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Biomedical subjects

B T Teh

Publications and source records attributed to B T Teh.

At least 91 records · Page 5Linked to original sources
PubMed1997

Differential loss of heterozygosity in familial, sporadic, and uremic hyperparathyroidism.

Various genetic loci harboring oncogenes, tumor suppressor genes, and genes for calcium receptors have been implicated in the development of parathyroid tumors. We have carried out loss of heterozygosity (LOH) studies in chromosomes 1p, 1q, 3q, 6q, 11q, 13q, 15q, and X in a total of 89 benign parathyroid tumors. Of these, 28 were sporadic parathyroid adenomas from patients with no family history of the disease, 41 were secondary parathyroid tumors, 5 were from patients with a history of previous irradiation to the neck, 12 were from patients with a family history of hyperparathyroidism, and 3 were parathyroid tumors related to multiple endocrine neoplasia type 1 (MEN1). In addition, we determined the chromosomal localization of a second putative calcium-sensing receptor, CaS, for inclusion in the LOH studies. Based on analysis of somatic cell hybrids and fluorescent in situ hybridization to metaphase chromsomes, the gene for CaS was mapped to chromosomal region 2q21-q22. The following results were obtained from the LOH studies: (1) out of the 24 tumors that showed LOH, only 4 had more than one chromosomal region involved, (2) in the tumors from uremic patients, LOH of chromosome 3q was detected in a subset of the tumors, (3) LOH of the MEN1 region at 11q13 was the most common abnormality found in both MEN1-related and sporadic parathyroid tumours but was not a feature of the other forms of parathyroid tumors, (4) LOH in 1p and 6q was not as frequent as previously reported, and (5) tumor suppressor genes in 1q and X might have played a role, particularly on the X chromosome, in the case of familial parathyroid adenomas. We therefore conclude that the tumorigenesis of familial, sporadic, and uremic hyperparathyroidism involves different genetic triggers in a non-progressive pattern.

Adenoma↗
PubMed1997

Fine mapping of the MLK-3 gene within 11q13 and its exclusion as the MEN1 susceptibility gene.

MLK-3 kinase is a widely expressed serine/ threonine kinase that bears multiple protein interaction domains and regulates signals mediated by the stress-responsive pathway. Thus, MLK-3 signaling affects numerous cellular processes, raising the possibility that MLK-3 might play a role in oncogenesis. In this report, we describe the fine mapping of the MLK-3 gene within the 11q13.1 chromosomal region. By integrating data from somatic cell hybrids and double color fluorescence in situ hybridization on metaphase chromosomes and DNA fibers. MLK-3 has been assigned approximately 1 Mb telomeric of PYGM, close to the D11S546 locus. Since the MEN1 susceptibility locus is also located within the 11q13.1 region, we have carried out Southern and Northern blot analyses, as well as protein truncation assays to establish whether abnormalities in MLK-3 lead to the development of this familial cancer syndrome. Our observations exclude MLK-3 as the MEN1 gene.

Animals↗
PubMed1997

Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by tumours of the parathyroids, pancreas and anterior pituitary that represents one of the familial cancer syndromes. The MEN1 locus has been previously localised to chromosome 11q13, and a <300 kb gene-rich region flanked centromerically by PYGM and telomerically by D11S1783 defined by combined meiotic and tumour deletion mapping studies. Two candidate genes, ZFM1 and PPP2R5B, from this region have been previously excluded, and in order to identify additional candidate genes we used a BAC to isolate cDNAs from a bovine parathyroid cDNA library by direct selection. One of the novel genes that we identified, SCG2, proved to be identical to the recently published MEN1 gene, which is likely to be a tumour suppressor gene. The SCG2 transcript was 2.9 kb in all tissues with an additional 4.2 kb transcript also being present in the pancreas and thymus. Mutational analysis of SCG2 in 10 unrelated MEN1 families identified one polymorphism and nine different heterozygous mutations (one missense, four non-sense, one insertional and three deletional frameshifts) that segregated with the disease, hence providing an independent confirmation for the identification of the MEN1 gene.

Animals↗
PubMed1997

Clinicopathologic studies of thymic carcinoids in multiple endocrine neoplasia type 1.

Thymic carcinoid is part of the multiple endocrine neoplasia type 1 (MEN1) syndrome occurring predominantly in male patients who were heavy smokers, presenting most commonly in middle age. In contrast with metastatic midgut carcinoids, MEN1-related thymic carcinoid is not associated with carcinoid syndrome, nor is it associated with Cushing syndrome, in contrast with sporadic thymic carcinoids. Local invasion and metastasis are common. Prognosis is poor because of late detection, lack of effective treatment, and the aggressive nature of the tumor. All patients with thymic carcinoids should be investigated for MEN1, including thorough clinical evaluation and family studies. Anterior mediastinal lesions in MEN1 male patients should be considered thymic carcinoids until proven otherwise. All male MEN1 patients and asymptomatic gene carriers should be warned of the risk of thymic carcinoids and the possible link to smoking. Computed tomography (CT) of the chest is recommended on first screening for MEN1 in male patients more than 25 years of age, followed by yearly chest X-rays and chest CT every 3 years. Prophylactic thymectomy should be carried out during subtotal or total parathyroidectomy on MEN1 patients.

Adult↗
PubMed1997

Oculopharyngeal muscular dystrophy (OPMD)--report and genetic studies of an Australian kindred.

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant disease. Due to a founder effect, it is most commonly found in the French Canadian population. The gene has recently been mapped to chromosome 14q11.2-q13 in some of these families. Here we report an Australian kindred of German descent with OPMD. Linkage analysis supports its locus to chromosome 14q. Repeat expansion studies were also carried out, but a CAG trinucleotide repeat expansion detected did not cosegregate with the disease. We conclude that there is no evidence of genetic heterogeneity or involvement of repeat expansion in OPMD.

Australia↗
PubMed1997

Multiple endocrine neoplasia type 1 and the search for the genetic trigger.

Multiple endocrine neoplasia type 1 (MEN-1) is characterized by primary hyperparathyroidism, endocrine pancreatic-duodenal and anterior pituitary tumors. The diagnosis is challenging and involves the exclusion of other endocrine neoplasia syndromes with overlapping features. The predisposing genetic defect was assigned to chromosomal region 11q13 based on linkage analysis. Combined tumor and pedigree genotype analysis showed that allele losses in pancreatic, parathyroid and pituitary tumors eliminated the wild-type allele at the 11q13 loci, suggesting inactivation of a tumor suppressor gene in this region. A 5-Mb integrated map of the region has been established by the European consortium on MEN-1. Based on this mapping the critical interval was restricted to 2 Mb, a region within which eight candidate genes are located.

Chromosome Mapping↗
PubMed1997

A large multiple endocrine neoplasia type 1 family with clinical expression suggestive of anticipation.

We describe a large multigenerational multiple endocrine neoplasia Type 1 (MEN1) family with clinical expression suggestive of anticipation. In the second and third generations, two deceased obligate gene carriers died at the ages of 85 and 76 without the history of MEN1, whereas two other living gene carriers above the age of 65 have had no clinical evidence of MEN1 to date. In the fourth generation, eight members were affected, with four having severe MEN1-related and atypical malignancies: a case of metastatic endocrine pancreatic tumor, two cases of metastatic thymic carcinoids, and a case of spinal ependymoma. In the fifth generation, all five patients were below the age of 22 when the disease was detected. MEN1 was confirmed in the family by linkage analysis using MEN1-linked microsatellite markers and by identification of a nonsense mutation in the MEN1/menin gene. Alleotyping showed loss of heterozygosity (LOH) involving the wild-type alleles in seven tumors in the family including the ependymoma, which is the first MEN1-related case that shows genetic abnormality in chromosome 11q13, suggesting that MEN1 gene might be involved in the tumorigenesis of a subset of ependymomas. In relation to clinical anticipation, repeated expansion studies were carried out but failed to detect any expansion. We conclude that this is a unique MEN1 family and that an unknown genetic mechanism might be contributing to the anticipation phenomenon. We demonstrate in this family that all gene carriers, including the very young members, will need close and careful follow-up.

Adult↗
PubMed1997

A kindred with a variant of multiple endocrine neoplasia type 1 demonstrating frequent expression of pituitary tumors but not linked to the multiple endocrine neoplasia type 1 locus at chromosome region 11q13.

Acromegaly is uncommon in kindreds with multiple endocrine neoplasia type 1 (MEN1), whereas primary hyperparathyroidism (PHP) has the highest penetrance of any endocrinopathy. We report an unusual MEN1 kindred with frequent expression of pituitary tumors and a low penetrance of PHP. Four members were found to have disease: PHP in generation I, acromegaly (2 cases) in generation II, and hyperprolactinemia associated with a pituitary tumor in generation III. There was no evidence for PHP in 1 patient with acromegaly (age 60 yr), the patient with hyperprolactinemia and the pituitary tumor (age 22 yr), and 1 asymptomatic obligate carrier (age 50 yr). Screening of 26 members revealed the possible diagnosis of PHP in 1 family member in generation II and possible early acromegaly in 2 members of generation III with elevated serum concentrations of insulin-like growth factor I and insulin-like growth factor-binding protein-3 but normal patterns of pulsatile GH release. Although the predisposing genetic defect in typical MEN1 families has previously been mapped to chromosome location 11q13 without evidence of heterogeneity among the 87 families analyzed, linkage of disease in this family to the MEN1 region is unlikely based on haplotype analysis. Localization of the gene(s) responsible for disease in such atypical families may aid in the understanding of the pathogenesis of MEN1. In addition, further study of the earliest changes in patterns of pulsatile GH release in familial acromegaly may allow more insight into the pathogenesis and natural history of this disease.

Acromegaly↗
PubMed1996

Definition of the minimal MEN1 candidate area based on a 5-Mb integrated map of proximal 11q13. The European Consortium on Men1, (GENEM 1; Groupe d'Etude des Néoplasies Endocriniennes Multiples de type 1).

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder with a high penetrance characterized by tumors of the parathyroid glands, the endocrine pancreas, and the anterior pituitary. The MEN1 gene, a putative tumor suppressor gene, has been mapped to a 3- to 8-cM region in chromosome 11q13 but it remains elusive as yet. We have combined the efforts and resources from four laboratories to form the European Consortium on MEN1 with the aims of establishing the genetic and the physical maps of 11q13 and of further narrowing the MEN1 region. A 5-Mb integrated map of the region was established by fluorescence in situ hybridization on both metaphase chromosomes and DNA fibers, by hybridization to DNA from somatic cell hybrids containing various parts of human chromosome 11, by long-range restriction mapping, and by characterization of YACs and cosmids. Polymorphic markers were positioned and ordered by physical mapping and genetic linkage in 86 MEN1 families with 452 affected individuals. Two critical recombinants identified in two affected cases placed the MEN1 gene in an approximately 2-Mb region around PYGM, flanked by D11S1883 and D11S449.

Animals↗
PubMed1996

Sporadic primary hyperparathyroidism in the setting of multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant disease characterized by neoplasia involving the parathyroid glands, the endocrine pancreas, the duodenum, and the anterior pituitary. The most commonly involved gland is the parathyroid gland, which has been found to be abnormal in 90% to 95% of all patients with MEN 1. The disease process is invariably multiglandular and histologically described as either hyperplasia or multiple adenoma, although the histological distinction between the 2 entities remains difficult and controversial. The prevalence of MEN 1 is approximately 0.002 in 100, whereas the prevalence of sporadic primary hyperparathyroidism due to a solitary adenoma is estimated to be as high as 1 in 100.(2.3) We report herein the first case of sporadic primary hyperparathyroidism in the setting of MEN 1 based on clinical, biochemical, pathological, and genetic studies.

Adenoma, Oxyphilic↗
PubMed1996

Confirmation of susceptibility locus on chromosome 13 in Australian breast cancer families.

Two major genes determining predisposition to breast cancer, termed BRCA1 and BRCA2, have been mapped to the long arms of chromosomes 17 and 13, respectively. Each locus is believed to account for approximately 40% of cases of familial breast cancer. We used linkage and haplotype analysis with simple tandem repeat polymorphisms at chromosomal bands 17q21 and 13q12 to determine the contribution of the BRCA1 and BRCA2 genes to predisposition to breast cancer in four Australian breast cancer kindreds, one of which had two male cousins with breast cancer. Surprisingly all families segregated a haplotype of markers on 13q and showed positive lod scores supporting linkage to BRCA2. In addition, haplotype analysis identified an informative recombination between D13S260 and D13S171 in one affected individual, which refines the localisation of BRCA2 to between D13S260 and D13S267; a distance of 2-3 cM. Tumours of the stomach and cervix, as well as melanoma and leukaemia/lymphoma also occur in these pedigrees but the numbers are too low to determine whether they may be significantly associated with BRCA2 carrier status. Our results confirm the existence of BRCA2 on the long arm of chromosome 13 and support previous findings that this locus is likely to confer risk in families with affected males. Furthermore, our observations suggest that the BRCA2 gene may also contribute to the development of other neoplasma.

Australia↗
PubMed1996

Molecular genetics of primary and secondary hyperparathyroidism.

Hyperparathyroidism (HPT) can be caused by solitary parathyroid adenomas and carcinomas, and primary and secondary multiglandular parathyroid disease. Primary HPT is also a feature of several hereditary diseases e.g. multiple endocrine neoplasia type 1 and type 2A (MEN1 and 2A), familial hypocalciuric hyperparathyroidism (FHH), the HPT-jaw tumor syndrome (HPT-JT), and familial isolated HPT. Summarizing data from the literature and our own observations, various genetic abnormalities are observed in the pathogenesis of HPT. These include chromosomal deletions of the MEN1 locus on 11q in sporadic and MEN1 associated primary HPT, of RB1 on 13q in carcinomas, and of the FHH gene located on 3q in sporadic primary and secondary HPT. Genetic material is also lost from chromosomes 1p, 6q, 15q and X suggesting loss of yet unidentified tumor suppressor genes in these regions. In addition the HRPT2 gene on 1q, as well as the proto-oncogenes RET on 10q and PRAD1 on 11q are associated with a subset of parathyroid tumors.

Gene Deletion↗
PubMed1996

Predictive diagnosis of multiple endocrine neoplasia (MEN 1) in four Australian kindreds.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN 1) is a tumour predisposition syndrome that usually manifests in the first four decades of life. It has an autosomal dominant mode of inheritance which means that any new member of a MEN1 kindred has roughly a 50% chance of developing the disorder during their lifetime. The localisation of the MEN1 gene to a small region of chromosome band 11q13 has led to the development of DNA-based predictive diagnosis for this disease. AIMS: To establish a polymerase chain reaction (PCR)-based system, using simple tandem repeat polymorphisms (STRPs), to predict gene carriers in four Australian MEN 1 kindreds. METHODS: Six STRP markers flanking the MEN1 region of chromosome band 11q13 were used to screen individuals for a common haplotype in order to determine carrier status. RESULTS: The accuracy of prediction was calculated to be > 95% in informative individuals. CONCLUSIONS: DNA-based presymptomatic detection of affected members of MEN 1 kindreds could facilitate their care and reduce the inconvenience and expense of repeated testing of unaffected members. However, due to occasional recombination events or uninformativeness of markers in certain individuals, carrier status cannot always be predicted.

Adult↗
PubMed1996

Autosomal dominant primary hyperparathyroidism and jaw tumor syndrome associated with renal hamartomas and cystic kidney disease: linkage to 1q21-q32 and loss of the wild type allele in renal hamartomas.

Hereditary hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant disease (OMIM 145001) that has recently been mapped to chromosomal region 1q21-q32 (HRPT2). Here we report two families with HPT-JT syndrome in which adult renal hamartomas or cystic kidney disease were prominent associated features, possibly representing a new phenotypic variant of the HPT-JT syndrome. In the first family, renal lesions were present in five out of six affected individuals, whereas HPT and JT were seen in four and two cases, respectively. In the second family, JT was found in three of the five affected individuals and two affected members also exhibited polycystic kidney disease. The possibility of the latter cosegregating as a separate autosomal dominant gene can not be ruled out. A sex-dependent penetrance of primary HPT, resulting in predominantly male-affected cases was evident in the two families. Twenty microsatellite markers in the HRPT2 region were typed, in addition to markers in the multiple endocrine neoplasia (MEN) types 1 and 2 regions at 11q13 and 10q11. The disease in these two kindreds was linked to five markers in the 1q21-q32 region (logarithm-of-odds scores: 3.2-4.2), whereas linkage to the MEN1 and MEN2 regions was excluded. Meiotic recombinations detected in affected individuals placed the locus telomeric of D1S215, thus narrowing the HRPT2 region from > 60 to approximately 34 centimorgans. Loss of heterozygosity was studied in seven renal hamartomas from two affected individuals in the first family, as well as in a jaw tumor and a parathyroid tumor from the second family. All renal hamartomas showed loss of heterozygosity at the 1q21-q32 region. The losses invariably involved the wild type allele derived from the unaffected parent, suggesting the inactivation of a tumor suppressor gene in this region.

Adult↗
PubMed1996

Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains.

The predominant variety of familial benign hypocalciuric hypercalcemia (FBHH) is FBHH(3q), which is associated with presumed inactivating mutations of the cell surface calcium receptor (CaR) gene on chromosome 3q13.3-q21. We sought mutations of the CaR gene in FBHH by direct sequencing of PCR-amplified genomic DNA from 14 affected families: 8 mapped to 3q13, 1 mapped to chromosome 19p, and 5 unmapped. We sequenced the entire coding region of the gene (exons 2-7) in one or two affected members of each family and found six point mutations that altered one amino acid, cosegregated with hypercalcemia, and were absent in more than 100 unaffected persons. Four mutations were unique (S53P, D215G, S657Y, and P748R), and two had been reported previously (P55L and R185Q). Of four mutant CaR proteins expressed in Xenopus oocytes, three were deficient in extracellular Ca2+-induced signaling. No CaR mutations were found in eight families, including the one mapped to chromosome 19p. Three benign polymorphisms occurred in the COOH-terminal region of the CaR protein in 10%, 15%, and 30% of more than 100 unaffected persons. Thus, FBHH-causing CaR mutations were clustered in the NH2-terminal extracellular and membrane-spanning regions of the receptor protein. We suggest that these are important functional domains, probably for calcium binding and signal transduction, respectively. Finally, mutations in regulatory or intronic regions of the CaR gene may also underlie many cases of FBHH.

Amino Acid Sequence↗
PubMed1996

Allelic loss of the retinoblastoma tumor suppressor gene: a marker for aggressive parathyroid tumors?

Allelic loss of the retinoblastoma tumor suppressor gene has recently been shown to be highly specific for parathyroid carcinoma. It has been proposed that this genetic abnormality may have diagnostic and prognostic implications for parathyroid carcinoma, but to date no further studies are available to substantiate these findings. In the present study, three cases of atypical recurrent hyperparathyroidism were examined: a patient with parathyroid carcinoma and an autotransplanted adenoma that progressed into carcinoma, a patient with recurrent juvenile hyperparathyroidism, and a patient with severe recurrent secondary hyperparathyroid disease due to rapidly growing autotransplant. Six pairs each of sporadic parathyroid adenoma and secondary parathyroid disease were also studied for comparison. Allelic losses of RB and D13S71 at 13q14 was found in the parathyroid carcinoma and the corresponding autotransplant that had previously been considered benign tissue and in the case of recurrent juvenile hyperparathyroidism, but not in any of the other tumors. Our findings support the findings of the previous study that RB or 13q loss is specific for parathyroid tumors with increased aggressiveness and might be of clinical significance.

Adenoma↗