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Biomedical subjects

R F Gagel

Publications and source records attributed to R F Gagel.

At least 55 records · Page 3Linked to original sources
PubMed1997

Unresolved issues in the genesis and management of multiple endocrine neoplasia type 2.

It has been slightly less than 3 years since mutations of the RET proto-oncogene were identified in multiple endocrine neoplasia type 2. The period since the initial report has been one of intense activity with a wide spectrum of mutations identified in exons 10, 11, 13, 14, 15 and 16 of this gene. Recent studies have provided experimental evidence for an activating effect of the exon 11 and 16 mutations. Two questions are addressed in this report: the high rate of false positive tests in prospective screening studies and the implications for future interpretation of this test: and the mechanism of transformation in MEN 2.

Carcinoma, Medullary↗
PubMed1996

The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis.

OBJECTIVE: Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant disorder. The 3 recognized subtypes include MEN 2A, characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), and hyperparathyroidism (HPT); MEN 2B, by MTC, pheo, and characteristic stigmata; and familial MTC (FMTC), by the presence of MTC only. The purpose of this study was to establish the relationship between specific mutations and the presence of certain disease features in MEN 2 which could help in clinical decision making. DESIGN: Correlative survey study of 477 MEN 2 families. SETTING: Eighteen tertiary referral centers worldwide. PATIENTS: A total of 477 independent MEN 2 families. MAIN OUTCOME MEASURES: Association between the position and type of germline mutation in the RET proto-oncogene and the presence or absence of MTC, pheo, HPT, and/or other features in a family. RESULTS: There is a statistically significant association between the presence of any mutation at a specific position (codon 634) and the presence of pheo and HPT. The presence of a specific mutation, CGC at codon 634, has yet to be associated with FMTC. Conversely, mutations at codons 768 and 804 are thus far seen only with FMTC, while codon 918 mutation is MEN 2B--specific. Rare families with both MEN 2 and Hirschsprung disease were found to have MEN 2-specific codon mutations. Patients with Hirschsprung disease presenting with such mutations should be monitored for the possible development of MEN 2 tumors. CONCLUSIONS: This consortium analysis suggests that genotype-phenotype correlations do exist and, if made reliably absolute, could prove useful in the future in clinical management with respect to screening, surveillance, and prophylaxis, as well as provide insight into the genetic effects of particular mutations.

Carcinoma, Medullary↗
PubMed1996

An intron enhancer recognized by splicing factors activates polyadenylation.

Alternative processing of the pre-messenger RNA encoding calcitonin/calcitonin gene-related peptide (CT/CGRP) involves alternative inclusion of a 3'-terminal exon (exon 4) embedded within a six exon primary transcript. Expression of CT/CGRP in transgenic mice indicates that inclusion of exon 4 occurs in a wide variety of tissues, suggesting that the factors responsible for exon 4 inclusion are widely distributed. Inclusion of exon 4 requires an enhancer sequence located within the intron downstream of the poly(A) site of exon 4. Here we show that the intron enhancer activated in vitro polyadenylation cleavage of precursor RNAs containing the CT/CGRP exon 4 poly(A) site or heterologous poly(A) sites. To our knowledge this is the first example of an intron-located enhancer that facilitates polyadenylation. Within the enhancer sequence is a 5' splice site sequence immediately preceded by a pyrimidine tract. This 5' splice site sequence was required for enhanced polyadenylation and was recognized by both U1 small nuclear ribonucleoproteins (snRNPs) and alternative splicing factor/splicing factor 2 (ASF/SF2). Enhancement of polyadenylation required U1 RNA, suggesting that the 5' splice site sequence within the enhancer mediates enhancement via interaction with factors normally associated with functional 5' splice sites. Mutation of the polypyrimidine track of the enhancer also inhibited in vitro polyadenylation cleavage. Oligonucleotide competitions and UV cross-linking indicated that the enhancer pyrimidine track binds the polypyrimidine tract binding protein (PTB), but not U2 snRNP auxiliary factor (U2AF), and that binding of PTB was required for maximal enhancer-mediated polyadenylation. These results suggest that the enhancer binds known splicing factors, and that binding of these factors activates polyadenylation cleavage. Furthermore, these results suggest that regulation of alternative processing of CT/CGRP could occur at the level of polyadenylation, rather than splicing.

Alternative Splicing↗
PubMed1996

Cortical-sparing adrenalectomy for patients with bilateral pheochromocytoma.

BACKGROUND: Bilateral pheochromocytomas are common in patients with multiple endocrine neoplasia type 2 (MEN 2) and von Hippel-Lindau disease (VHL). In an effort to avoid long-term steroid dependence and Addisonian crisis, we have performed cortical-sparing adrenalectomy in this patient population. METHODS: Retrospective chart review was completed for patients with MEN 2- or VHL-related pheochromocytomas who underwent laparotomy at our institution for intended cortical-sparing adrenalectomy between June 1965 and March 1995. RESULTS: Fifteen patients (MEN 2A [10], MEN 2B [2], VHL [3]) underwent laparotomy for cortical-sparing adrenalectomy. None of the tumors were malignant. Cortical-sparing adrenalectomy was possible in 14 (93%). Thirteen of these 14 patients (93%) had normal postoperative plasma cortisol measurements and did not require steroid hormone supplementation. At a median follow-up of 138 months, two patients had died of metastatic medullary thyroid cancer, no patient had suffered Addisonian crisis, and three patients (21%) had recurrent pheochromocytomas (at 118, 176, and 324 months after operation). The remaining nine patients were alive without pheochromocytomas. CONCLUSIONS: Cortical-sparing adrenalectomy can be performed successfully in MEN 2 or VHL patients with bilateral pheochromocytomas, avoiding chronic steroid hormone replacement and the risk of Addisonian crisis in most patients. Long-term follow-up is necessary because recurrence may develop many years after operation.

Adolescent↗
PubMed1996

Application of genetic screening information to the management of medullary thyroid carcinoma and multiple endocrine neoplasia type 2.

Application of RET proto-oncogene mutation analysis to the clinical management of MEN 2 and FMTC has simplified and enhanced the power of earlier used screening and treatment efforts for hereditary MTC. The approaches outlined herein are cost-effective, have improved diagnostic accuracy, and hold the promise of improved cure rates for this neoplasm. Further studies to elucidate the mechanism by which these activating mutations cause transformation may lead to other strategies for prevention or treatment of this neoplasm.

Base Sequence↗
PubMed1996

RET protooncogene mutational analysis in multiple endocrine neoplasia syndrome type 2B: case report and review of the literature.

Multiple endocrine neoplasia, type 2B (MEN 2B), is a phenotypic variant of a group of autosomal-dominant neurocristopathies. MEN 2B is associated with medullary thyroid carcinoma and pheochromocytoma with oral, ocular, and alimentary submucosal ganglioneuromas and Marfanoid body features. Approximately 50% of cases are thought to be spontaneous mutations. The RET protooncogene (RET) is a 21-exon gene encoding a tyrosine kinase receptor. A codon 918 germ line mutation, which converts a highly conserved methionine to a threonine in the intracellular tyrosine kinase portion of this receptor of RET, has been identified in 95% of patients with MEN 2B. This mutation is easily detected by a direct deoxyribonucleic acid sequencing or restriction enzyme (Fok 1) analysis of amplified polymerase chain reaction products. The RET gene is normally expressed in the oral and gastrointestinal submucosal neural ganglia, and the codon 918 mutation is thought to cause neuromas by virtue of its transforming activity in these ganglia. Identifying clinical features of MEN 2B in an 11-year-old boy by an oral pathologist led to confirmation by mutational analysis. Before genetic testing was available, the patient, and at a later date his mother, underwent thyroidectomies based solely on biochemical testing. Results indicated the patient had the codon 918 mutation, whereas his phenotypically normal mother, father, and older brother had normal RET analyses. Studies in families have demonstrated that the mutant allele is derived from the father with possible acquisition during spermatogenesis. We believe the mother of our affected patient to be normal; the absence of phenotypic features of MEN 2B and a normal genotype suggest her calcitonin abnormalities and minimal evidence for C-cell hyperplasia were inconsequential. Molecular analysis for RET abnormalities will likely supplant biochemical methods of diagnosis in patients with MEN 2B.

Carcinoma, Medullary↗
PubMed1996

Increased efficiency of calcium absorption during short periods of inadequate calcium intake in girls.

Adequate calcium intake is essential for skeletal integrity, particularly during the period of peak bone mass acquisition from 9 to 17 y of age. Currently, the calcium intake of many adolescent girls is below the recommended dietary allowance. The purpose of this study was to evaluate the ability of girls to respond to acute periods of inadequate dietary calcium intake. Calcium absorption was evaluated in 11 girls aged 11.6 +/- 2.4 y after 10 d on both a low-calcium (7.05 +/- 2.03 mmol/d) and a high-calcium (35.30 +/- 2.28 mmol/d) diet. Fractional calcium absorption was determined by using oral (46Ca) and intravenous (42Ca) stable isotopes of calcium. During a low calcium intake, fractional calcium absorption was significantly greater (0.582 +/- 0.087 compared with 0.260 +/- 0.068, P < 0.0001) and urinary calcium excretion was significantly lower (1.30 +/- 0.83 compared with 3.08 +/- 1.98 mmol/d, P < 0.004) than values obtained during a high calcium intake. Concentrations of 1,25-dihydroxyvitamin D (combination of cholecalciferol and ergocalciferol) were greater during the low calcium intake, although the difference was not significant (108.7 +/- 30.6 compared with 90.0 +/- 25.1 pmol/L, P < 0.1; n = 9). Excretion of N-telopeptide was significantly greater during the low calcium intake (761 +/- 508 compared with 413 +/- 341 nmol bone collagen equivalent (BCM)/mmol creatinine, P < 0.02; n = 9), indicating that bone resorption was increased. These results suggest that during short periods of inadequate calcium intake, girls are able to significantly increase the efficiency of calcium absorption and decrease urinary calcium losses to conserve calcium required for bone mineral acquisition.

Absorption↗
PubMed1996

Genetic heterogeneity of familial primary cutaneous amyloidosis: lack of evidence for linkage with the chromosome 10 pericentromeric region in Chinese families.

Primary cutaneous amyloidosis is a relatively common skin disease in Southeast Asia, South America, and the Republic of China. Although most cases are sporadic, some patients have a family history, suggesting that genetic factors may play a role in its pathogenesis. Some patients with multiple endocrine neoplasia type 2A also have a clinical picture of primary cutaneous amyloidosis. It is thus suggested that the gene of familial primary cutaneous amyloidosis is linked to the pericentromeric region of chromosome 10, the location of the RET proto-oncogene. We have carried out linkage analysis in seven families with cutaneous amyloidosis using four dinucleotide repeat markers from the RET region. Negative lod scores at all recombination frequencies were obtained. We thus conclude that there is no evidence for linkage between Chinese families with primary cutaneous amyloidosis and the pericentromeric region of chromosome 10. The distinct genetic basis, plus their apparent phenotypic differences in sex ratio, age of onset, and sites of cutaneous lesions, suggests that familial primary cutaneous amyloidosis includes clinical subtypes attributable to genetic heterogeneity.

Adolescent↗
PubMed1996

Relevance of RET proto-oncogene mutations in sporadic medullary thyroid carcinoma.

Analysis of peripheral blood or tumor DNA samples from 101 patients with apparent sporadic medullary thyroid carcinoma (MTC) was performed to assess the frequency of RET proto-oncogene mutations in this patient population. Peripheral blood and/or tumor DNA was amplified by polymerase chain reaction. DNA sequence or restriction enzyme analysis was performed to detect mutations of RET proto-oncogene codons 609, 611, 618, 620, 634, 768, and 918. Six of 101 patients with apparent sporadic MTC had peripheral blood DNA mutations more commonly associated with hereditary MTC. In 4 patients, these mutations led to the identification of previously unrecognized kindreds. The remaining 2 patients were examples of de novo mutations. A codon 918 mutation was found in 14 of 57 (approximately 25%) tumor DNA samples. Mutations were not identified in the remaining patients. In this large cancer center population, approximately 6% of patients with sporadic MTC carry peripheral blood DNA mutations, either inherited or de novo, more commonly associated with MEN 2A or familial MTC. Seven additional gene carriers were identified as a direct result of these studies, a 2-fold multiplying effect. We conclude routine application of RET proto-oncogene testing should be included in all cases of apparent sporadic MTC.

Base Sequence↗
PubMed1996

Inactivation of the first nucleotide-binding fold of the sulfonylurea receptor, and familial persistent hyperinsulinemic hypoglycemia of infancy.

Familial persistent hyperinsulinemic hypoglycemia of infancy is a disorder of glucose homeostasis and is characterized by unregulated insulin secretion and profound hypoglycemia. Loss-of-function mutations in the second nucleotide-binding fold of the sulfonylurea receptor, a subunit of the pancreatic-islet beta-cell ATP-dependent potassium channel, has been demonstrated to be causative for persistent hyperinsulinemic hypoglycemia of infancy. We now describe three additional mutations in the first nucleotide-binding fold of the sulfonylurea-receptor gene. One point mutation disrupts the highly conserved Walker A motif of the first nucleotide-binding-fold region. The other two mutations occur in noncoding sequences required for RNA processing and are predicted to disrupt the normal splicing pathway of the sulfonylurea-receptor mRNA precursor. These data suggest that both nucleotide-binding-fold regions of the sulfonylurea receptor are required for normal regulation of beta-cell ATP-dependent potassium channel activity and insulin secretion.

ATP-Binding Cassette Transporters↗
PubMed1996

The molecular basis for familial persistent hyperinsulinemic hypoglycemia of infancy.

Familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a glucose metabolism disorder in neonates characterized by inappropriate insulin secretion in the presence of profound hypoglycemia. Loss of function mutations in the sulfonylurea receptor (SUR) gene recently have been implicated as a cause for familial PHHI in nine independent families. This review will describe the combined positional cloning and candidate gene strategy used to identify the SUR gene as the one responsible for PHHI. Potential roles for SUR in other disorders of insulin secretion remains to be determined.

ATP-Binding Cassette Transporters↗
PubMed1995

Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy.

Familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disorder characterized by unregulated insulin secretion, is linked to chromosome 11p14-15.1. The newly cloned high-affinity sulfonylurea receptor (SUR) gene, a regulator of insulin secretion, was mapped to 11p15.1 by means of fluorescence in situ hybridization. Two separate SUR gene splice site mutations, which segregated with disease phenotype, were identified in affected individuals from nine different families. Both mutations resulted in aberrant processing of the RNA sequence and disruption of the putative second nucleotide binding domain of the SUR protein. Abnormal insulin secretion in PHHI appears to be caused by mutations in the SUR gene.

ATP-Binding Cassette Transporters↗
PubMed1995

Cytogenetic characterization of three human and three rat medullary thyroid carcinoma cell lines.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor of the thyroid C-cells. MTC may arise as a sporadic tumor or as a component of one of three autosomal dominant familial cancer syndromes, MEN 2A, MEN 2B, or familial MTC. Recent studies have identified mutations of the RET proto-oncogene in the proximal long arm of chromosome 10, which are thought to be causative for these syndromes. To facilitate the search for other genes involved in the development of MTC, we characterized cytogenetically three human MTC cell lines and three rat MTC cell lines. The human cell lines studied were TT and RO-H85-1, previously reported, and an uncharacterized cell line, MZ-CRC-1, derived from a malignant pleural effusion from a patient with metastatic MTC. The rat MTC cell lines characterized were CA-77, 6-23C6, and 44-2. Cytogenetic abnormalities present in the human and rat cell lines were compared with 13 reported cytogenetic studies of human MTC tumors and three other cytogenetically analyzed MTC cell lines. The human 9q/rat 3 and human 3p/rat 15 chromosomes were affected in six of the comparable cell lines and tumors. These findings suggest human chromosome regions 9q and 3p may contain genes involved in the pathogenesis of MTC.

Animals↗