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A E Bale

Publications and source records attributed to A E Bale.

At least 55 records · Page 3Linked to original sources
PubMed1994

Mapping the gene for hereditary hyperparathyroidism and prolactinoma (MEN1Burin) to chromosome 11q: evidence for a founder effect in patients from Newfoundland.

An autosomal dominant syndrome of prolactinomas, carcinoids, and hyperparathyroidism was described in four Newfoundland kindreds in 1980 and in one kindred from the Pacific Northwest in 1983. Because this syndrome shares many features with multiple endocrine neoplasia type 1, the gene for which maps to proximal chromosome 11q, we performed linkage studies with chromosome 11 markers in prolactinoma families to determine whether the two genes map to the same location. All proximal chromosome 11q markers gave positive LOD scores, and no recombinants were seen with PYGM (LOD score 15.25, recombination fraction .0). All affected individuals from Newfoundland shared the same PYGM allele, providing evidence for a founder effect. The disease in the Pacific Northwest kindred cosegregated with a different PYGM allele.

Base Sequence↗
PubMed1994

Molecular mechanisms of neoplasia in multiple endocrine neoplasia type 1-related and sporadic tumors of the pancreatic islet cells.

Pancreatic islet tumors are relatively rare in the general population but occur frequently in patients with MEN 1. Delineation of the genetic events leading to neoplastic transformation of islet cells is at an early stage; but based on tumor deletion studies, it appears that inactivation of the MEN 1 gene is an early step in carcinogenesis for both sporadic and MEN 1-related tumors. Limited data also suggested a role for other tumor suppressors including the retinoblastoma, adenomatous polyposis coli, and Gorlin syndrome genes. Activation of oncogenes has not been identified in pancreatic islet tumors.

Adenoma, Islet Cell↗
PubMed1993

Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancers.

To identify the sites in the p53 tumor suppressor gene most susceptible to carcinogenic mutation by sunlight, the entire coding region of 27 basal cell carcinomas (BCCs) of the skin was sequenced. Fifty-six percent of tumors contained mutations, and these were UV-like: primarily CC-->TT or C-->T changes at dipyrimidine sites. Such mutations can alter more than half of the 393 amino acids in p53, but two-thirds occurred at nine sites at which mutations were seen more than once in BCC or in 27 previously studied squamous cell carcinomas of the skin. Seven of these mutation hotspots were specific to skin cancers. Internal-cancer hotspots not located at dipyrimidine sites were not mutated in skin cancers; moreover, UV photoproducts were absent at these nucleotides. The existence of hotspots altered the process of inactivating p53 in BCC compared to other cancers: allelic loss was rare, but 45% of the point mutations were accompanied by a second point mutation on the other allele. At least one of each pair was located at a hotspot. Sunlight, acting at mutation hotspots, appears to cause mutations so frequently that it is often responsible for two genetic events in BCC development.

Aged↗
PubMed1993

Cutaneous malignant melanoma and atypical moles associated with a constitutional rearrangement of chromosomes 5 and 9.

Hereditary cutaneous malignant melanoma (HCMM) with or without atypical moles has been described in several large kindreds worldwide. Despite numerous studies of these kindreds, the gene or genes responsible for this disorder has not yet been identified. Cytogenetic and molecular studies of melanoma tumor tissue and cell lines suggest that a gene involved in the pathogenesis of malignant melanoma lies on chromosome 9p. We describe a woman with atypical moles and multiple primary melanomas, who lacks a family history of HCMM, and, has a de novo constitutional unbalanced reciprocal translocation involving the short arms of chromosomes 5 and 9 with a cytogenetically visible deletion of 5p or 9p: [46,XX,-5,-9, +der(5)t(5;9) (p13.3 or 14.2;p13.3 or 21.2), +der(9)t(5;9)]. This finding supports the hypothesis that a gene predisposing to HCMM lies on the short arm of chromosome 9.

Adult↗
PubMed1993

A pulsed-field gel electrophoresis (PFGE) map of twelve loci on chromosome 11q11-q13.

We report a pulsed-field gel electrophoresis map of 12 loci on proximal human chromosome 11q. Linkage studies have shown that this region of chromosome 11 contains the genes for familial atopic disease (APY) and multiple endocrine neoplasia type I (MEN1) (4). A physical map containing polymorphic loci will aid in the isolation of these disease genes. The map reported here has two noncontiguous groups of loci accounting for 8 of the 12 loci evaluated. One group spans a maximum distance of 1600 kb and includes D11S146, BCL1, PRAD1, INT2, and HSTF1. The other group includes FTH1, C1NH, and COX8. TCN1, PGA, and PYGM did not yield any comigrating fragments and could not be physically linked on this PFGE map. These data enhance previously published physical maps of proximal 11q by refining the localization of and distances between markers in the BCL1 region. Additionally, new information about the locations and physical relationships between FTH1, C1NH, and COX8 is presented.

Autoradiography↗
PubMed1993

Progression of uremic hyperparathyroidism involves allelic loss on chromosome 11.

In occasional cases of secondary hyperparathyroidism, long term stimulation of the parathyroid glands leads from compensatory to autonomous hyperfunction, and thus, hypercalcemia develops. This clinical entity, named tertiary hyperparathyroidism, is possibly due to the formation of an adenoma in one of the hyperplastic glands. Previous studies have shown that parathyroid adenomas may arise with allelic loss on chromosome 11. We tested for allelic loss at several loci on chromosome 11 in 12 enlarged parathyroid glands from 6 uremic patients and found loss of heterozygosity in 2 of the glands from 2 different patients with higher serum calcium levels (11.3 +/- 0.29 vs. 9.8 +/- 0.28 mg/dL; P < 0.004) and, therefore, ascribable to the so-called tertiary hyperparathyroidism. The 2 glands with allelic loss were significantly greater in mass than those without loss (3.42 +/- 0.37 vs. 1.60 +/- 0.54 g; P < 0.001). These data offer new evidence that autonomous parathyroid proliferation in uremic patients can develop through overgrowth by a monoclonal tumor, presumably with inactivation of a tumor suppressor gene(s) on chromosome 11.

Adenoma↗
PubMed1993

Molecular definition of a chromosome 9p21 germ-line deletion in a woman with multiple melanomas and a plexiform neurofibroma: implications for 9p tumor-suppressor gene(s).

Cutaneous malignant melanoma (CMM) is often familial, but the mode of inheritance and the chromosomal location of melanoma susceptibility locus are controversial. Identification of a 34-year-old woman with eight primary malignant melanomas, multiple atypical moles, and a de novo constitutional cytogenetic rearrangement involving chromosomes 5p and 9p suggested the presence of a melanoma predisposition gene at one of these locations. A high-resolution karyotype showed a partial deletion of a dark-staining Giemsa band, either 5p14 or 9p21. The patient was heterozygous for five 5p14 RFLPs. In situ hybridization with D9S3 indicated that this 9p21 marker was deleted. Gene dosage studies demonstrated the deletion of two more distal 9p21 markers, D9S126 and IFNA. In addition, she was hemizygous for the more proximal 9p21 short tandem-repeat polymorphism at D9S104. D9S18, D9S19, and D9S33 were retained, localizing the deletion to 9p21 between D9S19 on the proximal side and D9S33 on the distal side. Pulsed-field gel electrophoresis with D9S19 and D9S33 did not reveal any junction fragments in the patient's DNA. This germ-line deletion suggests that mutations in a 9p21 gene may initiate melanoma tumorigenesis.

Adult↗
PubMed1992

Allelic loss from chromosome 11 in parathyroid tumors.

Parathyroid tumors may occur in a sporadic fashion or, more rarely, as part of a familial syndrome (such as familial multiple endocrine neoplasia type I). The MENI gene has been mapped by linkage analysis to chromosome 11 at band q11-q13, and presumably acts as a tumor suppressor gene. In the present study, which is an extension of our previous studies, we examined 41 parathyroid tumors from patients with familial multiple endocrine neoplasia type I and 61 sporadic parathyroid tumors with markers on chromosome 11, to assess the extent of allelic loss in those tumors. Twenty-four of the MENI-associated tumors (58%) and 16 of the sporadic parathyroid tumors (26%) displayed allelic loss from chromosome 11. The region of overlap of the allelic losses in the MENI-associated tumors enables us to place the MENI gene between PGA centromerically and INT2 telomerically, a region spanning about 7.5 cM. Taken together with locus ordering by linkage analysis, this clearly localizes the MENI gene telomeric to the PGA locus. Our inability to detect allelic loss on chromosome 11 in some parathyroid tumors suggests the existence of other genes involved in the development and/or progression of this subgroup of presumably monoclonal tumors; or that localized events involving the 11q tumor suppressor gene have occurred in some parathyroid tumors whose detection is beyond the sensitivity of our analysis; or that at least some of the specimens analyzed were in fact primarily hyperplastic parathyroid tissue.

Adenoma↗
PubMed1992

Assignment of a locus for familial melanoma, MLM, to chromosome 9p13-p22.

Linkage analysis of ten Utah kindreds and one Texas kindred with multiple cases of cutaneous malignant melanoma (CMM) provided evidence that a locus for familial melanoma susceptibility is in the chromosomal region 9p13-p22. The genetic markers analyzed reside in a candidate region on chromosome 9p21, previously implicated by the presence of homozygous deletions in melanoma tumors and by the presence of a germline deletion in an individual with eight independent melanomas. Multipoint linkage analysis was performed between the familial melanoma susceptibility locus (MLM) and two short tandem repeat markers, D9S126 and the interferon-alpha (IFNA) gene, which reside in the region of somatic loss in melanoma tumors. An analysis incorporating a partially penetrant dominant melanoma susceptibility locus places MLM near IFNA and D9S126 with a maximum location score of 12.71. Therefore, the region frequently deleted in melanoma tumors on 9p21 presumably contains a locus that plays a critical role in predisposition to familial melanoma.

Adolescent↗
PubMed1992

Regional localization of the selenocysteine tRNA gene (TRSP) on human chromosome 19.

The human selenocysteine tRNA gene (TRSP) has been localized on chromosome 19q13.2-->q13.3 by in situ hybridization and ordered with respect to other genes and anonymous DNA markers in this region by linkage analysis in the forty CEPH pedigrees. These loci span only 10 cM in males and about 30 cM in females. The order of the loci is cen ... D19S7-D19S9-D19S47-CYP2A-CYP2F1-APOC2++ +-(TRSP, CKM). CYP2B flanks the CYP2A and CYP2F1 loci, but it cannot be determined whether it is proximal or distal to the other two cytochrome P450 loci with respect to the centromere.

Chromosome Banding↗
PubMed1992

DNA diagnosis with mutation-specific artificial methylation sites: application to rapid screening of delta F508.

Many polymerase chain reaction (PCR)-based methods for diagnosis of minute mutations are suboptimal for automated screening because of their reliance on gel electrophoresis or probe hybridization. In the method reported here, PCR products containing artificial methylation sites are analyzed by measuring incorporation of radiolabeled methyl groups. Primers are designed to amplify the possible mutation-containing region such that the 3' end of one primer lies adjacent to the possible mutation. Sequence modification near that end creates either a mutation- or wild type (WT)-specific artificial methylation site in the PCR product. The product is briefly incubated with an appropriate DNA methylase and tritiated S-adenosylmethionine ([3H]SAM), separated from free SAM by column chromatography, and analyzed for incorporation of tritium. Applying this technique to the cystic fibrosis delta F508 deletion, we accurately diagnosed five homozygotes, five heterozygotes, and five normal individuals within 40 min of PCR completion. The method can be generalized to rapid, automated detection of a variety of point mutations and small deletions.

Base Sequence↗
PubMed1991

PRAD1, a candidate BCL1 oncogene: mapping and expression in centrocytic lymphoma.

Rearrangement of the BCL1 (B-cell lymphoma 1) region on chromosome 11q13 appears to be highly characteristic of centrocytic lymphoma and also is found infrequently in other B-cell neoplasms. Rearrangement is thought to deregulate a nearby protooncogene, but transcribed sequences in the immediate vicinity of BCL1 breakpoints had not been identified. PRAD1, previously designated D11S287E, was identified on 11q13 as a chromosomal breakpoint region rearranged with the parathyroid hormone gene in a subset of parathyroid adenomas; this highly conserved putative oncogene, which encodes a novel cyclin, has been linked to BCL1 and implicated also in subsets of breast and squamous cell neoplasms with 11q13 amplification. We report pulsed-field gel electrophoresis data showing BCL1 and PRAD1 to be no more than 130 kilobases apart. PRAD1 mRNA is abundantly expressed in seven of seven centrocytic lymphomas (Kiel classification), in contrast to 13 closely related but noncentrocytic lymphomas. Three of the seven centrocytic lymphomas had detectable BCL1 DNA rearrangement. Also, two unusual cases of CLL with BCL1 rearrangement overexpressed PRAD1, in contrast to five CLL controls. Thus, PRAD1 is an excellent candidate "BCL1 oncogene." Its overexpression may be a key consequence of rearrangement of the BCL1 vicinity in B-cell neoplasms and a unifying pathogenetic feature in centrocytic lymphoma.

Chromosomes, Human, Pair 11↗
PubMed1991

Relationship between head circumference and height in normal adults and in the nevoid basal cell carcinoma syndrome and neurofibromatosis type I.

Occipitofrontal circumference (OFC) was strongly correlated with height in 72 normal Caucasian men (r = 0.28, P = 0.018) and 78 women (r = 0.53, P less than 0.0001). OFC:height ratios were approximately normally distributed in each sex with a mean of 0.326 (standard deviation [sd] = 0.0139) in males and 0.335 (sd = 0.0177) in females. Relative macrocephaly (an OFC greater than the 95th centile for height) was seen in seven of nine probands with the nevoid basal cell carcinoma syndrome (NBCC), eight of 32 non-probands with NBCC, three of four neurofibromatosis type 1 (NF1) probands, and six of nine non-probands with NF1. Thirty-one percent of the non-proband NBCC cases had OFC less than the 50th centile for height, while none of the NF1 cases had this finding. Head size appears to be related to proband status in NBCC, while the evidence suggests that NF1 is a true macrocephaly syndrome. Objective detection of relative abnormalities in head size may aid in syndrome delineation and diagnosis.

Adult↗
PubMed1991

Allelic loss on chromosome 11 in hereditary and sporadic tumors related to familial multiple endocrine neoplasia type 1.

Familial multiple endocrine neoplasia type 1 (FMEN1) is an autosomal dominant disorder characterized by tumors of the parathyroid glands, pancreatic islets, and anterior pituitary. The gene for this disease maps to chromosome 11q12-11q13, and allelic loss in this region has been shown in both sporadic and FMEN1-related parathyroid tumors. FMEN1-related pancreatic islet tumors, and rarely in sporadic anterior pituitary tumors. We tested for allelic loss at 7 loci on chromosome 11 in 17 tumors outside the parathyroid. We found loss of heterozygosity in 2 of 2 FMEN1-related benign pancreatic islet tumors but in none of 8 informative sporadic islet tumors (P = 0.02) including 5 malignant gastrinomas. Of 3 islet tumors from patients who had some but not all features of FMEN1, one showed allelic loss for 5 of 5 informative restriction fragment length polymorphisms, and the other 2 retained heterozygosity for all informative markers. A bronchial carcinoid from an FMEN1 patient and 3 sporadic anterior pituitary tumors showed no allelic loss. These data provide new evidence that many sporadic pancreatic islet neoplasms, even when malignant, do not develop through homozygous inactivation of the MEN1 gene.

Adenoma, Islet Cell↗
PubMed1991

Tight linkage of the human c-erbA beta gene with the syndrome of generalized thyroid hormone resistance is present in multiple kindreds.

Generalized thyroid hormone resistance recently was reported to map in a single kindred to the same chromosomal region as the c-erbA beta gene, which codes for a putative thyroid hormone receptor. Restriction fragment length polymorphisms (RFLPs) of c-erbA beta were linked with GTHR in three kindreds with variable neuropsychologic dysfunction; two unrelated kindreds have been reported to possess different single base mutations in the T3 binding domain of c-erbA beta. In order to ascertain if tight linkage with c-erbA beta could be generalized to other families with this syndrome, we performed RFLP analysis in a separate laboratory on an unrelated family with GTHR which lacks the neuropsychologic defects or short stature often associated with GTHR (Kindred WR). RFLPs were identified after Bam Hl and Eco RV digestion of DNA from leukocytes from 14 family members. The Bam Hl RFLPs were 2.8 and 5.3 kb bands, and the Eco RV RFLPs were 1.6 and 3.3 kb bands. These RFLPs cosegregated with the GTHR phenotype and 11 family members were informative when both RFLPs were employed. The logarithm of the odds ratio between GTHR and c-erbA beta was 3.67, and therefore GTHR mapped to the c-erbA beta locus in this kindred. Allelic-specific hybridization with a probe constructed to identify the C to A mutation at nucleotide position 1643 (previously identified in one other kindred) suggested that our family has a different c-erbA beta abnormality. Although GTHR appears to be commonly associated with alterations in the human c-erbA beta gene, different kindreds may inherit different genetic defects.

Base Sequence↗
PubMed1991

Localization of a DNA segment encompassing four tRNA genes to human chromosome 14q11 and its use as an anchor locus for linkage analysis.

The chromosomal location of an 8.2-kb genomic fragment encompassing a cluster of four human tRNA genes has been determined by three complementary methods including Southern analysis of human/rodent somatic cell hybrids, in situ hybridization, and genetic linkage analysis. This tRNA cluster (TRP1, TRP2, and TRL1) is located near the T-cell receptor alpha (TCRA) locus at 14q11, and several RFLPs were detected at this site. These RFLPs and those at the TCRA and MYH7 (cardiac beta-MHC gene) loci have been used to type all informative members of the CEPH pedigrees. This has permitted ordering of these three gene loci and two anonymous probes (D14S26 and D14S25) in a 20-cM interval just below the centromere of chromosome 14. Based upon the chromosomal location and the polymorphisms at this site, one or more members of this gene cluster could serve as a useful anchor locus on chromosome 14.

Amino Acid Sequence↗