenesis of Parkinson's disease.

Aged↗
PubMed1995

Haplotype analysis of the delta 2642 and (CAG)n polymorphisms in the Huntington's disease (HD) gene provides an explanation for an apparent 'founder' HD haplotype.

The discovery of the intragenic delta 2642 deletion/insertion polymorphism in the Huntington's disease (HD) gene provides a tool to explore HD evolution, as the deletion is rare in normal chromosomes but overrepresented in HD chromosomes. Thus, delta 2642 deletion alleles were thought to mark normal chromosomes that are particularly prone to becoming HD chromosomes. We have examined this polymorphism in a range of human and non-human primate populations. Our results suggest that the deletion event probably occurred in the human lineage on a chromosome with a CAG allele length at the upper end of the normal size range, as the deletion seemed to be only associated with human chromosomes with 20 or more repeats. These deletion chromosomes are prone to expansion into the HD range because they are at the upper end of the normal range. These data explain the apparent 'founder' HD haplotype defined by the deletion and suggest that chromosomes carrying the deletion are no more mutable than non-deletion chromosomes with similar sized CAG repeats.

Alleles↗
PubMed1995

Molecular genetic analysis of exons 1 to 6 of the APC gene in non-polyposis familial colorectal cancer.

Familial adenomatous polyposis coli is caused by constitutional mutations in the APC gene. The hallmark of familial adenomatous polyposis coli is the presence of numerous (> 100) colorectal polyps, but mutations in the 5' end of the APC gene have been associated with familial colorectal cancer without florid polyposis. Although familial adenomatous polyposis coli accounts for only a minority of familial colorectal cancer cases, we hypothesised that APC mutations which were not associated with florid polyposis might make a significant contribution to nonpolyposis familial colorectal cancer. To investigate this possibility, we analysed 40 unrelated patients with familial colorectal cancer without classical familial adenomatous polyposis coli for mutations in exons 1 to 6 (codons 1 to 243) of the APC gene. No mutations were detected, but a C-->T polymorphism at nucleotide 333 (Arg-->Trp at codon 99) was identified. No 5' APC mutations were detected in two patients with desmoid tumours and a family history of colorectal cancer and polyps. We conclude that mutations in exons 1 to 6 of the APC gene are infrequent in patients with familial colorectal cancer who do not have many colorectal polyps.

Adult↗
PubMed1995

Genetic linkage analysis in hereditary non-polyposis colon cancer syndrome.

Hereditary Non-polyposis Colon Cancer Syndrome (HNPCC) is the most common cause of familial colorectal cancer. Molecular genetic studies of HNPCC have shown evidence of locus heterogeneity, and mutations in four genes (hMSH2, hMLH1, hPMS1, and hPMS2) which encode components of the mismatch enzyme repair system may cause HNPCC. To determine the extent and nature of locus heterogeneity in HNPCC, we performed genetic linkage studies in 14 HNPCC families from eastern and north-western England. Linkage to hMLH1 was excluded in six families, each of which were likely to be linked to hMSH2 (lod score > 1.0 in each family and total lod score for all six families = 7.64). Linkage to hMSH2 was excluded in three families, each of which were likely to be linked to hMLH1 (lod score > 1.0 in each family and total lod score at hMLH1 for all three families = 3.93). In the remaining five families linkage to hMSH2 or hMLH1 could not be excluded. These results confirm locus heterogeneity in HNPCC and suggest that, in the population studied, most large families with HNPCC will have mutations in hMSH2 or hMLH1. We did not detect any correlation between clinical phenotype and the genetic linkage results, but a Muir-Torre syndrome family excluded from linkage to hMLH1 was likely to be linked to hMSH2 and showed microsatellite instability in a tumour from an affected relative.

Adaptor Proteins, Signal Transducing↗
PubMed1994

Stickler syndrome: correlation between vitreoretinal phenotypes and linkage to COL 2A1.

Stickler syndrome is an autosomal dominantly inherited condition characterised by ocular, articular, facial, auditory and oral features. There is locus heterogeneity with about two thirds of families showing linkage to the gene encoding type II procollagen (COL 2A1). Clinical overlap with Marshall's, Wagner's and other syndromes has caused considerable confusion but the importance of the congenital vitreous anomaly, as first described by Scott, has not previously been emphasised. This study examines the linkage of two vitreo-retinal phenotype subgroups of Stickler syndrome to COL 2A1. A total of 97 affected patients from 24 pedigrees were examined. This is the largest published series of Stickler syndrome patients to date and all have undergone full clinical and ophthalmological examination by a single investigator. A clinical classification is proposed based on vitreoretinal phenotype. All patients demonstrating the congenital vitreous anomaly have been designated Stickler syndrome type 1 and those without the congenital vitreous anomaly as Stickler syndrome type 2 patients. There were 69 affected patients from 20 unrelated type 1 pedigrees and 28 affected patients from 4 unrelated type 2 pedigrees. Using two markers at the COL 2A1 locus, Stickler syndrome type 1 pedigrees showed complete linkage to COL 2A1 with a maximum lod score of 12.33 at zero recombination. Linkage to COL 2A1 was excluded in the two type 2 pedigrees that were informative. From these data it appears that this clinical classification is a useful first step in resolving the genetic heterogeneity in this condition.

Base Sequence↗
PubMed1994

Mutational bias provides a model for the evolution of Huntington's disease and predicts a general increase in disease prevalence.

Huntington's disease (HD) correlates with abnormal expansion in a block of CAG repeats in the Huntington's disease gene. We have investigated HD evolution by typing CAG alleles in several human populations and in a variety of primates. We find that human alleles have expanded from a shorter ancestral state and exhibit unusual asymmetric length distributions. Computer simulations are used to show that the human state can be derived readily from a primate ancestor, without the need to invoke natural selection. The key element is a simple length-dependent mutational bias towards longer alleles. Our model can explain a number of empirical observations, and predicts an ever-increasing incidence of HD.

Alleles↗
PubMed1994

Somatic NF2 gene mutations in familial and non-familial vestibular schwannoma.

Vestibular schwannoma occurs both as a sporadic tumour and in the dominantly inherited familial cancer syndrome neurofibromatosis type 2 (NF2). The gene for NF2 has recently been isolated on chromosome 22, and the demonstration of inactivating germline mutations in NF2 patients and NF2 associated tumours suggests that it act as a tumour suppressor. We have investigated 85 sporadic and 2 NF2 associated vestibular schwannomas, and one vagal schwannoma for chromosome 22 allele loss and NF2 gene mutations. A further 7 vestibular schwannomas were investigated for NF2 mutations only. Chromosome 22 allele loss was detected in 34 of 87 vestibular schwannomas and in the vagal nerve schwannoma. Six exons of the NF2 gene were investigated by SSCP analysis in all 95 tumours. Somatic NF2 gene mutations were detected in 13 non-familial vestibular schwannomas and in one of the NF2 vestibular schwannomas. Seven non-familial tumours with an NF2 gene mutation also displayed a chromosome 22 allele loss. Thirteen of the mutations were predicted to produce truncation of the NF2 protein. These results suggest that somatic mutations of the NF2 tumour suppressor gene are a critical step in the pathogenesis of both familial and non-familial vestibular schwannoma and that the mechanism of tumourigenesis complies with a 'two-hit' mutation model.

Adult↗
PubMed1994

Direct, non-radioactive detection of mutations in multiple endocrine neoplasia type 2A families.

We have designed PCR primers that permit the rapid non-isotopic detection of mutations in codon 634 of the RET proto-oncogene, the causative mutations in over 80% of MEN 2A and 50% of FMTC families. In this paper we report the investigation of eleven MEN 2A families referred to the East Anglian Regional Genetics Service. Nine of these families carry codon 634 mutations. We were able to confirm the diagnosis of MEN 2A in twenty six affected individuals and to determine the carrier status of forty one individuals thought to be at risk of developing the disease. Of those at risk, thirty one patients lacked the familial mutation and ten were presymptomatic carriers of MEN 2A. In five cases the direct test proved that patients who had been treated by thyroidectomy but who lacked confirmed cancer, did not carry the familial mutation, removing the perceived risk of MEN 2A from their children. This group included one patient who had been diagnosed as having mild C-cell hyperplasia, confirming that in MEN 2A families C-cell hyperplasia can result from causes other than the presence of the MEN 2A mutation.

Base Sequence↗
PubMed1994

Carrier detection in X linked ocular albinism using linked DNA polymorphisms.

Sixty two females at 50% carrier risk were assessed from 19 families affected by X linked ocular albinism (OA1). Twenty nine (47%) had definite fundus changes of the carrier state with a mud splattered fundus appearance and 23 (37%) had a normal ophthalmic examination. Ten (16%) had mild peripheral retinal pigmentary changes so that it was difficult to exclude the carrier state; six of these females were shown to be at low risk and only one at high risk of being a carrier by DNA analysis using linked DNA polymorphisms, including a highly informative dinucleotide repeat at the Kallmann locus. Mild peripheral retinal pigmentary changes are not a definite indication of carrier status and in 45 age matched female controls five (11%) had similar changes. No female with a clinically normal fundus was found to be at high risk by DNA analysis. Molecular genetic analysis improves the accuracy of carrier detection in OA1 families and should be considered if the clinical findings are equivocal.

Albinism, Ocular↗
PubMed1994

Mosaic uniparental disomy in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome with variable expression. The major features are anterior abdominal wall defects, macroglossia, and gigantism and less commonly neonatal hypoglycaemia, organomegaly, congenital renal anomalies, hemihypertrophy and embryonal tumours occur. BWS is a genetically heterogeneous disorder; most cases are sporadic but approximately 15% are familial and a small number of BWS patients have cytogenetic abnormalities involving chromosome 11p15. Genomic imprinting effects have been implicated in familial and non-familial BWS, and uniparental disomy (UPD) for chromosome 11 has been reported in sporadic cases. We investigated the incidence, pathogenesis, and clinical associations of UPD in 49 patients with non-familial BWS and a normal karyotype. UPD for chromosome 11p15 was detected in nine of 32 (28%) informative patients. A further two patients appeared to be disomic at the WT1 locus in chromosome 11p13, but were uninformative at chromosome 11p15.5 loci tested. In all cases with UPD the affected person was mosaic for a paternal isodisomy and a normal cell line indicating that UPD had arisen as a postzygotic event. Compared to cases in which paternal isodisomy for chromosomes 11p15.5 had been excluded (n = 23), BWS patients with UPD was more likely to have hemihypertrophy (6/9 versus 1/23, p < 0.001) and less likely to have exomphalos (0/9 versus 13/23, p < 0.01), but there were no significant differences between disomic and non-disomic cases in the incidence of hypoglycaemia, nephromegaly, neoplasia, and developmental delay. The detection of UPD in BWS patients allows accurate genetic counselling to be provided and provides an insight into the molecular pathogenesis of BWS.

Adolescent↗
PubMed1994

Chimaerism shown by cytogenetics and DNA polymorphism analysis.

A child with ambiguous genitalia, brought up phenotypically male, had a 46,XX/46,XY karyotype. At laparotomy, he had a left sided ovary and uterus, and a right sided scrotal testis. The 46,XX line made up 50% of cells in the blood and 90% of cells in a skin biopsy. There were no cytogenetic polymorphisms. Analysis of lymphocyte DNA with seven polymorphic DNA markers showed him to be chimaeric, with four, three, and two parental alleles at different loci. He had one paternal and one maternal X chromosome at the marker DXS1053. Based on our data, we would suggest that chimaerism arose as a result of postzygotic fusion of two embryos. We have shown by DNA polymorphisms the presence of autosomal chimaerism in a case of sex chromosome chimaerism, and indicated the usefulness of DNA polymorphisms in determining the origin of chimaerism.

Chimera↗
PubMed1994

Study of the Huntington's disease (HD) gene CAG repeats in schizophrenic patients shows overlap of the normal and HD affected ranges but absence of correlation with schizophrenia.

The CAG repeats in the Huntington's disease gene were investigated in chromosomes from 71 unrelated schizophrenic persons and 18 patients with schizoaffective disorder in order to determine if any of these patients had abnormal expansions. All of the probands had repeat sizes in the normal range (< 35 repeats) and there was no significant difference between the allele distributions of these patients and the normal controls. The families of two patients with 32 repeats and one patient with 34 repeats were investigated further and showed no uniform segregation of the disease with the large repeat alleles. The proband with 34 repeats inherited a chromosome that originally had 36 repeats in her father. The presence of 36 CAG repeats in members of her family and in HD patients suggests that there is an overlap between the normal and Huntington's disease CAG repeat size ranges. The more recently described CCG polymorphism in this gene was also examined in the schizophrenic and schizoaffective persons. All patients had alleles in the normal range.

Alleles↗
PubMed1994

Myotonic dystrophy CTG repeats and the associated insertion/deletion polymorphism in human and primate populations.

Myotonic dystrophy (DM) is associated with abnormal expansions of the CTG repeats in the 3' untranslated region of its gene. Previous studies in individuals of European origin demonstrated strong linkage disequilibrium between different CTG repeat length alleles and an Alu element insertion/deletion polymorphism in intron 8 of the DM gene: CTG11-13 chromosomes were almost exclusively associated with the deletion allele, while chromosomes with five or 19-30 repeats or disease chromosomes were only found on the insertion allele. One of the models suggested by these results proposed that the triplet repeats on insertion-associated chromosomes were particularly prone to mutation. Studies of other triplet repeat disorders have suggested that arrays of perfect repeats are more prone to instability than those that are interrupted. We have examined the evolution of this locus by typing a variety of primates and samples drawn from several different human populations for both CTG repeat length and the insertion/deletion polymorphism. DM gene sequences from different primates revealed inter- and intraspecies variability in the number of CTG repeats. Human chromosomes with five repeats or 11-13 repeats (the two major modes of the human CTG repeat distributions) showed no evidence of preferential stabilization of these repeat sizes by imperfect sequences. The insertion and deletion allele frequencies showed large interpopulation variation and the degree of association between these alleles and various CTG repeat lengths is not nearly as complete as was previously supposed. We have found deletion alleles carrying long normal (> 19) CTG repeats and insertion alleles associated with CTG11 - 13 in two african populations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Issues in Huntington's disease testing.

The gene that is mutated in Huntington's disease has a polymorphic (CAG)n tract close to the 5' end of its message that is unstable and abnormally expanded in disease chromosomes. Rapid PCR tests that measure the CAG repeat number in this gene will become an important clinical tool. However, this test should be approached with caution, as its specificity and sensitivity have not been absolutely determined. The possibility that one might be able to predict the age of onset from the size of the CAG expansion in cases that have more than 50 repeats has been considered. We have also made a case for retaining the diagnostic option of prenatal exclusion testing.

Age of Onset↗
PubMed1993

Molecular genetic analysis of the mechanism of tumorigenesis in acoustic neuroma.

OBJECTIVE: Acoustic neuroma, both familial and sporadic, is clinically and biologically a heterogeneous condition with a wide variation in age of presentation, length of history, and tumor growth rate. In an attempt to correlate this clinical diversity with the underlying molecular pathology, we have analyzed 43 paired blood-tumor DNA samples from patients with acoustic neuromas. DESIGN: Molecular genetic analysis. SETTING: Molecular genetic research laboratory. PATIENTS: Paired blood-tumor DNA samples were obtained from 43 patients (41 sporadic and two patients with neurofibromatosis type 2). MAIN OUTCOME MEASURES: Loss of constitutional heterozygosity was looked for in the region of tumor suppressor genes on chromosomes 3p, 5q, 11p, 17p, 17q, and 22. RESULTS: We found loss of heterozygosity exclusively for markers on chromosome 22. Thirty-nine percent of tumors showed allele loss, and in each case the loss of heterozygosity included the region of the neurofibromatosis type 2 (NF2) gene. No loss of heterozygosity was detected in the region of known or putative suppressor genes in chromosomes 3p, 5q, 11p, 17p, and 17q. CONCLUSIONS: This study has demonstrated that (1) chromosome 22 allele loss is a frequent event in sporadic acoustic neuroma; (2) the minimal region of loss of heterozygosity in acoustic neuroma includes the NF2 gene; (3) the known tumor suppressor genes investigated (VHL, adenomatous polyposis coli, WT2, p53, and NF1) do not appear to be important in the pathogenesis of acoustic neuroma; and (4) patients with extensive chromosome 22 loss tended to be younger and with a slightly shorter clinical history than those with no detectable allele loss.

Adult↗