Infrequent Detectable Somatic Mutations of the RET and Glial Cell Line-Derived Neurotrophic Factor (GDNF) Genes in Human Pituitary Adenomas.

RET is a receptor tyrosine kinase expressed in neuroendocrine cells and tumors. RET is activated by a ligand complex comprising glial cell line-derived neurotrophic factor (GDNF) and GDNF receptor-alpha (GDNFR-alpha). Activating mutations of the RET proto-oncogene were found in multiple endocrine neoplasia (MEN) 2 and in sporadic medullary thyroid carcinoma and pheochromocytoma of neuroendocrine origin. Mutations of the RET proto-oncogene and the glial cell line-derived neurotrophic factor (GDNF) gene were examined in human pituitary tumors. No mutations of the RET proto-oncogene including the cysteine-rich region or codon 768 and 918 in the tyrosine kinase domain were detected in 172 human pituitary adenomas either by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) or by PCR-restriction fragment length polymorphism (RFLP). Further, somatic mutations of the GDNF gene in 33 human pituitary adenomas were not detected by PCR-SSCP. One polymorphism of the GDNF gene at codon 145 of TGC or TGT was observed in a prolactinoma. The RET proto-oncogene message was detected in a normal human pituitary gland or 4 of 4 human pituitary adenomas with reverse transcription (RT)-PCR, and in rodent pituitary tumor cell lines with Western blotting. The expression of GDNF gene was detected in 1 of 4 human somatotroph adenomas, 1 of 2 corticotroph adenomas, and 2 of 6 rodent pituitary tumor cell lines with RT-PCR. Based on these, it is concluded that somatic mutations of the RET proto-oncogene or the GDNF gene do not appear to play a major role in the pituitary tumorigenesis in examined tumors.


Analysis of loss of heterozygosity on chromosome 11 and infrequent inactivation of the MEN1 gene in sporadic pituitary adenomas

To investigate the role of tumor suppressor genes in sporadic pituitary adenomas, we first analyzed loss of heterozygosity on 11q13 with microsatellite analysis in 31 tumors. Loss of heterozygosity on 11q13 was detected in 1 mixed GH/PRL adenoma, and the somatic 22-bp deletion of the multiple endocrine neoplasia type 1 (MEN1) gene encoding menin was detected in this tumor. Trisomy 11 suggested by the decreased mean allelic ratios of 66% or 65% for 16 or 13 microsatellite markers, respectively, in 2 of 31 pituitary adenomas was confirmed by interphase fluorescence in situ hybridization. Screening for mutations of the MEN1 gene did not find mutations with PCR-single strand conformation polymorphism analysis in other pituitary adenomas retaining heterozygosity on 11q13. Based on these, it is concluded that inactivation of the MEN1 gene comprises a rare etiology for tumorigenesis of the pituitary gland, and that trisomy 11 or another gene(s) may contribute to the pathogenesis of sporadic pituitary adenomas.

The Journal of Clinical Endocrinology and Metabolism


Abrogation of Autoimmune Diabetes in Nonobese Diabetic Mice and Preotection against Effector Lymphocytes by Transgenic Paracrine TGFb-1.


Germ-Line Mutations in MEN1 Patients-Authors' Response.


Analysis of Loss of Heterozygosity on Chromosome 11 and Infrequent Inactivation of MEN1 Gene in Sporadic Pituitary Adenomas.


Absence of Germline Mutations of the MEN1 Gene in Familial Pituitary Adenoma in Contrast to Multiple Endocrine Neoplasia Type 1 in Japanese.


Frequent overexpression of the cyclin D1 oncogene in invasive lobular carcinoma of the breast.


Familial Isolated Primary Hyperparathyroidism with Parathyroid Carcinomas: Clinical and Molecular Features.

Familial isolated primary hyperparathyroidism (FIHP) is a rare hereditary disorder. We present four patients from a single family with FIHP, and genetic analysis of their parathyroid adenomas and parathyroid carcinoma. DNA was extracted from tumours resected at surgery. Tumours were examined for loss of heterozygosity (LOH) with microsatellite polymorphic markers. The 27-year-old proband (Patient 1) died of parathyroid carcinoma with metastases to the lungs and chest wall. Sixteen years later, his 34-year-old sister (Patient 2) presented with a neck tumour and primary hyperparathyroidism. Family screening revealed parathyroid tumours in his 36-year-old sister (Patient 3) and 29-year-old cousin (Patient 4). Histological examination of resected tumours showed parathyroid carcinoma and adenoma in Patient 2, a parathyroid adenoma in Patient 3, and an atypical parathyroid adenoma in Patient 4. Autopsy of the proband ruled out multiple endocrine neoplasia (MEN) type 1, and the three patients who underwent parathyroidectomy did not exhibit any abnormalities in the pancreas or the pituitary gland. Analysis of tumour DNA from one parathyroid carcinoma (Patient 2), the atypical parathyroid adenoma (Patient 4), and two parathyroid adenomas (Patients 2 and 3) showed limited LOH on chromosomes 13q12.3-q32 in an adenoma of Patient 2 and 9p21-p22 and 13q12.3-q32 in an adenoma of Patient 3. These results suggest the possible contribution of tumour suppressor genes including the retinoblastoma gene and the hereditary breast cancer susceptibility gene (BRCA2) on 13q to parathyroid tumours in this family.


Multiple Endocrine Neoplasia Type 1 Presented with Manic-Depressive Disorder: A Case Report with an Identified MEN 1 Gene Mutation.

We report a case of multiple endocrine neoplasia type 1 who had repeated hypoglycemic episodes and had previously been diagnosed with bipolar manic-depressive disorder. The patient had a positive family history of multiple endocrine neoplasia type 1 and had multiple pancreatic endocrine tumors, hyperparathyroidism and possibly a pituitary tumor. The pancreatic tumors were resected by subtotal pancreatectomy and examined by histochemical staining and gene analysis. The tumor cells were positive for immunoreactive insulin and glucagon. A microsatellite polymorphism analysis revealed loss of heterozygosity on 11q13 in the tumors. By polymerase chain reaction-based nucleotide sequencing, we identified a germline mutation 483del2 of the MEN1 gene in the normal pancreatic tissue of the patient. This mutation causes a shift of the reading frame of menin mRNA at codon 125. It seems that the wild type allele of the MEN1 gene had been lost in the tumor cells whereas the mutant allele remained intact. This is the first identified MEN1 gene mutation in Japanese families and is different from all MEN1 gene mutations reported previously.


Infrequent Mutations of p27Kip1 Gene and Trisomy 12 in a Subset of Human Pituitary Adenomas.


Amidophosphoribosyltransferase Limits the Rate of Cell Growth-linked de Novo Purine Biosynthesis in the Presence of Constant Capacity of Salvage Purine Biosynthesis.


p53 Gene Mutation in N-(4-hydroxybutyl) nitrosamine-induced Urinary Bladder Tumors and N-methyl-N-nitrosourea-induced Colon Tumors of Rats.


Cystic Glucagonoma with Loss of Heterozygosity on chromosome 11 in Multiple Endocrine Neoplasia Type 1.

A 52-year-old man with a past history of a pituitary adenoma and hyperparathyroidism due to a parathyroid adenoma was admitted because of a solitary tumour of the pancreas revealed by ultrasonography. His family history was unremarkable. Plasma glucagon levels were slightly elevated (280 ng/l, normal range, 40-180 ng/l) with decreased plasma amino acid levels. Plasma glucagon levels disclosed an exaggerated response during an arginine infusion test and paradoxical elevation during a 75 g oral glucose tolerance test. Endoscopic ultrasonography revealed a monolocular cystic mass of about 3 cm in diameter in the body of the pancreas. A pancreatic tumour was diagnosed before surgery as a cystic glucagonoma. Intra-operative ultrasonography showed one cystic mass in the body of pancreas and two other solid tumours, about 1 cm and 0.5 cm in diameter, in the tail of the pancreas. Histologically, all three tumours showed neoplastic epithelial cells with round nuclei forming cords and/or a ribbon-like arrangement. They showed positive staining for Grimelius' silver stain and immunopositive cells for glucagon. Genetic analysis of the main cystic tumour revealed loss of heterozygosity (LOH) on chromosome 11. After the operation, the responses of plasma glucagon to arginine infusion and oral glucose became normal. Here we describe the usefulness of these provocation tests for early diagnosis and post-operative follow-up in a rare cystic glucagonoma associated with multiple endocrine neoplasia type 1 (MEN 1) which had LOH on chromosome 11.


p53 Gene Mutation Analysis in Porokeratosis and Porokeratosis-associated Squamous Cell Carcinoma.

In this and previous studies, we have shown p53 overexpression immunohistochemically in 14 of 17 porokeratotic specimens obtained from 14 lesions of nine cases, and in all six specimens of squamous cell carcinoma (SCC) arising on porokeratotic lesions of two cases. We screened mutations in exons 5 to 10 of the p53 gene in all these specimens by polymerase chain reaction-single strand conformation polymorphism analysis. Mutations of the p53 gene were detected in two of the six SCCs but not in any of the 17 porokeratotic specimens. These two mutations were C to T transitions at codons 146 and 175 in exon 5, which were a nonsense mutation at a dipyrimidine site and a missense mutation at a CG site, respectively. To our knowledge, neither of these mutations has been identified in skin cancers before. Our observations indicate that mutations of the p53 gene are not the major molecular etiology for porokeratosis, but are related to its skin carcinogenesis, and that p53 overexpression in porokeratosis is not due to p53 gene mutations.


Infrequent Mutations of p16INK4A and p15INK4B Genes in Human Pituitary Adenomas.


Inactivation of the Tumor Suppressor Gene on 11q13 in Brothers with Familial Acrogigantism without Multiple Endocrine Neoplasia Type 1.


Prevention of Adoptively Transferred Diabetes in Non-Obese Diabetic Mice with IL-10-Transduced Islet-Specific Th1 Lymphocytes: A Gene Therapy Model for Autoimmune Diabetes.


Molecular Cloning of a cDNA Encoding Human Ribosomal Protein L39.

A cDNA clone encoding a human ribosomal protein L39 (hRPL39) was isolated through a random cDNA sequencing approach to a cDNA library constructed from a human colon carcinoma cell line of COLO 205. Although levels of hRPL39 mRNA were different in several cell lines including carcinoma cell lines from different tissues, they were shown not to be cell cycle-dependent in a human fibroblast cell line of TIG-1.

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression


Molecular Cloning of a Human cDNA Encoding a Trifunctional Enzyme of Carbamoyl- Phosphate Synthetase-Aspartate Transcarbamoylase-Dihydroorotase in de Novo Pyrimidine Synthesis.

Biochemical and Biophysical Research Communications


Detection of Different Quasispecies of Hepatitis C Virus Core Region in Cancerous and Non-cancerous Regions.


GGAAT Motifs Play a Major Role in Transcriptional Activity of the Human Insulin Gene in a Pancreatic Islet Beta Cell Line of MIN6.


Multiple Fluorescence-Based PCR-SSCP Analysis Using Internal Fluorescent Labeling of PCR Products.


Absence of Mutations at Codon 768 of the RET Proto-Oncogene in Sporadic and Hereditary Pheochromocytomas.

Sixteen sporadic pheochromocytomas, 3 pheochromocytomas in neurofibromatosis 1, and 4 pheochromocytomas in multiple endocrine neoplasia (MEN) 2A or 2B were screened for mutations at codon 768 of the RET proto-oncogene by AluI digestion of polymerase chain reaction PCR products and mutations in exon 13 by PCR-single strand conformation polymorphism (SSCP) analysis. Although mutations at codon 768 (GAG --> GAC; Glu --> Asp) of the RET proto-oncogene were recently reported to be found in 40% of sporadic medullary thyroid carcinomas (MTCs), the absence of missense mutations at codon 768 was confirmed both with PCR-restriction fragment length polymorphism (RFLP) and PCR-SSCP analysis in all examined cases of pheochromocytomas. These results suggest that mutations at codon 768 of the RET proto-oncogene do not represent a frequent mechanism of tumorigenesis for both sporadic and hereditary pheochromocytomas.


Obvious mRNA and Protein Expression but Absence of Mutations of the RET Proto-Oncogene in Parathyroid Tumors.


Loss of Ganciclovir Sensitivity by Exclusion of Thymidine Kinase Gene from Transplanted Proinsulin-Producing Fibroblasts as a Gene Therapy Model for Diabetes.

To establish a practical method of somatic gene therapy, we aimed to develop a regulatory system at the cellular level using a suicide vector. We introduced the herpes simplex virus type 1 thymidine kinase (HSV-tk) gene into the human proinsulin-producing Ltk-cells and examined whether ganciclovir (GCV) administration could control proinsulin production in vivo. The cells transfected with the HSV-tk gene showed more than 100-fold increase in sensitivity to GCV compared with the parent cells. Analysis of blood glucose in diabetic nude mice with transplanted cells showed that proinsulin production by these cells was strongly suppressed by GCV treatment in vivo as reflected by the reversal to hyperglycemia. However, in the in vivo experiment, the plasmid containing the HSV-tk gene was spontaneously lost from the transplanted cells in one of six cases resulting in the resistance to GCV as reflected by the persistent hypoglycemia and increased tumor size. This system of HSV-tk and administration of GCV may be applicable to gene therapy as a suicide vector, but the system of stable expression of the HSV-tk gene must be established.


Frequent p53 Accumulation in the Chronically Sun-Exposed Epidermis and Clonal Expansion of p53 Mutant Cells in the Epidermis Adjacent to Basal Cell Carcinoma.

The Journal of Investigative Dermatology


Rat Genomic Structure of Amidophosphoribosyltransferase, cDNA Sequence of Aminoimidazole Ribonucleotide Carboxylase, and Cell Cycle-Dependent Expression of These Two Physically Linked Genes.

Genomic structure of rat amidophosphoribosyltransferase (ATase; EC 2.4.2.14), which catalyzes the first committed step in de novo purine nucleotide synthesis, was determined by polymerase chain reaction (PCR)-based methods. There are 11 exons and all exon-intron boundaries were conserved among rat, human, and chicken ATase genes. A rat aminoimidazole ribonucleotide carboxylase (AIRC) cDNA encoding a bifunctional enzyme of AIRC (EC 4.1.1.21) at step 6 and SAICAR synthetase (EC 6.3.2.6) at step 7 in de novo purine nucleotide synthesis was cloned and sequenced. The size of the cloned rat AIRC cDNA was 1329 bp, and amino acid identity with human and chicken AIRC was 96 and 85%, respectively. The intergenic sequence using a phage clone and the PCR product disclosed that ATase and AIRC genes are physically linked with the 736 bp sequence between the translation start sites, and the determination of the transcriptional start sites by the primer extension assay for these genes disclosed that distance between the two major transcriptional start sites is 585 bp. The amount of mRNAs of both genes showed approx. 5-6-fold increase in G1/S phase of the cell cycle over those in G0 phase in synchronized rat 3Y1 fibroblasts.


Lack of CD54 Expression and Mutation of p53 Gene Relate to the Prognosis of Childhood Burkitt's Lymphoma.


Mutations in the Cysteine-Rich Region of the RET Proto-Oncogene in Patients Diagnosed as Having Sporadic Medullary Thyroid Carcinoma.

Medullary thyroid carcinoma (MTC) and pheochromocytoma appear in either a sporadic or a hereditary form as components of multiple endocrine neoplasia (MEN). Many germline mutations of the RET proto-oncogene have been reported in patients with MEN 2A and 2B, and familial MTC (FMTC). To elucidate the etiological roles in tumorigenesis of sporadic MTCs and pheochromocytomas, mutations in the cysteine-rich region of the RET proto-oncogene were analyzed by using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. Exons 10 and 11 were studied in genomic DNAs from 3 clinically apparent sporadic MTCs, MTCs and pheochromocytomas from 2 patients with MEN 2A, 1 with FMTC, 4 with MEN 2B, 3 with neurofibromatosis type 1 (NF1), 12 sporadic pheochromocytomas and an MTC cell line, TT. All tumors from two patients with MEN 2A and one patient with FMTC had mutations at codon 618 and 634 as well as their leukocytes, reflecting their germline mutations. In this region, no mutations were detected in any tumors from patients with MEN 2B and NF1, and sporadic pheochromocytomas. But mutations were detected and identified in 3 clinically apparent sporadic MTCs and TT cells. A 6 base pair (bp) deletion causing the loss of a cysteine residue at codon 634 and a mutation causing substitution from cysteine to tyrosine at codon 634 were detected in 2 sporadic MTCs as somatic events. In a female patient diagnosed as having sporadic MTC, a mutation at codon 618 was detected not only in tumor tissues, but also in her leukocytes, suggesting a germline mutation of the RET proto-oncogene.(ABSTRACT TRUNCATED AT 250 WORDS)


Two Different Pituitary Adenomas in a Patient with Multiple Endocrine Neoplasia Type 1Associated with Growth Hormone-Releasing Hormone-Producing Pancreatic Tumor: Clinical and Genetic Features.

The clinical and genetic features of a 43-year-old male patient with multiple endocrine neoplasia type 1 were reported. He developed hyperparathyroidism, a GHRH-producing pancreatic tumor, and acromegaly between 1980 and 1983. Because his pituitary gland increased in size even after resecting the GHRH-producing pancreatic tumor, transsphenoidal hypophysectomy was performed six years later. The pituitary contained two histologically-different adenomas composed of somatotroph cells and null cells. Genetic analyses revealed loss of heterozygosity on chromosome 11 in common in the pituitary adenomas, the pancreatic endocrine tumors, and a parathyroid hyperplasia. On the other hand, mutations of ras, p53, Gs alpha, and Gi2 alpha genes were not found in these tumors. The loss of the tumor suppressor gene on chromosome 11q12-13 was involved in the formation of two pituitary adenomas, two pancreatic endocrine functioning tumors, and a parathyroid hyperplasia in this patient, but the tumorigenic factors in the specific endocrine organs remain to be studied.


Point Mutation of the Somatostatin Receptor 2 Gene in the Human Small Cell Lung Cancer Cell line COR-L103.

Biochemical and Biophysical Research Communications


Galactose-Induced Albuminuria in Transgenic Mice Expressing Human Aldose Reductase.


Multiple Fluorescence-Based PCR-SSCP Analysis with Postlabeling.


Tumor-Specific Mutations in the Tyrosine Kinase Domain of the RET Proto-Oncogene in Pheochromocytomas of Sporadic Type.

Sporadic pheochromocytomas, sporadic medullary thyroid carcinomas (MTCs), pheochromocytomas and/or MTCs in multiple endocrine neoplasia (MEN) 2A or 2B were screened for mutations in the tyrosine kinase domain of the RET proto-oncogene by direct sequencing of PCR-amplified products or sequencing subcloned DNAs from PCR-products. All tumors of 4 MEN 2B patients were confirmed to contain a heterozygous missense mutation at codon 918 (ATG-->ACG; Met-->Thr) of the RET proto-oncogene as well as their leukocytes. The same tumor-specific mutations at codon 918 were also found in 5/16 (31%) sporadic pheochromocytomas. These results suggest that mutations of the RET proto-oncogene in its tyrosine kinase domain play a role not only as the predisposing gene for MEN 2B, but also as a tumorigenic factor for pheochromocytomas of sporadic type.


Human Calgizzarin; One Colorectal Cancer-Related Gene Selected by a Large Scale Random cDNA Sequencing and Northern Blot Analysis.


Molecular Cloning of a Group of Mouse Pancreatic Islet B Cell and Glucose Concentration-Related Genes by Random cDNA Sequencing.


Point mutation of the somatostatin receptor 2 gene in the human small cell lung cancer cell line COR-L103


p53 Gene Mutations in Human Skin Cancers and Precancerous Lesions: Comparison with Immunohistochemical Analysis.

The Journal of Investigative Dermatology


Transgenic Expression of IL-10 in Pancreatic Islet A cells Accelerates Autoimmune Insulitis and Diabetes in Non-Obese Diabetic Mice.


PCR with End Trimming and Cassette Ligation: A Rapid Method to Clone Exon-Intron Boundaries and a 5'-Upstream Sequence of Genomic DNA Based on a cDNA Sequence.


T-Cassette Ligation: A Method for Direct Sequencing and Cloning of PCR-Amplified DNA Fragments.


Multiple Fluorescence-Based PCR-SSCP Analysis.


An End-Trimming Method to Amplify Adjacent cDNA Fragments by PCR.


Critical Commentary to "MEN 1 with Mediastinal Carcinoid".


Relatively Good Prognosis of Multiple Endocrine Neoplasia Type 2B in Japanese: Review of Cases in Japan and Analysis of Genetic Changes in Tumors.

Since 1968, a total of 23 patients with multiple endocrine neoplasia type 2B (MEN 2B) have been identified in Japan. The mean age at diagnosis was 20.3 years (range, 6 to 39 years). All patients had neuromas and bumpy lips. All patients underwent thyroidectomy for medullary thyroid carcinoma (MTC). Ten of 23 patients had pheochromocytomas. One patient died of cerebral bleeding at the age of 43, 2 patients died of MTC at the age of 35 and 12. Five-, 10-, and 15-year survival rates were 100%, 92%, and 88%, respectively. The clinical course of MTC in MEN 2B in Japanese is not so aggressive when compared with about a 50% 10-year survival reported for Caucasians. Genetic analysis of 4 MTC and 1 pheochromocytoma from 4 patients with MEN 2B revealed no common changes in regard to loss of heterozygosity on 21 chromosomes or point mutations of the ras, Gs alpha, or p53 genes.


PCR-SSCP Screening of b-Amyloid Precursor Protein Mutations in Two Japanese Pedigrees with Familial Early Onset Alzheimer's Disease.


Rare Mutation of Gs Alpha Subunit Gene in Human Endocrine Tumors: Mutation Detection by Polymerase Chain Reaction-Primer-Introduced Restriction Analysis.

The Gs alpha (Gs alpha) gene can be activated to the putative oncogene gsp by specific point mutations at codons 201 or 227. Such mutations have been reported in growth hormone (GH)-secreting pituitary adenomas and thyroid tumors. To clarify the role of Gs alpha gene in human endocrine tumors, 197 tumors were screened for point mutations at codons 201 or 227 of the Gs alpha gene. Mutations were detected by primer-introduced restriction analysis (PIRA) of the polymerase chain reaction (PCR) product of genomic DNA. These Gs alpha mutations were present in 4 of 53 pituitary adenomas (4 of 43 GH-secreting adenomas; 1 of these 4 was a GH- and prolactin-secreting adenoma from a patient with familial multiple endocrine neoplasia Type 1), 4 of 66 thyroid tumors (4 of 30 papillary carcinomas), and 1 of 19 adrenocortical adenomas (1 of 6 aldosterone-secreting adenomas). In contrast, none of these Gs alpha mutations were detected in parathyroid tumors, endocrine pancreatic tumors, or pheochromocytomas. Gs alpha mutations at these two loci may play a role in the pathogenesis of a small population of GH-secreting pituitary adenomas, papillary thyroid carcinomas, and adrenocortical adenomas, but that they are not involved in the pathogenesis of other types of endocrine tumors.


Molecular Cloning of Rat Amidophosphoribosyltransferase.


Molecular Cloning of Human Amidophosphoribosyltransferase.

Biochemical and Biophysical Research Communications


Ras Mutations in Endocrine Tumors: Mutation Detection by PCR-SSCP.


Molecular and Genetic Analysis of a Compound Heterozygote for Dysprothrombinemia of Prothrombin Tokushima and Hypoprothrombinemia.


Two New Nonsense Mutations in Type Ia Antithrombin III Deficiency at Leu 140 and Arg 197.


Detection of a New Polymorphism of the Human Prothrombin (F2) Gene by Combination of PASA and Mutated Primer-Mediated PCR-RFLP.


Role of p53 Gene Mutations for Endocrine Tumorigenesis: Mutation Detection by Polymerase Chain Reaction-Single Strand Conformation Polymorphism.


Highly Polymorphic Region of the Human Prothrombin (F2) Gene.


Detection of a Single Base Substitution of the Gene for Prothrombin Tokushima: The Application of PCR-SSCP for the Genetic and Molecular Analysis of Dysprothrombinemia.

The genetic and molecular basis of a mutant prothrombin of 'prothrombin Tokushima' was studied by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and PCR-restriction fragment length polymorphism (PCR-RFLP) analyses. The abnormal gene was detected by altered migration by PCR-SSCP and by the loss of an MspI site by PCR-RFLP. The gene for prothrombin Tokushima was shown to be inherited from the mother of the proband. Sequencing analysis using PCR-amplified genomic DNA clarified a substitution of thymine (T) for cytosine (C) at position 9,490, changing arginine (Arg) to tryptophan (Trp) at position 418 of the polypeptide chain. This point mutation is assumed to be the molecular basis of prothrombin Tokushima, firstly, because of the absence of distinct changes in Southern blot analysis of the proband's DNA (using a full-length human prothrombin cDNA as a probe), secondly, because it has the same molecular weight as the abnormal gene product, and, thirdly, because of the absence of other amino acid abnormalities in the proteolytic peptide-fragments. It is concluded that PCR-SSCP and PCR-RFLP were useful for detecting the abnormal gene and for directly diagnosing the carrier status of dysprothrombinemia. This is the first report of gene analysis of dysprothrombinemia.


Detection of Point Mutations by SSCP of PCR-Amplified DNA after Endonuclease Digestion.


A Kindred of Multiple Endocrine Neoplasia Type 2B.


NcoI RFLP in the Human Prothrombin (F2) Gene.


胆嚢摘出後に高カルシウム血症性クリーゼを来たした原発性副甲状腺機能亢進症の1例

胆嚢摘出後に高カルシウム血症性クリーゼを来たした原発性副甲状腺機能亢進症の1例


本邦における多発性内分泌腺腫瘍症1型の実態調査

本邦における多発性内分泌腺腫瘍症1型の実態調査


Loss of Heterozygosity on Chromosome 1p in Thyroid Adenoma and Medullary Carcinoma, but not in Papillary Carcinoma.


Allele Loss on Chromosome 11 in a Pituitary Tumor from a Patient with Multiple Endocrine Neoplasia Type I.


先天性anti-thrombin III (ATIII) 欠乏症家系におけるATIII遺伝子のDNA解析


Loss of Heterozygosity on Chromosomes 1 and 11 in Sporadic Pheochromocytomas.


Ectopic Production of Parathyroid Hormone by Small Cell Lung Cancer in a Patient with Hypercalcemia.

The Journal of Clinical Endocrinology and Metabolism


Japanese Journal of Cancer and Chemotherapy


Loss of the Same Allele of HRAS1 and D11S151 in Two Independent Pancreatic Cancers from a Patient with Multiple Endocrine Neoplasia Type 1.


A polymorphic HindIII site within the human multidrug resistance gene 1 (MDR1).


Ectopic Growth Hormone-Releasing Hormone (GHRH) Syndrome in a Case with Multiple Endocrine Neoplasia Type 1.


Rearrangement of the c-myc Gene in Two Giant Cell Carcinoma of the Lung.


Increased Expression of the c-myc Gene without Gene Amplification in Human Lung Cancer and Colon Cancer Cell Lines.


Reciprocal Modulation of Growth and Differentiated Functions of Mature Rat Hepatocytes in Primary Culture by Cell-Cell Contact and Cell Membranes.

Proceedings of the National Academy of Sciences of the United States of America


Reciprocal Effects of Epidermal Growth Factor on Key Lipogenic Enzymes in Primary Cultures of Adult Rat Hepatocytes. --- Induction of Glucose-6-Phosphate Dehydrogenase and Suppression of Malic Enzyme and Lipogenesis.


Hormonal Regulation of Translatable mRNA of Glucose-6-Phosphate Dehydrogenase in Primary Cultures of Adult Rat Hepatocytes.

The quantity of translatable mRNA of glucose-6-phosphate dehydrogenase (D-glucose-6-phosphate: NADP+ 1-oxidoreductase, EC 1.1.1.49) in primary cultures of adult rat hepatocytes subjected to different hormonal conditions was determined with a reticulocyte-lysate, cell-free system. The level of glucose-6-phosphate dehydrogenase mRNA was about 5-fold higher in the presence of insulin than in its absence. This increase of glucose-6-phosphate dehydrogenase mRNA reached a maximum 12 h after the addition of insulin. The maximum level of induction of glucose-6-phosphate dehydrogenase mRNA required 10(-8) M insulin. Glucagon and triiodothyronine had no effect on the glucose-6-phosphate dehydrogenase mRNA level. The increase of glucose-6-phosphate dehydrogenase activity correlated with the increase in level of mRNA of this enzyme. This suggests that the changes in glucose-6-phosphate dehydrogenase activity in response to the above hormonal changes are primarily due to changes in the amount of mRNA coding for this enzyme.

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression


Hormonal Regulations of Glucose-6-Phosphate Dehydrogenase and Lipogenesis in Primary Cultures of Rat Hepatocytes.