Genetic basis of endocrine disease. 1. Molecular genetics of insulin resistant diabetes mellitus.
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Acanthosis Nigricans↗
Biomedical subjects
A Cama
Publications and source records attributed to A Cama.
Normal coding sequence of insulin gene in Pima Indians and Nauruans, two groups with highest prevalence of type II diabetes.
The nucleotide sequence of the insulin gene was determined in American Pima Indians and Micronesian Nauruans, two populations in whom the prevalence of non-insulin-dependent (type II) diabetes mellitus is the highest in the world. The insulin gene was amplified by the polymerase chain reaction to generate single-stranded DNA suitable for direct sequencing. The nucleotide sequences of the coding and adjacent regions of the insulin gene in six Pima Indians and two Nauruans with type II diabetes were identical to previously published insulin gene sequences of nondiabetic subjects.
Adult↗
[Cerebral arteriovenous malformations (CAVM)].
Two infants with endocranic A-V malformations and irreversible picture of congestive cardiac failure are presented: the first is a newborn with a very large angioma, the second is a newborn with a large aneurysm of the vein of Galen. A review of the literature is presented: the salient age-related features required to make a diagnosis are discussed.
Cerebral Arteries↗
Rare primary cranial vault and base of the skull tumors in children. Report of 30 cases with a short literature review.
Twenty-six cases of rare primary cranial vault tumors are reported, together with 4 cases of primary tumors of the base of the skull and 3 cases of monostotic cranial neuroblastoma. Whereas some rare primary cranial vault tumors may present with characteristic radiographic patterns (e.g. hemangioma, aneurysmal bone cyst, osteoma, progonoma), most of them can be recognised only after histology. The most frequent tumor in the region of previous irradiation is osteosarcoma. The only "common" primary bone tumor of the base of the skull is chordoma. The radiological differential diagnosis of primary tumors of the skull vault and base is discussed.
Adolescent↗
Mutagenesis of lysine 460 in the human insulin receptor. Effects upon receptor recycling and cooperative interactions among binding sites.
Mutations in the insulin receptor gene can cause insulin resistance. Previously, we have identified a mutation substituting glutamic acid for lysine at position 460 in the alpha-subunit of the insulin receptor in a patient with a genetic form of insulin resistance. In the present work, we have investigated the effect upon receptor function of amino acid substitutions at position 460. Decreasing the pH from 8.0 to 5.5 caused a progressive acceleration of the dissociation of 125I-insulin from the wild-type insulin receptor. Substitution of acidic amino acids (Glu or Asp) for Lys460 decreased the ability of acid pH to accelerate dissociation of 125I-insulin. In contrast, substitution of Arg or neutral amino acids (Val, Met, Thr, or Gln) had no effect upon the sensitivity to acid pH. Correlated with decreased sensitivity to acid pH, substitution of Glu or Asp at position 460 retarded the dissociation of 125I-insulin from intracellular receptors subsequent to receptor-mediated endocytosis. Furthermore, retardation of dissociation of 125I-insulin from the internalized receptor was associated with a decreased half-life of the receptor. In summary, the Glu460 mutation appears to cause insulin resistance by accelerating receptor degradation and, thereby, decreasing the number of insulin receptors on the cell surface. Additional studies suggested that Lys460 may provide the amino groups whereby disuccinimidyl suberate cross-links the two alpha-subunits to each other. Consistent with the hypothesis that Lys460 is located at the interface between adjacent alpha-subunits, substitutions at position 460 impair cooperative interactions among insulin binding sites. The Glu460 mutation decreases positively cooperative binding interactions; the Arg460 mutation impairs negative cooperativity. Mutations at position 460 in the alpha-subunit did not decrease the ability of insulin to stimulate receptor tyrosine kinase.
Amino Acid Sequence↗
Occult spinal dysraphism: neuroradiological study.
We present a retrospective study of occult spinal dysraphism in 47 children aged 0 to 14 years, all studied with plain X-rays, 60% with CT and myelo-CT, and 40% with MR. We consider the classification and grading of these malformations, clinical, neuroradiological patterns, and indications for surgery. In the light of our findings and of the published data MR emerges as the key investigation. Only in a few cases of great anatomical complexity is it now necessary to perform CT and myelo-CT as well. A case in point is when the conus and thickened filum terminale are inextricably bound together and can no longer be considered separate structures. We propose the term "neurofibrous structure" to define the conus-thickened-filum-terminale unit when these structure are no longer distinguishable.
Adolescent↗
Percutaneous interbody osteosynthesis in the treatment of thoracolumbar traumatic or tumoural lesions. A review of 51 cases.
The authors describe a technique of percutaneous interbody osteosynthesis applicable to the dorsal and lumbar spine. 51 patients were so treated for different aetiologies: traumatic conditions (35 cases) and tumoural lesions (16 cases). The material used consisted of special instruments that are positioned in double obliquity by a percutaneous posterolateral approach. A posterior approach limited to the pathological focus was used jointly whenever a graft or a decompression was necessary (19 cases). Several types of anaesthesia were used (local, local-regional, general, neuroleptanalgesia). The patients benefited by the advantages that usually accompany percutaneous techniques. The advantages and limitations of the method are discussed.
Adolescent↗
Mutations in the insulin receptor gene in genetic forms of insulin resistance.
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Diabetes Mellitus, Type 2↗
The amino acid sequence of the insulin receptor is normal in an insulin-resistant Pima Indian.
Insulin resistance is an early predictor of development of noninsulin-dependent diabetes mellitus (NIDDM) in Pima Indians, a population with the highest reported prevalence of NIDDM. The insulin receptor plays a central role in mediating insulin action, and previous studies have demonstrated that mutations in the insulin receptor gene may cause insulin resistance. Therefore, we have cloned the insulin receptor cDNA from an insulin-resistant Pima Indian to determine if there is a mutation in the patient's insulin receptor gene. We obtained nine cDNA clones spanning exons 4-10 and 12-22 of the patient's insulin receptor gene. Polymorphisms in the nucleotide sequences for codons 523 (Ala), 1058 (His), and 1062 (Leu) provided useful markers to differentiate the patient's two alleles of the insulin receptor gene. These substitutions were silent, in that they did not alter the predicted amino acid sequence. The sequence of exons 1-3 and 11 was determined directly from genomic DNA that had been amplified using the polymerase chain reaction catalyzed by Taq DNA polymerase. Other investigators have reported defects in insulin binding and insulin receptor tyrosine kinase activity in diabetic Pima Indians. However, we did not detect any mutations in this patient's insulin receptor gene. Thus, these observations are consistent with the interpretation that the defects in insulin receptor function are acquired rather than derived from defects in the primary structure of the receptor.
Adult↗
Two unrelated patients with familial hyperproinsulinemia due to a mutation substituting histidine for arginine at position 65 in the proinsulin molecule: identification of the mutation by direct sequencing of genomic deoxyribonucleic acid amplified by polymerase chain reaction.
Mutations in the insulin gene can impair the bioactivity of the insulin molecule. Previously, two classes of mutations have been identified: 1) those that impair posttranslational processing of proinsulin to insulin, and 2) those that alter the structure of the insulin molecule, thereby reducing the affinity of the molecule for the insulin receptor. We have investigated two apparently unrelated patients, both of which have mutations that inhibit the conversion of proinsulin to insulin. By directly sequencing genomic DNA amplified by polymerase chain reaction, we have demonstrated that both patients are heterozygous for the same point mutation converting codon 65 from an arginine (CGT) to a histidine (CAT) codon. Because Arg65 is one of the two dibasic amino acids at the site of proteolytic cleavage between the insulin A-chain and C-peptide, this mutation explains the impairment in the cleavage of proinsulin to insulin. Interestingly, the same His65 mutation has been identified in the insulin gene of a Japanese kindred with familial hyperproinsulinemia. Thus, this mutation has occurred in three apparently unrelated kindreds from two different racial groups. This observation is consistent with the hypothesis that the dinucleotide sequence CpG, the first two nucleotides in the arginine (CGT) codon, is a "hot spot" for mutations.
Alleles↗
Mutations in insulin-receptor gene in insulin-resistant patients.
Defects in insulin-receptor function have been associated with insulin-resistant states such as obesity and non-insulin-dependent diabetes mellitus (NIDDM). Several types of mutations in the insulin-receptor gene have been identified in patients with genetic syndromes of extreme insulin resistance. In some patients, insulin resistance results from a decrease in the number of insulin receptors on the cell surface. In one patient with leprechaunism (leprechaun/Minn-1), there is greater than 90% decrease in the levels of insulin-receptor mRNA. This patient is a compound heterozygote for two mutations in the insulin-receptor gene, both of which act in a cis-dominant fashion to decrease levels of mRNA transcribed from that allele. In one allele, there is a nonsense mutation at codon 897. All 22 exons of the other allele have a normal sequence, so that the mutation in this allele appears to map outside the coding sequence of the gene. Impaired insertion in the plasma membrane also causes insulin resistance. In two sisters (patients A-5 and A-8) with type A extreme insulin resistance, there is an 80-90% decrease in the number of insulin receptors expressed on the surface of their cells. Both sisters, whose parents are first cousins, are homozygous for a point mutation in which valine is substituted for phenylalanine at position 382 in the alpha-subunit of the insulin receptor. This mutation retards the posttranslational processing of the receptor and impairs the transport of receptors to the cell surface. Another patient with leprechaunism (leprechaun/Ark-1) is a compound heterozygote with two different mutant alleles of the insulin-receptor gene. In the allele derived from the father, there is a nonsense mutation at codon 672 that truncates the insulin receptor by deleting the COOH-terminal of the alpha-subunit and the entire beta-subunit. This truncated receptor, lacking a transmembrane domain, appears not to be expressed at the plasma membrane. In leprechaun/Ark-1, there is a missense mutation in the allele of the insulin-receptor gene derived from the mother. This point mutation results in substitution of glutamic acid for lysine at position 460 in the COOH-terminal half of the alpha-subunit. This mutation increases receptor affinity and impairs the ability of acid pH to dissociate insulin from the receptor within the endosome. There is a defect in recycling the receptor back to the plasma membrane associated with this defect. This results in an accelerated rate of receptor degradation and a consequent decrease in the number of receptors on the cell surface in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)
Base Sequence↗
Discectomies of the lower cervical spine using interbody biopolymer (B.O.P.) implants. Advantages in the treatment of complicated cervical arthrosis. A review of 150 cases.
The authors report their experience with 150 cases of discectomies performed with interbody grafts using a copolymer (Biocompatible Orthopedic Polymer or BOP). Made of N-Vinylpyrrolidone-Methylmethacrylate monomers, polyamide fibres and calcium gluconate. BOP is a biocompatible, biodegradable, osteoconductive matrix, easy to use and quite safe. These properties are quite well appreciated for cervical interbody grafting. After discectomy, stabilization of the spine is immediate, and fusion slowly occurs around and through the biopolymer within one year. The biomaterial avoids morbidity inherent in the harvesting of an autograft, as well as any limitations resulting from the use of allografts.
Adult↗
[The use of 3-dimensional CT reconstruction in childhood. Technics and dosimetry].
A new computer method has been developed that allows the reprocessing of standard CT scans to produce 3D surface images. We employed the 3D reconstruction program developed by Hitachi Medical System using an Ansaldo A-TOM XR 1200 scanner. The process requires only standard CT scanner hardware, and reconstruction time is comparable to that of sagittal and coronal reconstructions. The applications of this technique and methodology to pediatric patients are discussed. In order to assess the relationship between image quality and radiation dose, we performed many CT scans with different protocols. A skull was employed for phantom, and plunged into a physiological solution, which helped us to determine the radiation exposure dose from every single CT scan. The measurements were taken with film and thermoluminescent crystal dosimeters (TLD). The results confirm that low-dose techniques allow a significant reduction in the total exposure. The authors discuss the clinical indications and the eventual applications of these techniques.
Child↗
[Diagnosis and treatment of craniosynostoses: the usefulness of CT combined with 3-dimensional reconstruction].
Craniosynostoses are craniocerebral and craniofacial dysmorphic states, characterized by early closure of one or more cranial sutures. In this pathology the perpendicular growth of the bone to the involved suture is disturbed (Virchow's theory). Craniosynostoses can be divided into: 1) single-suture synostoses (scaphocephaly, plagiocephaly, trigonocephaly), 2) multiple-suture synostoses (brachycephaly, oxycephaly) and 3) craniofacial dysostoses. From 1976 to 1987, 63 children with craniosynostosis were studied in our Institute. All patients underwent radiologic and neuroradiologic research with CT scans both before and after surgery; in the past year three-dimensional reconstructions of CT images were also employed. Major advantages of 3-DCT have been obtained in craniofacial malformations. In fact, this technique helps reduce surgical risks and allows the surgeon to evaluate partial results and to make eventual corrections in the last phase. The processing of images is useful to simulate the operation, thus allowing the surgeon to take the best therapeutic choice by computer. This technique is especially useful for postoperative follow-up. In craniosynostoses, early surgical treatment (within the first 6-8 months of life) is necessary in order to obtain excellent functional and cosmetic results.
Cranial Sutures↗
Two mutant alleles of the insulin receptor gene in a patient with extreme insulin resistance.
Insulin receptor complementary DNA has been cloned from an insulin-resistant patient with leprechaunism whose receptors exhibited multiple abnormalities in insulin binding. The patient is a compound heterozygote, having inherited two different mutant alleles of the insulin receptor gene. One allele contains a missense mutation encoding the substitution of glutamic acid for lysine at position 460 in the alpha subunit of the receptor. The second allele has a nonsense mutation causing premature chain termination after amino acid 671 in the alpha subunit, thereby deleting both the transmembrane and tyrosine kinase domains of the receptor. Interestingly, the father is heterozygous for this nonsense mutation and exhibits a moderate degree of insulin resistance. This raises the possibility that mutations in the insulin receptor gene may account for the insulin resistance in some patients with non-insulin-dependent diabetes mellitus.
Alleles↗
Anti-endothelial cell antibodies: detection and characterization in sera from patients with autoimmune hypoparathyroidism.
In a previous report, we described antibodies in autoimmune hypoparathyroidism (AHP) that are cytotoxic for cultured bovine parathyroid cells. In the present study, we show that sera from six AHP patients, but not from 26 patients with other autoimmune diseases or from 7 healthy subjects, react with bovine endothelial cells in culture (by flow cytometry and fluorescence microscopy) and in tissue sections (by immunohistology). We found uniformly that the immunoglobulin class reacting is IgM. Adsorption experiments showed that the antigenic determinants reacting with AHP sera were similar on bovine cultured endothelial cell membranes and in tissue sections of bovine parathyroid glands. The AHP sera also reacted with endothelial cells cultured from bovine adrenal medulla and pulmonary artery. Immunoblot analysis showed antibody binding to two major bands of 200 and 130 kDa solubilized from the membrane fraction of bovine parathyroid endothelial cells. Only one AHP serum consistently recognized endothelium-related structures on frozen sections of three different human parathyroid adenomas; two other sera reacted with one adenoma each; and three did not react with human adenomas. This indicates that human material is less suitable than bovine in detecting endothelium-related immune phenomena in AHP sera. The anti-endothelium IgM antibodies appear to be disease-specific but are not organ- or species-specific. The identification of endothelial cells as the target for antibodies in AHP raises the possibility that the endothelium subserves an important local function for endocrine epithelium.
Animals↗
Immunological abnormalities in insulin receptors on cultured EBV-transformed lymphocytes from insulin-resistant patient with leprechaunism.
Defects in insulin-receptor structure can impair insulin-receptor function. We have previously identified qualitative abnormalities in insulin binding to insulin receptors from an insulin-resistant patient (Lep/Ark-1). The defects in insulin binding are probably caused by a defect in receptor structure. In this study, we used immunological probes to investigate the structural defect(s) responsible for the abnormal function. Several anti-receptor antibodies were impaired in their abilities to bind to the insulin receptor of Lep/Ark-1. For example, monoclonal antibody MoAb-51 was much less effective in inhibiting binding to insulin receptors from Lep/Ark-1 (ID50 70 nM) than to those of normal subjects (ID50 8 nM). In addition, there was a 10-fold reduction of the avidity with which human polyclonal antibody B-d immunoprecipitated the patient's insulin receptors. The avidity of antibody B-10 was also reduced, although to a lesser extent. In contrast, several site-specific antibodies against epitopes on the beta-subunit of the receptor bound to receptors from Lep/Ark-1 with normal avidity. The data with monoclonal and polyclonal antibodies are consistent with the hypothesis that the structural defect resides in the extracellular domain of this patient's insulin receptor. The normal immunoreactivity of two putative phosphorylation sites on the beta-subunit with site-specific antibodies gives further support to the conclusion that this patient's receptors have normal tyrosine kinase activity.
Adolescent↗
Tyrosine kinase activity of insulin receptors from an insulin-resistant patient with leprechaunism.
Defects in insulin receptor function can impair the response of target cells to insulin. Previously we have described an insulin resistant patient (leprechaun/Ark-1) with qualitative abnormalities in insulin binding suggestive of a structural defect in her insulin receptors. In the present work, we have studied the tyrosine kinase activity associated with insulin receptors from cultured Epstein-Barr virus-transformed lymphocytes. In studies of insulin receptors from leprechaun/Ark-1, we observed that both the magnitude and the dose-dependency of insulin's effect to stimulate the tyrosine kinase activity were normal. This suggests that the defect causing this patient's insulin resistance is independent of the receptor-associated tyrosine kinase. In the course of these studies, we noted that an anti-receptor antiserum (B-d) had a markedly decreased ability to immunoprecipitate insulin receptors from leprechaun/Ark-1. This observation further supports our previous conclusion that the insulin receptor from leprechaun/Ark-1 is abnormal in structure. Moreover, it emphasizes the importance of choosing anti-receptor antisera which are equally effective at immunoprecipitating receptors from both patients and normal subjects when the anti-receptor antisera are employed as reagents in investigations of receptors from insulin-resistant patients.
Cell Line↗