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Biomedical subjects

B Glaser

Publications and source records attributed to B Glaser.

At least 19 recordsLinked to original sources
PubMed2000

Genetics of neonatal hyperinsulinism.

Congenital hyperinsulinism (HI) is a clinically and genetically heterogeneous entity. The clinical heterogeneity is manifested by severity ranging from extremely severe, life threatening disease to very mild clinical symptoms, which may even be difficult to identify. Furthermore, clinical responsiveness to medical and surgical management is extremely variable. Recent discoveries have begun to clarify the molecular aetiology of this disease and thus the mechanisms responsible for this clinical heterogeneity are becoming more clear. Mutations in 4 different genes have been identified in patients with this clinical syndrome. Most cases are caused by mutations in either of the 2 subunits of the beta cell ATP sensitive K(+) channel (K(ATP)), whereas others are caused by mutations in the beta cell enzymes glucokinase and glutamate dehydrogenase. However, for as many as 50% of the cases, no genetic aetiology has yet been determined. The study of the genetics of this disease has provided important new information about beta cell physiology. Although the clinical ramifications of these findings are still limited, in some situations genetic studies might greatly aid in patient management.

B-Lymphocytes↗
PubMed1999

Intragenic single nucleotide polymorphism haplotype analysis of SUR1 mutations in familial hyperinsulinism.

Familial hyperinsulinism (HI; MIM# 256450) is an autosomal recessive disorder of pancreatic beta-cell function, characterized by inadequate suppression of insulin secretion despite severe recurrent fasting hypoglycemia. Subtotal pancreatectomy is frequently required to prevent permanent neurologic sequelae. The incidence of HI in the Caucasian population is estimated at 1:50,000, however an apparent increased incidence among Ashkenazi Jews and Saudi Arabian Arabs has been reported. A locus for HI was assigned by linkage analyses to human chromosome 11p15.1. The sulfonylurea receptor (MIM# 600509, SUR1) and the potassium channel, inwardly rectifying, subfamily J member 11 (MIM# 600937, KIR6.2) genes, 2 components of the beta-cell K(ATP) channel, are clustered in this chromosomal region, and mutations in these genes have been implicated in HI. We previously demonstrated that two mutations in the SUR1 gene are present on approximately 88% of HI-associated chromosomes in Ashkenazi Jewish patients. Haplotype analysis with microsatellite markers flanking the gene revealed that one mutation (delF1388), reported only in Ashkenazi probands, occurred on two related extended haplotypes. By contrast, the second, more common mutation (3992-9g-->a) was associated with nine different intergenic haplotypes and has been reported in non-Jewish HI patients as well. In this study, we evaluated disease-associated chromosomes from 41 Ashkenazi Jewish and 2 non-Jewish HI patients carrying the 3992-9g-->a mutation by assessing haplotypes defined by nine common single nucleotide polymorphisms (SNPs), six in the SUR1 gene, and three in the KIR6.2 gene. Our results indicate that all 54 chromosomes carrying the 3992-9g-->a mutation in the Jewish patients appear to have originated from one founder mutation, whereas the same mutation on chromosomes from non-Jewish patients originated independently. Furthermore, our findings have implications concerning the HI-associated chromosomes on which no mutation has been identified.

ATP-Binding Cassette Transporters↗
PubMed1999

Neonatal Hyperinsulinism.

Hypoglycemia as a result of hyperinsulinism in the newborn (HI) is a clinically heterogeneous entity that presents a diagnostic and therapeutic challenge to the treating physician. Recent discoveries have shown that mutations in four different beta-cell genes cause HI. However, for many HI patients, the molecular etiology is unknown, and other genes might be involved. The study of the molecular biology of HI has led to a better understanding of pancreatic beta-cell physiology. In the future, this might result in the development of novel drugs for the treatment of both hyperinsulinism and non-insulin-dependent diabetes.

Journal Article↗
PubMed1999

Somatostatin receptor scintigraphy for early detection of regional and distant metastases of medullary carcinoma of the thyroid.

Three patients are described who had regional and distant metastases of medullary thyroid cancer detected by somatostatin receptor scintigraphy but not by CT; two had minimal disease that was amenable to surgery. The first patient had been followed for 2 years before having a repeated scan and positive CT, with subsequent surgical removal of metastatic paratracheal nodes. The plasma calcitonin level, however, did not approach normal values after surgery, and a third scan showed persistence of focal uptake in the left paratracheal area of the lower neck, whereas CT was negative. At repeated exploration, a tumor mass of medullary carcinoma, embedded in lymphatic tissue, was removed. Nine months after the last surgical procedure, calcitonin and carcinoembryonic antigen levels were normal. The second patient underwent microdissection of the mediastinum and removal of two metastatic nodes that were demonstrable only by the scintigraphic technique. The plasma calcitonin level subsequently became normal. The third patient, with multiple endocrine neoplasia IIB and associated pheochromocytoma, had bony metastatic involvement of the left shoulder, demonstrable initially on somatostatin receptor scintigraphy and subsequently with radioiodinated metaiodobenzylguanidine but not on CT.

3-Iodobenzylguanidine↗
PubMed1999

Sulfate transport is not impaired in pendred syndrome thyrocytes.

Pendred syndrome is the most common form of syndromic deafness, characterized by dyshormonogenic goiter associated with sensory-neural deafness. The gene responsible for the disease (PDS) has been cloned, but its function is as yet unknown and the connection between thyroid goiter and sensory-neural deafness remains an enigma. PDS codes for a novel protein, pendrin, which is closely related to a number of sufate transporters. Mechanisms by which abnormal sulfate transport could deleteriously affect iodide organification have been proposed. We tested sulfate transport in thyrocytes obtained from Pendred syndrome patients and found that it was not defective. This suggests that pendrin in fact may not be a sulfate transporter, and emphasizes the importance of functional studies on this novel protein.

Biological Transport↗
PubMed1999

Hyperinsulinism caused by paternal-specific inheritance of a recessive mutation in the sulfonylurea-receptor gene.

Neonatal hyperinsulinism (HI) is a genetic disorder of pancreatic beta-cells characterized by failure to suppress insulin secretion in the presence of hypoglycemia, resulting in brain damage or death if not adequately treated. Germline mutations in four genes have been associated with HI. Some patients have focal regions of beta-cell proliferation (focal HI). Seventy HI probands in whom at least one SUR-1 mutation was identified were studied. Clinical data from patients with two SUR-1 mutant alleles were compared with those from patients with single paternally inherited mutations. Thirty-seven probands were homozygous or compound heterozygous for SUR-1 mutations. In 33 probands, only a single mutation was identified, and in 31, the parental origin of the proband could be determined; in 29, the mutation was on the paternal allele (P < 0.0002). For three of these, pancreatic tissue was available and showed focal beta-cell hyperplasia. DNA extracted from the focal lesion and adjacent normal pancreas revealed loss of the maternal chromosome 11p15, resulting in reduction to homozygosity for the SUR-1 mutation within the focal lesion only. Using the Tdt-mediated dUTP nick end labeling (TUNEL) reaction, apoptotic beta-cells were identified exclusively within the focal region. At diagnosis, disease severity was similar in patients with paternally inherited mutations and those with two mutations. For patients who did not undergo surgery, those with only paternal mutations entered clinical remission within 16 +/- 6.2 months, compared with 48 +/- 23 months for those with two SUR-1 mutations (P = 0.001). In conclusion, we identified a novel mechanism to explain the pathophysiology of focal HI and provide evidence to suggest that this entity may be self-limiting, since affected beta-cells undergo apoptosis.

ATP-Binding Cassette Transporters↗
PubMed1998

Mapping of the human insulin receptor substrate-2 gene, identification of a linked polymorphic marker and linkage analysis in families with Type II diabetes: no evidence for a major susceptibility role.

Insulin receptor substrate 2 (IRS-2) is a substrate of the insulin receptor and mediates the action of the insulin. Disruption of the IRS-2 gene in mice results in peripheral insulin resistance and relative insulin deficiency. It is therefore possible that defects in the IRS-2 gene contribute to Type II (non-insulin-dependent) diabetes mellitus. We have examined the gene for evidence of linkage to Type II diabetes in Ashkenazi Jewish families. Radiation hybrid panel mapping was used to refine the map position of the IRS-2 gene and, in the absence of polymorphic markers within the gene, to identify nearby markers. The IRS-2 gene was placed 23cR from the marker D13S1265 on chromosome 13q34. 200 affected sib-pairs were genotyped for three markers across the region. Nonparametric linkage analysis (GENEHUNTER) used with this data found no evidence of excess allele sharing in the IRS-2 gene region. We therefore concluded that variation in the IRS-2 gene is unlikely to contribute to Type II diabetes in this discrete Caucasian population.

Animals↗
PubMed1998

Familial hyperinsulinism with apparent autosomal dominant inheritance: clinical and genetic differences from the autosomal recessive variant.

We describe three families with hypoglycemia caused by familial hyperinsulinism (HI) in whom vertical transmission of the disorder occurred, suggesting autosomal dominant (AD) inheritance. We therefore examined the relationship between the apparent AD disorder and the more common autosomal recessive (AR) form of HI, which has recently been linked to the sulfonylurea receptor on chromosome 11p15.1. The clinical features of the 11 patients with AD HI were milder than those seen in 14 patients with AR HI. Hypoglycemia was readily controlled with either diet alone or with diazoxide in 10 of 11 patients with AD HI but in none of those with the AR form. In one large pedigree, analysis of genomic DNA with polymorphic simple sequence repeat markers excluded linkage of AD HI to the SUR locus in a dominant manner. The possibility of linkage to the SUR locus could not be absolutely excluded in the two smaller pedigrees. None of the published mutations of the SUR gene identified in patients with AR HI were detected in the patients with the AD form. We conclude that the AD form of hyperinsulinism is phenotypically different from the AR variant. The identification of more families with this form of HI may make it possible to locate the responsible gene by the use of linkage analysis.

Adolescent↗
PubMed1998

Genetic heterogeneity in familial hyperinsulinism.

Familial hyperinsulinism (HI) is a disorder characterized by dysregulation of insulin secretion and profound hypoglycemia. Mutations in both the Kir6.2 and sulfonylurea receptor (SUR1) genes have been associated with the autosomal recessive form of this disorder. In this study, the spectrum and frequency of SUR1 mutations in HI and their significance to clinical manifestations of the disease were investigated by screening 45 HI probands of various ethnic origins for mutations in the SUR1 gene. Single-strand conformation polymorphism (SSCP) and nucleotide sequence analyses of genomic DNA revealed a total of 17 novel and three previously described mutations in SUR1 . The novel mutations comprised one nonsense and 10 missense mutations, two deletions, three mutations in consensus splice-site sequences and an in-frame insertion of six nucleotides. One mutation occurred in the first nucleotide binding domain (NBF-1) of the SUR1 molecule and another eight mutations were located in the second nucleotide binding domain (NBF-2), including two at highly conserved amino acid residues within the Walker A sequence motif. The majority of the remaining mutations was distributed throughout the three putative transmembrane domains of the SUR1 protein. With the exception of the 3993-9G-->A mutation, which was detected on 4.5% (4/88) disease chromosomes, allelic frequencies for the identified mutations varied between 1.1 and 2.3% for HI chromosomes, indicating that each mutation was rare within the patient cohort. The clinical manifestations of HI in those patients homozygous for mutations in the SUR1 gene are described. In contrast with the allelic homogeneity of HI previously described in Ashkenazi Jewish patients, these findings suggest that a large degree of allelic heterogeneity at the SUR1 locus exists in non-Ashkenazi HI patients. These data have important implications for genetic counseling and prenatal diagnosis of HI, and also provide a basis to further elucidate the molecular mechanisms underlying the pathophysiology of this disease.

ATP-Binding Cassette Transporters↗
PubMed1998

Somatostatin-receptor scintigraphy in the management of gastroenteropancreatic tumors.

OBJECTIVE: This study evaluates the diagnostic and therapeutic implications of somatostatin-receptor scintigraphy in the management of patients with proven or high clinical suspicion of gastroenteropancreatic endocrine tumors. METHODS: Forty-one patients were studied by planar and tomographic imaging at 4 h and 24 h after 111In-pentetreotide injection. Scintigraphic findings were compared with computed tomography, and in several patients also with ultrasound, angiography, biopsy, and/or surgery, when performed. RESULTS: Among 23 patients with carcinoid tumor, three of nine primary tumors were initially identified by scintigraphy. Unsuspected mesenteric metastases found on scintigraphy in three patients led to octreotide treatment. Scintigraphic detection of multiple metastases in a patient with thyroid metastasis of bronchial carcinoid spared her an unnecessary total thyroidectomy. Among 18 patients with 19 islet-cell tumors, scintigraphy detected three of five insulinomas, whereas computed tomography identified only one. Receptor positivity in an islet-cell tumor (vipoma?) with no metastases on the scan led to surgical removal of the primary tumor. Receptor-positive metastases of gastrinoma (two of three patients), glucagonoma (two of three patients), and parathyroid hormone-related peptide-producing tumor (one patient) led to octreotide treatment. Nonvisualization of metastases of a glucovipoma led to chemotherapy. CONCLUSIONS: Somatostatin-receptor scintigraphy contributes to the management of patients with gastroenteropancreatic tumors in the following ways: 1) localization of a primary occult tumor, allowing surgical removal; 2) staging of the disease for optimal therapy-surgical excision or systemic treatment; and 3) identification of receptor status of the metastases for octreotide treatment or chemotherapy.

Adenoma, Islet Cell↗
PubMed1998

Monilethrix: a keratin hHb6 mutation is co-dominant with variable expression.

Monilethrix is a rare autosomal dominant disease characterized by hair fragility and hyperkeratotic papules. Mutations in type-II hair specific keratins hHb6 and hHb1 have recently been reported. We describe a large family with a E410D mutation in the evolutionary conserved helix termination motif of keratin hHb6 that was variably expressed among 12 heterozygous members, and severely expressed among 3 homozygous members. These 3 patients had essentially complete lack of scalp hair since the age of 2 months with no improvement over time as well as follicular keratotic involvement extensively expressed over the scalp and large body areas. The variability seen in heterozygous patients, along with seasonal and pregnancy-related improvement suggest that other genetic or environmental factors may modify keratin gene expression. This represents the first report of a co-dominant keratin hHb6 mutation resulting in severe disease.

Base Sequence↗
PubMed1998

Hyperinsulinism: molecular aetiology of focal disease.

Persistent hypoglycaemia in infancy is most commonly caused by hyperinsulinism. A case is reported of the somatic loss of the maternal 11p in an insulin secreting focal adenoma in association with a germline SUR-1 mutation on the paternal allele in a baby boy with hyperinsulinism diagnosed at 49 days old. A reduction to homozygosity of an SUR-1 mutation is proposed as a critical part of the cause of focal hyperinsulinism.

ATP-Binding Cassette Transporters↗
PubMed1998

Pancreatic beta-cell glucokinase: closing the gap between theoretical concepts and experimental realities.

There remains a wide gap between theoretical concepts and experimental realities in the enzyme kinetics and biochemical genetics of the pancreatic beta-cell glucokinase-glucose sensor. It is the goal of present efforts in many laboratories to bridge this gap. This perspective intends to provide a timely review of this crucial aspect of research in glucose homeostasis. It deals briefly with some fundamentals of glucokinase enzyme kinetics, offers some pertinent biochemical genetic considerations, takes stock of the current experimental database of the field by emphasizing human studies and referring to recent mouse studies, and ventures a few extrapolations into the future of this endeavor.

Animals↗
PubMed1998

Functional analyses of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy.

The ATP-sensitive potassium channel, K(ATP) channel, a functional complex of the sulfonylurea receptor 1, SUR1, and an inward rectifier potassium channel subunit, Kir6.2, regulates insulin secretion in the pancreas. Mutations in both the Kir6.2 and SUR1 genes are associated with persistent hyperinsulinemic hypoglycemia of infancy (PHHI), a disorder of pancreatic beta-cell function characterized by excess insulin secretion and hypoglycemia. We have studied the functional properties of novel SUR1 mutations identified in PHHI patients, including H125Q, N188S, F591L, T1139M, R1215Q, G1382S, and R1394H. R1394H and deltaF1388 SUR1, a previously identified PHHI mutation, resulted in no functional channels when coexpressed with Kir6.2 in COS cells, while H125Q, N188S, F591L, T1139M, R1215Q, and G1382S SUR1 generated functional channels in the absence of ATP. With the exception of N188S and H125Q, all mutants had reduced response to stimulation by MgADP. These results indicate that lack of, or reduction of, K(ATP) channel sensitivity to MgADP is a common molecular defect associated with the disease. The mutant channels also showed varied response to activation by the potassium channel opener diazoxide. Because these mutations are distributed throughout the molecule, our data have new implications for structure-function relationships of the K(ATP) channel, suggesting that structural elements in SUR1 outside of the two nucleotide-binding folds are also important in regulating channel activity.

ATP-Binding Cassette Transporters↗